Cellular and molecular mechanisms of asthma and COPD



Clinical Science 2017 Revised unmarkedCellular and molecular mechanisms of asthma and COPDPeter J. Barnes FRS, FMedSciNational Heart and Lung Institute, Imperial College, London, UK Correspondence: Prof PJ Barnes, Airway Disease Section, National Heart and Lung Institute, Dovehouse St, London SW3 6LY, UK. (tel: +44 207-351-8174; fax: +44 207-351-5675; email: p.j.barnes@imperial.ac.uk)Running head: Airway disease mechanismsABSTRACTAsthma and COPD both cause airway obstruction and are associated with chronic inflammation of the airways. However, the nature and sites of the inflammation differ between these diseases, resulting in different pathology, clinical manifestations and response to therapy. In this review the inflammatory and cellular mechanisms of asthma and COPD are compared and the differences in inflammatory cells and profile of inflammatory mediators are highlighted. These differences account for the differences in clinical manifestations of asthma and COPD and their response to therapy. Although asthma and COPD are usually distinct, there are some patients who show an overlap of features, which may be explained by the coincidence of two common disease or distinct phenotypes of each disease. It is important to better understand the underlying cellular and molecular mechanisms of asthma and COPD in order to develop new treatments in areas of unmet need, such as severe asthma, curative therapy for asthma and effective anti-inflammatory treatments for COPD.Key words: inflammation, airway remodelling, cytokine, chemokine, T-lymphocytes, eosinophil, neutrophil, macrophageAbbreviations: ACO, asthma-COPD overlap; AHR, airway hyperresponsiveness; ASC, apoptosis-associated speck-like protein containing a CARD; BAFF, B-cell activating factor of the TNF family; BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein;CTGF, connective tissue growth factor; Cys-LT, cysteinyl-leukotriene; GM-CSF, granulocyte-macrophage colony stimulating factor; ICS, inhaled corticosteroid; IL, interleukin; ILC, innate lymphoid cell; LABA, long-acting β2-agonist; LAMA, long-acting muscarinic antagonist; LT, leukotriene; MMP, matrix metalloproteinase; MPO, myeloperoxidase; mTOR, mammalian target of rapamycin; NLRP, nucleotide-binding domain leucine rich repeat containing protein; Nrf2, nuclear erythroid-2 related factor-2; PG, prostaglandin; PI3K, phosphoinositide-3-kinase; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; SCF, stem cell factor; Tc, cytotoxic T lymphocyte; TGF, transforming growth factor; Th, T helper lymphocyte; TNF, tumour necrosis factor; Treg, regulatory T lymphohocyte; TRP, transient receptor potential; TSLP, thymic stromal lymphopoieitin; VEGF, vascular-endothelial growth factor.INTRODUCTIONAsthma and chronic obstructive pulmonary disease (COPD) are very common global diseases, both are increasing and have an enormous impact on the lives of patients and their carers. Both diseases are characterised by chronic inflammation in the lung, but the nature of the inflammation differs between diseases and also within each disease, accounting for a large number of clinical phenotypes. Indeed, some patients share features of asthma and COPD and asthma-COPD overlap (ACO) is important to recognise clinically because of the choice of therapy (Fig. 1) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3N0bWE8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTI0NDY8L1JlY051bT48RGlzcGxheVRleHQ+WzEtM108L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI0NDY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTQ0NzE2NzM3MSI+MTI0NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBvc3RtYSwgRC4gUy48L2F1dGhvcj48YXV0aG9yPlJhYmUsIEsuIEYuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBBc3RobWEtQ09QRCBPdmVy

bGFwIFN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25k

YXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8

L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjQxLTk8L3BhZ2VzPjx2b2x1bWU+Mzcz

PC92b2x1bWU+PG51bWJlcj4xMzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDkvMjQ8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuZXJnaWMgYmV0YS1BZ29uaXN0cy90aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5IE9ic3RydWN0aW9uL2RydWcgdGhlcmFweS9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Bc3RobWEvKmNvbXBsaWNhdGlvbnMvZGlhZ25vc2lzL2Ry

dWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpYWwgSHlwZXJyZWFjdGl2aXR5L2Rp

YWdub3Npcy9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsczwva2V5d29yZD48

a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

TXVzY2FyaW5pYyBBbnRhZ29uaXN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1Y3RpdmUvKmNvbXBsaWNhdGlvbnMvZGlh

Z25vc2lzL2RydWcgdGhlcmFweTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDAyOC00NzkzPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2Mzk4MDcyPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNcmEx

NDExODYzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJhdGVtYW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+MTI3ODQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNzg0PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZl

dnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NjEwNzM3NzAiPjEyNzg0PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5CYXRlbWFuLCBFLiBELjwvYXV0aG9y

PjxhdXRob3I+UmVkZGVsLCBILiBLLjwvYXV0aG9yPjxhdXRob3I+dmFuIFp5bC1TbWl0LCBSLiBO

LjwvYXV0aG9yPjxhdXRob3I+QWd1c3RpLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIFB1bG1vbm9sb2d5LCBEZXBhcnRtZW50IG9m

IE1lZGljaW5lLCBGYWN1bHR5IG9mIEhlYWx0aCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBDYXBl

IFRvd24sIENhcGUgVG93biwgU291dGggQWZyaWNhLiBFbGVjdHJvbmljIGFkZHJlc3M6IGVyaWMu

YmF0ZW1hbkB1Y3QuYWMuemEuJiN4RDtXb29sY29jayBJbnN0aXR1dGUgb2YgTWVkaWNhbCBSZXNl

YXJjaCwgVW5pdmVyc2l0eSBvZiBTeWRuZXksIFN5ZG5leSwgQXVzdHJhbGlhLiYjeEQ7RGl2aXNp

b24gb2YgUHVsbW9ub2xvZ3ksIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIEZhY3VsdHkgb2YgSGVh

bHRoIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhcGUgVG93biwgQ2FwZSBUb3duLCBTb3V0aCBB

ZnJpY2EuJiN4RDtUaG9yYXggSW5zdGl0dXRlLCBIb3NwaXRhbCBDbGluaWMsIElESUJBUFMsIENJ

QkVSRVMsIFVuaXZlcnNpdHkgb2YgQmFyY2Vsb25hLCBTcGFpbi48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5UaGUgYXN0aG1hLUNPUEQgb3ZlcmxhcCBzeW5kcm9tZTogdG93YXJkcyBhIHJl

dmlzZWQgdGF4b25vbXkgb2YgY2hyb25pYyBhaXJ3YXlzIGRpc2Vhc2VzPzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

VGhlIExhbmNldC4gUmVzcGlyYXRvcnkgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48YWJici0x

PlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxh

bHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48

YWJici0xPlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVy

aW9kaWNhbD48cGFnZXM+NzE5LTI4PC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjk8

L251bWJlcj48ZWRpdGlvbj4yMDE1LzA4LzEwPC9lZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MjIxMy0yNjAwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MjU1MTA4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMjIxMy0yNjAwKDE1

KTAwMjU0LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlk

ZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QmFybmVzPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjEyNjIwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMjYyMDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVm

ZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxNDU1MDIwNTU0Ij4xMjYyMDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFybmVzLCBQLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5hdGlvbmFsIEhlYXJ0IGFu

ZCBMdW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgRW5nbGFu

ZC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBwLmouYmFybmVzQGltcGVyaWFsLmFjLnVrLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFzdGhtYS1DT1BEIE92ZXJsYXA8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+Q2hlc3Q8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkNoZXN0PC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3Q8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRsZT48

L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz43LTg8L3BhZ2VzPjx2b2x1bWU+MTQ5PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MjAxNi8wMS8xMzwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjAwMTItMzY5MjwvaXNibj48YWNjZXNzaW9uLW51bT4yNjc1NzI4MTwvYWNjZXNzaW9u

LW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5jaGVz

dC4yMDE1LjA4LjAxNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1w

cm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5n

dWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3N0bWE8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTI0NDY8L1JlY051bT48RGlzcGxheVRleHQ+WzEtM108L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI0NDY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTQ0NzE2NzM3MSI+MTI0NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBvc3RtYSwgRC4gUy48L2F1dGhvcj48YXV0aG9yPlJhYmUsIEsuIEYuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBBc3RobWEtQ09QRCBPdmVy

bGFwIFN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25k

YXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8

L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjQxLTk8L3BhZ2VzPjx2b2x1bWU+Mzcz

PC92b2x1bWU+PG51bWJlcj4xMzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDkvMjQ8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuZXJnaWMgYmV0YS1BZ29uaXN0cy90aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5IE9ic3RydWN0aW9uL2RydWcgdGhlcmFweS9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Bc3RobWEvKmNvbXBsaWNhdGlvbnMvZGlhZ25vc2lzL2Ry

dWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpYWwgSHlwZXJyZWFjdGl2aXR5L2Rp

YWdub3Npcy9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsczwva2V5d29yZD48

a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

TXVzY2FyaW5pYyBBbnRhZ29uaXN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1Y3RpdmUvKmNvbXBsaWNhdGlvbnMvZGlh

Z25vc2lzL2RydWcgdGhlcmFweTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDAyOC00NzkzPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2Mzk4MDcyPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNcmEx

NDExODYzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJhdGVtYW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+MTI3ODQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNzg0PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZl

dnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NjEwNzM3NzAiPjEyNzg0PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5CYXRlbWFuLCBFLiBELjwvYXV0aG9y

PjxhdXRob3I+UmVkZGVsLCBILiBLLjwvYXV0aG9yPjxhdXRob3I+dmFuIFp5bC1TbWl0LCBSLiBO

LjwvYXV0aG9yPjxhdXRob3I+QWd1c3RpLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIFB1bG1vbm9sb2d5LCBEZXBhcnRtZW50IG9m

IE1lZGljaW5lLCBGYWN1bHR5IG9mIEhlYWx0aCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBDYXBl

IFRvd24sIENhcGUgVG93biwgU291dGggQWZyaWNhLiBFbGVjdHJvbmljIGFkZHJlc3M6IGVyaWMu

YmF0ZW1hbkB1Y3QuYWMuemEuJiN4RDtXb29sY29jayBJbnN0aXR1dGUgb2YgTWVkaWNhbCBSZXNl

YXJjaCwgVW5pdmVyc2l0eSBvZiBTeWRuZXksIFN5ZG5leSwgQXVzdHJhbGlhLiYjeEQ7RGl2aXNp

b24gb2YgUHVsbW9ub2xvZ3ksIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIEZhY3VsdHkgb2YgSGVh

bHRoIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhcGUgVG93biwgQ2FwZSBUb3duLCBTb3V0aCBB

ZnJpY2EuJiN4RDtUaG9yYXggSW5zdGl0dXRlLCBIb3NwaXRhbCBDbGluaWMsIElESUJBUFMsIENJ

QkVSRVMsIFVuaXZlcnNpdHkgb2YgQmFyY2Vsb25hLCBTcGFpbi48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5UaGUgYXN0aG1hLUNPUEQgb3ZlcmxhcCBzeW5kcm9tZTogdG93YXJkcyBhIHJl

dmlzZWQgdGF4b25vbXkgb2YgY2hyb25pYyBhaXJ3YXlzIGRpc2Vhc2VzPzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

VGhlIExhbmNldC4gUmVzcGlyYXRvcnkgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48YWJici0x

PlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxh

bHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48

YWJici0xPlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVy

aW9kaWNhbD48cGFnZXM+NzE5LTI4PC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjk8

L251bWJlcj48ZWRpdGlvbj4yMDE1LzA4LzEwPC9lZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MjIxMy0yNjAwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MjU1MTA4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMjIxMy0yNjAwKDE1

KTAwMjU0LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlk

ZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QmFybmVzPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjEyNjIwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMjYyMDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVm

ZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxNDU1MDIwNTU0Ij4xMjYyMDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFybmVzLCBQLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5hdGlvbmFsIEhlYXJ0IGFu

ZCBMdW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgRW5nbGFu

ZC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBwLmouYmFybmVzQGltcGVyaWFsLmFjLnVrLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFzdGhtYS1DT1BEIE92ZXJsYXA8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+Q2hlc3Q8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkNoZXN0PC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3Q8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRsZT48

L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz43LTg8L3BhZ2VzPjx2b2x1bWU+MTQ5PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MjAxNi8wMS8xMzwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjAwMTItMzY5MjwvaXNibj48YWNjZXNzaW9uLW51bT4yNjc1NzI4MTwvYWNjZXNzaW9u

LW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5jaGVz

dC4yMDE1LjA4LjAxNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1w

cm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5n

dWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [1-3]. Many inflammatory cells and mediators have been implicated in asthma and COPD and several current therapies target this inflammation or its components. In asthma inflammation is usually responsive to low doses of corticosteroids and inhaled corticosteroids (ICS) are now the mainstay of management. However, some patients are resistant or relatively resistant to the anti-inflammatory effects of corticosteroids and alternative treatments are needed for asthma control. By contrast, most patients with COPD are corticosteroid-resistant, necessitating a search for alternative anti-inflammatory therapies.ASTHMAAsthma has now become the most prevalent chronic disease in developed countries and affects over 10% of adults. Because of more widespread use of ICS asthma mortality has fallen although in the UK over 1000 deaths/year are due to asthma, particularly in the elderly. Although there are now effective medications for asthma, it remains poorly controlled in the community with frequent symptoms and exacerbations, largely because of poor adherence to ICS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmljZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMjg0NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTI4NDQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTQ2ODQyMjY4MSI+MTI4NDQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlByaWNlLCBELjwvYXV0aG9yPjxhdXRob3I+RmxldGNoZXIsIE0uPC9hdXRob3I+PGF1dGhvcj52

YW4gZGVyIE1vbGVuLCBULjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkNlbnRyZSBvZiBBY2FkZW1pYyBQcmltYXJ5IENhcmUsIFVuaXZlcnNpdHkgb2YgQWJl

cmRlZW4sIEFiZXJkZWVuLCBVSy4mI3hEO0VkdWNhdGlvbiBmb3IgSGVhbHRoLCBXYXJ3aWNrLCBV

Sy4mI3hEO0RlcGFydG1lbnQgb2YgR2VuZXJhbCBQcmFjdGljZSwgVW5pdmVyc2l0eSBvZiBHcm9u

aW5nZW4sIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50cmUgR3JvbmluZ2VuLCBHcm9uaW5nZW4sIFRo

ZSBOZXRoZXJsYW5kcy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Bc3RobWEgY29udHJv

bCBhbmQgbWFuYWdlbWVudCBpbiA4LDAwMCBFdXJvcGVhbiBwYXRpZW50czogdGhlIFJFY29nbmlz

ZSBBc3RobWEgYW5kIExJbmsgdG8gU3ltcHRvbXMgYW5kIEV4cGVyaWVuY2UgKFJFQUxJU0UpIHN1

cnZleTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OUEogUHJpbSBDYXJlIFJlc3BpciBNZWQ8L3Nl

Y29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk5QSiBwcmltYXJ5IGNhcmUgcmVzcGlyYXRvcnkgbWVk

aWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OUEogUHJp

bSBDYXJlIFJlc3BpciBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5OUEogcHJpbWFyeSBjYXJlIHJl

c3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OUEogUHJpbSBDYXJlIFJlc3BpciBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5O

UEogcHJpbWFyeSBjYXJlIHJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVyaW9k

aWNhbD48cGFnZXM+MTQwMDk8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48ZWRpdGlvbj4yMDE0

LzA2LzEzPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50cy90aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hL2RydWcgdGhlcmFweS9wcmV2ZW50

aW9uICZhbXA7IGNvbnRyb2wvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QXR0aXR1ZGUgdG8g

SGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPkV1cm9wZS9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkhlYWx0aCBTdXJ2ZXlzPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1p

ZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlN1cnZleXMgYW5kIFF1ZXN0aW9ubmFpcmVzPC9r

ZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxrZXl3b3JkPllvdW5n

IEFkdWx0PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PC9kYXRl

cz48aXNibj4yMDU1LTEwMTA8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ5MjE5ODU8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQzNzMzMDI8L2N1c3RvbTI+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvbnBqcGNybS4yMDE0Ljk8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QcmljZTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

Y051bT4xMjg0NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTI4NDQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTQ2ODQyMjY4MSI+MTI4NDQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlByaWNlLCBELjwvYXV0aG9yPjxhdXRob3I+RmxldGNoZXIsIE0uPC9hdXRob3I+PGF1dGhvcj52

YW4gZGVyIE1vbGVuLCBULjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1h

ZGRyZXNzPkNlbnRyZSBvZiBBY2FkZW1pYyBQcmltYXJ5IENhcmUsIFVuaXZlcnNpdHkgb2YgQWJl

cmRlZW4sIEFiZXJkZWVuLCBVSy4mI3hEO0VkdWNhdGlvbiBmb3IgSGVhbHRoLCBXYXJ3aWNrLCBV

Sy4mI3hEO0RlcGFydG1lbnQgb2YgR2VuZXJhbCBQcmFjdGljZSwgVW5pdmVyc2l0eSBvZiBHcm9u

aW5nZW4sIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50cmUgR3JvbmluZ2VuLCBHcm9uaW5nZW4sIFRo

ZSBOZXRoZXJsYW5kcy48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Bc3RobWEgY29udHJv

bCBhbmQgbWFuYWdlbWVudCBpbiA4LDAwMCBFdXJvcGVhbiBwYXRpZW50czogdGhlIFJFY29nbmlz

ZSBBc3RobWEgYW5kIExJbmsgdG8gU3ltcHRvbXMgYW5kIEV4cGVyaWVuY2UgKFJFQUxJU0UpIHN1

cnZleTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OUEogUHJpbSBDYXJlIFJlc3BpciBNZWQ8L3Nl

Y29uZGFyeS10aXRsZT48YWx0LXRpdGxlPk5QSiBwcmltYXJ5IGNhcmUgcmVzcGlyYXRvcnkgbWVk

aWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OUEogUHJp

bSBDYXJlIFJlc3BpciBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5OUEogcHJpbWFyeSBjYXJlIHJl

c3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OUEogUHJpbSBDYXJlIFJlc3BpciBNZWQ8L2Z1bGwtdGl0bGU+PGFiYnItMT5O

UEogcHJpbWFyeSBjYXJlIHJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVyaW9k

aWNhbD48cGFnZXM+MTQwMDk8L3BhZ2VzPjx2b2x1bWU+MjQ8L3ZvbHVtZT48ZWRpdGlvbj4yMDE0

LzA2LzEzPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3b3JkPjxr

ZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50cy90aGVy

YXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hL2RydWcgdGhlcmFweS9wcmV2ZW50

aW9uICZhbXA7IGNvbnRyb2wvKnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QXR0aXR1ZGUgdG8g

SGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPkV1cm9wZS9lcGlkZW1pb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkhlYWx0aCBTdXJ2ZXlzPC9rZXl3b3JkPjxr

ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1p

ZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPlN1cnZleXMgYW5kIFF1ZXN0aW9ubmFpcmVzPC9r

ZXl3b3JkPjxrZXl3b3JkPlRyZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjxrZXl3b3JkPllvdW5n

IEFkdWx0PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PC9kYXRl

cz48aXNibj4yMDU1LTEwMTA8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjQ5MjE5ODU8L2FjY2Vzc2lv

bi1udW0+PHVybHM+PC91cmxzPjxjdXN0b20yPlBNQzQzNzMzMDI8L2N1c3RvbTI+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjEwMzgvbnBqcGNybS4yMDE0Ljk8L2VsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [4]. The majority of asthma patients are atopic and have an allergic pattern of inflammation in their airways, which extends from the trachea down to peripheral airways PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+MTEzMzQ8L1JlY051bT48RGlzcGxheVRleHQ+WzVdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjExMzM0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0NzkwMDAiPjExMzM0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CYXJuZXMsIFAuIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+TmF0aW9uYWwgSGVhcnQgYW5kIEx1bmcgSW5zdGl0dXRlLCBJbXBlcmlhbCBDb2xsZWdl

LCBMb25kb24sIFVLLiBwLmouYmFybmVzQGltcGVyaWFsLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+UGF0aG9waHlzaW9sb2d5IG9mIGFsbGVyZ2ljIGluZmxhbW1hdGlvbjwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5JbW11bm9sIFJldjwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0

bGU+SW1tdW5vbG9naWNhbCByZXZpZXdzPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SW1tdW5vbCBSZXY8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4z

MS01MDwvcGFnZXM+PHZvbHVtZT4yNDI8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFkcmVuYWwgQ29ydGV4IEhvcm1vbmVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bGxlcmdlbnMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5IEFnZW50cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+Qi1MeW1waG9jeXRlcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzLypiaW9zeW50aGVzaXM8L2tleXdv

cmQ+PGtleXdvcmQ+RE5BIE1ldGh5bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRlbmRyaXRpYyBD

ZWxscy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhpbHMv

aW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVwaWdlbm9taWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkVwaXRoZWxpYWwgQ2VsbHMvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkZpYnJvYmxhc3RzL2N5dG9sb2d5L2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HQVRBMyBUcmFuc2NyaXB0aW9uIEZhY3Rvci8qYmlvc3ludGhlc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPkhpc3RvbmVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVyc2Vuc2l0aXZpdHkvZHJ1ZyB0aGVyYXB5L2dl

bmV0aWNzL2ltbXVub2xvZ3kvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5JbmZs

YW1tYXRpb24vZHJ1ZyB0aGVyYXB5L2dlbmV0aWNzL2ltbXVub2xvZ3kvKnBoeXNpb3BhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5NYXN0IENlbGxzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5ORi1rYXBwYSBCLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1dHJvcGhpbHMvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN1cGVy

YW50aWdlbnMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5UaDIgQ2VsbHMvaW1tdW5vbG9n

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNjAw

LTA2NVggKEVsZWN0cm9uaWMpJiN4RDswMTA1LTI4OTYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjIxNjgyNzM3PC9hY2Nlc3Npb24tbnVtPjxsYWJlbD5CQVJORVMyMDExQTwvbGFiZWw+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjE2ODI3Mzc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjExMTEvai4xNjAwLTA2NVguMjAxMS4wMTAyMC54PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

ZWNOdW0+MTEzMzQ8L1JlY051bT48RGlzcGxheVRleHQ+WzVdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjExMzM0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0NzkwMDAiPjExMzM0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CYXJuZXMsIFAuIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+TmF0aW9uYWwgSGVhcnQgYW5kIEx1bmcgSW5zdGl0dXRlLCBJbXBlcmlhbCBDb2xsZWdl

LCBMb25kb24sIFVLLiBwLmouYmFybmVzQGltcGVyaWFsLmFjLnVrPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+UGF0aG9waHlzaW9sb2d5IG9mIGFsbGVyZ2ljIGluZmxhbW1hdGlvbjwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5JbW11bm9sIFJldjwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0

bGU+SW1tdW5vbG9naWNhbCByZXZpZXdzPC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+SW1tdW5vbCBSZXY8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4z

MS01MDwvcGFnZXM+PHZvbHVtZT4yNDI8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFkcmVuYWwgQ29ydGV4IEhvcm1vbmVzL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5B

bGxlcmdlbnMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9rZXl3b3JkPjxr

ZXl3b3JkPkFudGktSW5mbGFtbWF0b3J5IEFnZW50cy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+Qi1MeW1waG9jeXRlcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv

cmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzLypiaW9zeW50aGVzaXM8L2tleXdv

cmQ+PGtleXdvcmQ+RE5BIE1ldGh5bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRlbmRyaXRpYyBD

ZWxscy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhpbHMv

aW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkVwaWdlbm9taWNzPC9rZXl3

b3JkPjxrZXl3b3JkPkVwaXRoZWxpYWwgQ2VsbHMvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPkZpYnJvYmxhc3RzL2N5dG9sb2d5L2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwv

a2V5d29yZD48a2V5d29yZD5HQVRBMyBUcmFuc2NyaXB0aW9uIEZhY3Rvci8qYmlvc3ludGhlc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPkhpc3RvbmVzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+

SHVtYW5zPC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVyc2Vuc2l0aXZpdHkvZHJ1ZyB0aGVyYXB5L2dl

bmV0aWNzL2ltbXVub2xvZ3kvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5JbmZs

YW1tYXRpb24vZHJ1ZyB0aGVyYXB5L2dlbmV0aWNzL2ltbXVub2xvZ3kvKnBoeXNpb3BhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5NYXN0IENlbGxzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5

d29yZD48a2V5d29yZD5ORi1rYXBwYSBCLypiaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1dHJvcGhpbHMvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN1cGVy

YW50aWdlbnMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5UaDIgQ2VsbHMvaW1tdW5vbG9n

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNjAw

LTA2NVggKEVsZWN0cm9uaWMpJiN4RDswMTA1LTI4OTYgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Np

b24tbnVtPjIxNjgyNzM3PC9hY2Nlc3Npb24tbnVtPjxsYWJlbD5CQVJORVMyMDExQTwvbGFiZWw+

PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHA6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJt

ZWQvMjE2ODI3Mzc8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3Vy

Y2UtbnVtPjEwLjExMTEvai4xNjAwLTA2NVguMjAxMS4wMTAyMC54PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [5]. Allergic inflammation is driven by CD4+ T helper-2 (Th2) lymphocytes, which secrete interleukin(IL)-4, IL-5 and IL-13 and sometimes referred to as type 2 (T2) asthma, whereas some asthmatic patients do not have this pattern of inflammation and referred to as non-T2 asthma, which is usually associated with more severe disease ADDIN EN.CITE <EndNote><Cite><Author>Wenzel</Author><Year>2016</Year><RecNum>12924</RecNum><DisplayText>[6]</DisplayText><record><rec-number>12924</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482229668">12924</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wenzel, S. E.</author></authors></contributors><auth-address>Pulmonary Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.</auth-address><titles><title>Emergence of biomolecular pathways to define novel asthma phenotypes. Type-2 immunity and beyond</title><secondary-title>Am J Respir Cell Mol Biol</secondary-title><alt-title>American journal of respiratory cell and molecular biology</alt-title></titles><periodical><full-title>Am J Respir Cell Mol Biol</full-title></periodical><pages>1-4</pages><volume>55</volume><number>1</number><edition>2016/05/11</edition><keywords><keyword>asthma</keyword><keyword>eosinophils</keyword><keyword>phenotypes</keyword><keyword>type-2</keyword></keywords><dates><year>2016</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1044-1549</isbn><accession-num>27164162</accession-num><urls></urls><custom2>PMC4942211</custom2><electronic-resource-num>10.1165/rcmb.2016-0141PS</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[6]. The heterogeneity of asthma is now widely recognised, but so far it has been difficult to link molecular mechanisms (endotypes) to clinical phenotypes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3R2YWxsPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMzQ4PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTM0ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDAwIj4xMTM0ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+TG90dmFsbCxKLjwvYXV0aG9yPjxhdXRob3I+QWtkaXMsQy5BLjwvYXV0aG9yPjxhdXRob3I+

QmFjaGFyaWVyLEwuQi48L2F1dGhvcj48YXV0aG9yPkJqZXJtZXIsTC48L2F1dGhvcj48YXV0aG9y

PkNhc2FsZSxULkIuPC9hdXRob3I+PGF1dGhvcj5DdXN0b3ZpYyxBLjwvYXV0aG9yPjxhdXRob3I+

TGVtYW5za2UsUi5GLixKci48L2F1dGhvcj48YXV0aG9yPldhcmRsYXcsQS5KLjwvYXV0aG9yPjxh

dXRob3I+V2VuemVsLFMuRS48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVyZ2VyLFAuQS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QXN0aG1hIGVuZG90eXBl

czogYSBuZXcgYXBwcm9hY2ggdG8gY2xhc3NpZmljYXRpb24gb2YgZGlzZWFzZSBlbnRpdGllcyB3

aXRoaW4gdGhlIGFzdGhtYSBzeW5kcm9tZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsbGVy

Z3kgQ2xpbi5JbW11bm9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVub2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MzU1LTM2MDwvcGFnZXM+PHZvbHVtZT4xMjc8L3ZvbHVtZT48bnVtYmVyPjI8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFsbGVyZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QVBQUk9BQ0hFUzwva2V5d29y

ZD48a2V5d29yZD5Bc3BlcmdpbGxvc2lzLEFsbGVyZ2ljIEJyb25jaG9wdWxtb25hcnk8L2tleXdv

cmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPmNsYXNzaWZpY2F0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBMRVhFUzwva2V5d29y

ZD48a2V5d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5ERVNJR048L2tleXdvcmQ+

PGtleXdvcmQ+REVWRUxPUE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48

a2V5d29yZD5EUlVHPC9rZXl3b3JkPjxrZXl3b3JkPmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5

d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+

SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5NRUNIQU5J

U008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5d29yZD48a2V5d29yZD5ORVc8L2tl

eXdvcmQ+PGtleXdvcmQ+Tk9WRUw8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSE9QSFlTSU9MT0dJQ0FM

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPUEhZU0lPTE9HWTwva2V5d29yZD48a2V5d29yZD5QQVRJ

RU5UUzwva2V5d29yZD48a2V5d29yZD5QSEVOT1RZUEU8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lv

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBVVEFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlJF

UE9SVDwva2V5d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJ

Qzwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3

b3JkPjxrZXl3b3JkPlNVQlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+U3dlZGVuPC9rZXl3b3JkPjxr

ZXl3b3JkPlNZTkRST01FPC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29y

ZD5USEVSQVBJRVM8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5U

UkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5ERVJTVEFORElORzwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Mi8yMDExPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkxPVFZBTEwyMDExPC9sYWJlbD48dXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3R2YWxsPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMzQ4PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTM0ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDAwIj4xMTM0ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+TG90dmFsbCxKLjwvYXV0aG9yPjxhdXRob3I+QWtkaXMsQy5BLjwvYXV0aG9yPjxhdXRob3I+

QmFjaGFyaWVyLEwuQi48L2F1dGhvcj48YXV0aG9yPkJqZXJtZXIsTC48L2F1dGhvcj48YXV0aG9y

PkNhc2FsZSxULkIuPC9hdXRob3I+PGF1dGhvcj5DdXN0b3ZpYyxBLjwvYXV0aG9yPjxhdXRob3I+

TGVtYW5za2UsUi5GLixKci48L2F1dGhvcj48YXV0aG9yPldhcmRsYXcsQS5KLjwvYXV0aG9yPjxh

dXRob3I+V2VuemVsLFMuRS48L2F1dGhvcj48YXV0aG9yPkdyZWVuYmVyZ2VyLFAuQS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QXN0aG1hIGVuZG90eXBl

czogYSBuZXcgYXBwcm9hY2ggdG8gY2xhc3NpZmljYXRpb24gb2YgZGlzZWFzZSBlbnRpdGllcyB3

aXRoaW4gdGhlIGFzdGhtYSBzeW5kcm9tZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsbGVy

Z3kgQ2xpbi5JbW11bm9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVub2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MzU1LTM2MDwvcGFnZXM+PHZvbHVtZT4xMjc8L3ZvbHVtZT48bnVtYmVyPjI8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFsbGVyZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QVBQUk9BQ0hFUzwva2V5d29y

ZD48a2V5d29yZD5Bc3BlcmdpbGxvc2lzLEFsbGVyZ2ljIEJyb25jaG9wdWxtb25hcnk8L2tleXdv

cmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPmNsYXNzaWZpY2F0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBMRVhFUzwva2V5d29y

ZD48a2V5d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5ERVNJR048L2tleXdvcmQ+

PGtleXdvcmQ+REVWRUxPUE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48

a2V5d29yZD5EUlVHPC9rZXl3b3JkPjxrZXl3b3JkPmRydWcgdGhlcmFweTwva2V5d29yZD48a2V5

d29yZD5ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+

SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5NRUNIQU5J

U008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5d29yZD48a2V5d29yZD5ORVc8L2tl

eXdvcmQ+PGtleXdvcmQ+Tk9WRUw8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSE9QSFlTSU9MT0dJQ0FM

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPUEhZU0lPTE9HWTwva2V5d29yZD48a2V5d29yZD5QQVRJ

RU5UUzwva2V5d29yZD48a2V5d29yZD5QSEVOT1RZUEU8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lv

cGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBVVEFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlJF

UE9SVDwva2V5d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJ

Qzwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3

b3JkPjxrZXl3b3JkPlNVQlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+U3dlZGVuPC9rZXl3b3JkPjxr

ZXl3b3JkPlNZTkRST01FPC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29y

ZD5USEVSQVBJRVM8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5U

UkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5ERVJTVEFORElORzwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Mi8yMDExPC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkxPVFZBTEwyMDExPC9sYWJlbD48dXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [7]. Airway narrowing in asthma is largely due to contraction of airway smooth muscle, but vascular congestion and airway oedema from leaky bronchial vessels may also contribute. In addition, there are structural changes, such as increased airway smooth muscle bulk and fibrosis that may result in irreversible narrowing (Fig. 2) ADDIN EN.CITE <EndNote><Cite><Author>Hirota</Author><Year>2013</Year><RecNum>12925</RecNum><DisplayText>[8]</DisplayText><record><rec-number>12925</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482255187">12925</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hirota, N.</author><author>Martin, J. G.</author></authors></contributors><titles><title>Mechanisms of airway remodeling</title><secondary-title>Chest</secondary-title><alt-title>Chest</alt-title></titles><periodical><full-title>Chest</full-title></periodical><alt-periodical><full-title>Chest</full-title></alt-periodical><pages>1026-32</pages><volume>144</volume><number>3</number><edition>2013/09/07</edition><keywords><keyword>Airway Remodeling/*physiology</keyword><keyword>Animals</keyword><keyword>Asthma/pathology/*physiopathology</keyword><keyword>Humans</keyword><keyword>Lung/*physiopathology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/pathology/*physiopathology</keyword><keyword>Respiratory Mucosa/pathology/physiopathology</keyword><keyword>*Respiratory Physiological Phenomena</keyword></keywords><dates><year>2013</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0012-3692</isbn><accession-num>24008953</accession-num><urls></urls><electronic-resource-num>10.1378/chest.12-3073</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[8]. Mucus plugs, comprising mucus glycoproteins and plasma proteins may occlude the airways in fatal asthma ADDIN EN.CITE <EndNote><Cite><Author>Harvey</Author><Year>2013</Year><RecNum>12926</RecNum><DisplayText>[9]</DisplayText><record><rec-number>12926</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482325689">12926</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Harvey, B. C.</author><author>Lutchen, K. R.</author></authors></contributors><auth-address>Department of Biomedical Engineering, Boston University, Boston, Massachusetts.</auth-address><titles><title>Factors determining airway caliber in asthma</title><secondary-title>Crit Rev Biomed Eng</secondary-title><alt-title>Critical reviews in biomedical engineering</alt-title></titles><periodical><full-title>Crit Rev Biomed Eng</full-title><abbr-1>Critical reviews in biomedical engineering</abbr-1></periodical><alt-periodical><full-title>Crit Rev Biomed Eng</full-title><abbr-1>Critical reviews in biomedical engineering</abbr-1></alt-periodical><pages>515-32</pages><volume>41</volume><number>6</number><edition>2013/01/01</edition><keywords><keyword>Airway Remodeling</keyword><keyword>Animals</keyword><keyword>*Asthma/pathology/physiopathology</keyword><keyword>*Bronchial Hyperreactivity/pathology/physiopathology</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Muscle, Smooth</keyword><keyword>Rabbits</keyword><keyword>Rats</keyword><keyword>Respiratory Mechanics</keyword><keyword>*Respiratory System/pathology/physiopathology</keyword></keywords><dates><year>2013</year></dates><isbn>0278-940X (Print)&#xD;0278-940x</isbn><accession-num>24940663</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[9]. The inflammation in asthmatic airways not only leads to airway narrowing, but also to airway hyperresponsiveness (AHR), which is the defining physiological abnormality of asthma, which accounts for airway narrowing in response to various environmental triggers and produces the characteristic variable symptoms of asthma, including nocturnal worsening. The mechanisms of AHR are still not certain, but are likely to relate to increased release of mediators from inflammatory cells (particularly mast cells), increased contractility of airway smooth muscle, increased sensitivity of airway sensory nerves and to existing airway narrowing for geometric reasons.Although asthma is usually easy to control with appropriate therapy, some patients remain uncontrolled despite maximal inhaled therapy (ICS and long-acting β2-agonists) and this is termed severe asthma. Severe asthma accounts for less than 5% of all asthmatic patients, but consumes over 50% of medical expenditure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWtraW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjEyNDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI0ODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTQ1MDQzOTEzMiI+MTI0ODQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkhla2tpbmcsIFAuIFAuPC9hdXRob3I+PGF1dGhvcj5XZW5lciwgUi4gUi48L2F1dGhvcj48

YXV0aG9yPkFtZWxpbmssIE0uPC9hdXRob3I+PGF1dGhvcj5ad2luZGVybWFuLCBBLiBILjwvYXV0

aG9yPjxhdXRob3I+Qm91dnksIE0uIEwuPC9hdXRob3I+PGF1dGhvcj5CZWwsIEUuIEguPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBS

ZXNwaXJhdG9yeSBNZWRpY2luZSwgQWNhZGVtaWMgTWVkaWNhbCBDZW50cmUsIFVuaXZlcnNpdHkg

b2YgQW1zdGVyZGFtLCBBbXN0ZXJkYW0sIFRoZSBOZXRoZXJsYW5kcy4gRWxlY3Ryb25pYyBhZGRy

ZXNzOiBwLncuaGVra2luZ0BhbWMubmwuJiN4RDtEZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IE1l

ZGljaW5lLCBBY2FkZW1pYyBNZWRpY2FsIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBBbXN0ZXJkYW0s

IEFtc3RlcmRhbSwgVGhlIE5ldGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBF

cGlkZW1pb2xvZ3ksIEJpb3N0YXRpc3RpY3MgYW5kIEJpb2luZm9ybWF0aWNzLCBBY2FkZW1pYyBN

ZWRpY2FsIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBBbXN0ZXJkYW0sIEFtc3RlcmRhbSwgVGhlIE5l

dGhlcmxhbmRzLiYjeEQ7U0lSIEluc3RpdHV0ZSBmb3IgUGhhcm1hY3kgUHJhY3RpY2UgYW5kIFBv

bGljeSwgTGVpZGVuLCBUaGUgTmV0aGVybGFuZHMuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+VGhlIHByZXZhbGVuY2Ugb2Ygc2V2ZXJlIHJlZnJhY3RvcnkgYXN0aG1hPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkogQWxsZXJneSBDbGluIEltbXVub2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPlRoZSBKb3VybmFsIG9mIGFsbGVyZ3kgYW5kIGNsaW5pY2FsIGltbXVub2xvZ3k8L2Fs

dC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFsbGVyZ3kgQ2xpbiBJ

bW11bm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ODk2LTkwMjwvcGFnZXM+PHZv

bHVtZT4xMzU8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDE0LzEyLzAzPC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZG1pbmlzdHJhdGlvbiwgSW5oYWxhdGlvbjwva2V5

d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50

cy9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFzdGhtYS9kaWFnbm9zaXMvZHJ1ZyB0aGVyYXB5LyplcGlkZW1pb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lZGljYXRpb24gQWRoZXJlbmNlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5ldGhlcmxhbmRzL2VwaWRl

bWlvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlJp

c2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIEluZGV4PC9r

ZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5kaWZmaWN1bHQtdG8tY29u

dHJvbCBhc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+c2V2ZXJlIGFzdGhtYTwva2V5d29yZD48a2V5

d29yZD5zZXZlcmUgcmVmcmFjdG9yeSBhc3RobWE8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjAwOTEtNjc0OTwvaXNibj48YWNjZXNzaW9uLW51bT4yNTQ0MTYzNzwvYWNj

ZXNzaW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

ai5qYWNpLjIwMTQuMDguMDQyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFi

YXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8

L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWtraW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

UmVjTnVtPjEyNDg0PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI0ODQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTQ1MDQzOTEzMiI+MTI0ODQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkhla2tpbmcsIFAuIFAuPC9hdXRob3I+PGF1dGhvcj5XZW5lciwgUi4gUi48L2F1dGhvcj48

YXV0aG9yPkFtZWxpbmssIE0uPC9hdXRob3I+PGF1dGhvcj5ad2luZGVybWFuLCBBLiBILjwvYXV0

aG9yPjxhdXRob3I+Qm91dnksIE0uIEwuPC9hdXRob3I+PGF1dGhvcj5CZWwsIEUuIEguPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBS

ZXNwaXJhdG9yeSBNZWRpY2luZSwgQWNhZGVtaWMgTWVkaWNhbCBDZW50cmUsIFVuaXZlcnNpdHkg

b2YgQW1zdGVyZGFtLCBBbXN0ZXJkYW0sIFRoZSBOZXRoZXJsYW5kcy4gRWxlY3Ryb25pYyBhZGRy

ZXNzOiBwLncuaGVra2luZ0BhbWMubmwuJiN4RDtEZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IE1l

ZGljaW5lLCBBY2FkZW1pYyBNZWRpY2FsIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBBbXN0ZXJkYW0s

IEFtc3RlcmRhbSwgVGhlIE5ldGhlcmxhbmRzLiYjeEQ7RGVwYXJ0bWVudCBvZiBDbGluaWNhbCBF

cGlkZW1pb2xvZ3ksIEJpb3N0YXRpc3RpY3MgYW5kIEJpb2luZm9ybWF0aWNzLCBBY2FkZW1pYyBN

ZWRpY2FsIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBBbXN0ZXJkYW0sIEFtc3RlcmRhbSwgVGhlIE5l

dGhlcmxhbmRzLiYjeEQ7U0lSIEluc3RpdHV0ZSBmb3IgUGhhcm1hY3kgUHJhY3RpY2UgYW5kIFBv

bGljeSwgTGVpZGVuLCBUaGUgTmV0aGVybGFuZHMuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+VGhlIHByZXZhbGVuY2Ugb2Ygc2V2ZXJlIHJlZnJhY3RvcnkgYXN0aG1hPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkogQWxsZXJneSBDbGluIEltbXVub2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPlRoZSBKb3VybmFsIG9mIGFsbGVyZ3kgYW5kIGNsaW5pY2FsIGltbXVub2xvZ3k8L2Fs

dC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIEFsbGVyZ3kgQ2xpbiBJ

bW11bm9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ODk2LTkwMjwvcGFnZXM+PHZv

bHVtZT4xMzU8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDE0LzEyLzAzPC9l

ZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZG1pbmlzdHJhdGlvbiwgSW5oYWxhdGlvbjwva2V5

d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50

cy9hZG1pbmlzdHJhdGlvbiAmYW1wOyBkb3NhZ2UvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFzdGhtYS9kaWFnbm9zaXMvZHJ1ZyB0aGVyYXB5LyplcGlkZW1pb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1lZGljYXRpb24gQWRoZXJlbmNlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk5ldGhlcmxhbmRzL2VwaWRl

bWlvbG9neTwva2V5d29yZD48a2V5d29yZD5QcmV2YWxlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlJp

c2sgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIEluZGV4PC9r

ZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5kaWZmaWN1bHQtdG8tY29u

dHJvbCBhc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+c2V2ZXJlIGFzdGhtYTwva2V5d29yZD48a2V5

d29yZD5zZXZlcmUgcmVmcmFjdG9yeSBhc3RobWE8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAxNTwveWVhcj48cHViLWRhdGVzPjxkYXRlPkFwcjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxpc2JuPjAwOTEtNjc0OTwvaXNibj48YWNjZXNzaW9uLW51bT4yNTQ0MTYzNzwvYWNj

ZXNzaW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYv

ai5qYWNpLjIwMTQuMDguMDQyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFi

YXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8

L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [10]. It is now recognised that there are several subtypes of severe asthma with different patterns of inflammation that may benefit from more specific therapeutic targeting in the future ADDIN EN.CITE <EndNote><Cite><Author>Ray</Author><Year>2016</Year><RecNum>12908</RecNum><DisplayText>[11]</DisplayText><record><rec-number>12908</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1479483774">12908</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ray, A.</author><author>Raundhal, M.</author><author>Oriss, T. B.</author><author>Ray, P.</author><author>Wenzel, S. E.</author></authors></contributors><titles><title>Current concepts of severe asthma</title><secondary-title>J Clin Invest</secondary-title><alt-title>The Journal of clinical investigation</alt-title></titles><periodical><full-title>J Clin Invest</full-title></periodical><pages>2394-403</pages><volume>126</volume><number>7</number><edition>2016/07/02</edition><dates><year>2016</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>0021-9738</isbn><accession-num>27367183</accession-num><urls></urls><custom2>PMC4922699</custom2><electronic-resource-num>10.1172/jci84144</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[11].COPDCOPD has become a global epidemic, which is increasing as populations age and survive previous causes of death ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2015</Year><RecNum>12485</RecNum><DisplayText>[12]</DisplayText><record><rec-number>12485</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1450446154">12485</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, P.J.</author><author>Burney, P. G. J.</author><author>Silverman, E. K.</author><author>Celli, B.R.</author><author>Vestbo, J.</author><author>Wedzicha, J. A.</author><author>Wouters, E.F.M.</author></authors></contributors><titles><title>Chronic obstructive pulmonary disease</title><secondary-title>Nature Rev Primers</secondary-title></titles><periodical><full-title>Nature Rev Primers</full-title></periodical><pages>1-21</pages><volume>1</volume><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>[12]. COPD is now the fourth commonest cause of death worldwide and third ranked in the UK and other developed countries. It is predicted to become the fifth ranked cause of disability, affecting approximately 10% of people over 45 years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3phbm88L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE3NzE8L1JlY051bT48RGlzcGxheVRleHQ+WzEzXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTc3MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTc3MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+TG96YW5vLFIuPC9hdXRob3I+PGF1dGhvcj5OYWdoYXZpLE0uPC9hdXRob3I+PGF1dGhvcj5G

b3JlbWFuLEsuPC9hdXRob3I+PGF1dGhvcj5MaW0sUy48L2F1dGhvcj48YXV0aG9yPlNoaWJ1eWEs

Sy48L2F1dGhvcj48YXV0aG9yPkFib3lhbnMsVi48L2F1dGhvcj48YXV0aG9yPkFicmFoYW0sSi48

L2F1dGhvcj48YXV0aG9yPkFkYWlyLFQuPC9hdXRob3I+PGF1dGhvcj5BZ2dhcndhbCxSLjwvYXV0

aG9yPjxhdXRob3I+QWhuLFMuWS48L2F1dGhvcj48YXV0aG9yPkFsdmFyYWRvLE0uPC9hdXRob3I+

PGF1dGhvcj5BbmRlcnNvbixILlIuPC9hdXRob3I+PGF1dGhvcj5BbmRlcnNvbixMLk0uPC9hdXRo

b3I+PGF1dGhvcj5BbmRyZXdzLEsuRy48L2F1dGhvcj48YXV0aG9yPkF0a2luc29uLEMuPC9hdXRo

b3I+PGF1dGhvcj5CYWRkb3VyLEwuTS48L2F1dGhvcj48YXV0aG9yPkJhcmtlci1Db2xsbyxTLjwv

YXV0aG9yPjxhdXRob3I+QmFydGVscyxELkguPC9hdXRob3I+PGF1dGhvcj5CZWxsLE0uTC48L2F1

dGhvcj48YXV0aG9yPkJlbmphbWluLEUuSi48L2F1dGhvcj48YXV0aG9yPkJlbm5ldHQsRC48L2F1

dGhvcj48YXV0aG9yPkJoYWxsYSxLLjwvYXV0aG9yPjxhdXRob3I+QmlrYm92LEIuPC9hdXRob3I+

PGF1dGhvcj5CaW4sQWJkdWxoYWsgQS48L2F1dGhvcj48YXV0aG9yPkJpcmJlY2ssRy48L2F1dGhv

cj48YXV0aG9yPkJseXRoLEYuPC9hdXRob3I+PGF1dGhvcj5Cb2xsaWdlcixJLjwvYXV0aG9yPjxh

dXRob3I+Qm91Zm91cyxTLjwvYXV0aG9yPjxhdXRob3I+QnVjZWxsbyxDLjwvYXV0aG9yPjxhdXRo

b3I+QnVyY2gsTS48L2F1dGhvcj48YXV0aG9yPkJ1cm5leSxQLjwvYXV0aG9yPjxhdXRob3I+Q2Fy

YXBldGlzLEouPC9hdXRob3I+PGF1dGhvcj5DaGVuLEguPC9hdXRob3I+PGF1dGhvcj5DaG91LEQu

PC9hdXRob3I+PGF1dGhvcj5DaHVnaCxTLlMuPC9hdXRob3I+PGF1dGhvcj5Db2ZmZW5nLEwuRS48

L2F1dGhvcj48YXV0aG9yPkNvbGFuLFMuRC48L2F1dGhvcj48YXV0aG9yPkNvbHF1aG91bixTLjwv

YXV0aG9yPjxhdXRob3I+Q29sc29uLEsuRS48L2F1dGhvcj48YXV0aG9yPkNvbmRvbixKLjwvYXV0

aG9yPjxhdXRob3I+Q29ubm9yLE0uRC48L2F1dGhvcj48YXV0aG9yPkNvb3BlcixMLlQuPC9hdXRo

b3I+PGF1dGhvcj5Db3JyaWVyZSxNLjwvYXV0aG9yPjxhdXRob3I+Q29ydGlub3ZpcyxNLjwvYXV0

aG9yPjxhdXRob3I+ZGUgVmFjY2FybyxLLkMuPC9hdXRob3I+PGF1dGhvcj5Db3VzZXIsVy48L2F1

dGhvcj48YXV0aG9yPkNvd2llLEIuQy48L2F1dGhvcj48YXV0aG9yPkNyaXF1aSxNLkguPC9hdXRo

b3I+PGF1dGhvcj5Dcm9zcyxNLjwvYXV0aG9yPjxhdXRob3I+RGFiaGFka2FyLEsuQy48L2F1dGhv

cj48YXV0aG9yPkRhaG9kd2FsYSxOLjwvYXV0aG9yPjxhdXRob3I+RGUgTGVvLEQuPC9hdXRob3I+

PGF1dGhvcj5EZWdlbmhhcmR0LEwuPC9hdXRob3I+PGF1dGhvcj5EZWxvc3NhbnRvcyxBLjwvYXV0

aG9yPjxhdXRob3I+RGVuZW5iZXJnLEouPC9hdXRob3I+PGF1dGhvcj5EZXMsSmFybGFpcyxELkMu

PC9hdXRob3I+PGF1dGhvcj5EaGFybWFyYXRuZSxTLkQuPC9hdXRob3I+PGF1dGhvcj5Eb3JzZXks

RS5SLjwvYXV0aG9yPjxhdXRob3I+RHJpc2NvbGwsVC48L2F1dGhvcj48YXV0aG9yPkR1YmVyLEgu

PC9hdXRob3I+PGF1dGhvcj5FYmVsLEIuPC9hdXRob3I+PGF1dGhvcj5FcndpbixQLkouPC9hdXRo

b3I+PGF1dGhvcj5Fc3BpbmRvbGEsUC48L2F1dGhvcj48YXV0aG9yPkV6emF0aSxNLjwvYXV0aG9y

PjxhdXRob3I+RmVpZ2luLFYuPC9hdXRob3I+PGF1dGhvcj5GbGF4bWFuLEEuRC48L2F1dGhvcj48

YXV0aG9yPkZvcm91emFuZmFyLE0uSC48L2F1dGhvcj48YXV0aG9yPkZvd2tlcyxGLkcuPC9hdXRo

b3I+PGF1dGhvcj5GcmFua2xpbixSLjwvYXV0aG9yPjxhdXRob3I+RnJhbnNlbixNLjwvYXV0aG9y

PjxhdXRob3I+RnJlZW1hbixNLksuPC9hdXRob3I+PGF1dGhvcj5HYWJyaWVsLFMuRS48L2F1dGhv

cj48YXV0aG9yPkdha2lkb3UsRS48L2F1dGhvcj48YXV0aG9yPkdhc3BhcmksRi48L2F1dGhvcj48

YXV0aG9yPkdpbGx1bSxSLkYuPC9hdXRob3I+PGF1dGhvcj5Hb256YWxlei1NZWRpbmEsRC48L2F1

dGhvcj48YXV0aG9yPkhhbGFzYSxZLkEuPC9hdXRob3I+PGF1dGhvcj5IYXJpbmcsRC48L2F1dGhv

cj48YXV0aG9yPkhhcnJpc29uLEouRS48L2F1dGhvcj48YXV0aG9yPkhhdm1vZWxsZXIsUi48L2F1

dGhvcj48YXV0aG9yPkhheSxSLkouPC9hdXRob3I+PGF1dGhvcj5Ib2VuLEIuPC9hdXRob3I+PGF1

dGhvcj5Ib3RleixQLkouPC9hdXRob3I+PGF1dGhvcj5Ib3ksRC48L2F1dGhvcj48YXV0aG9yPkph

Y29ic2VuLEsuSC48L2F1dGhvcj48YXV0aG9yPkphbWVzLFMuTC48L2F1dGhvcj48YXV0aG9yPkph

c3Jhc2FyaWEsUi48L2F1dGhvcj48YXV0aG9yPkpheWFyYW1hbixTLjwvYXV0aG9yPjxhdXRob3I+

Sm9obnMsTi48L2F1dGhvcj48YXV0aG9yPkthcnRoaWtleWFuLEcuPC9hdXRob3I+PGF1dGhvcj5L

YXNzZWJhdW0sTi48L2F1dGhvcj48YXV0aG9yPktlcmVuLEEuPC9hdXRob3I+PGF1dGhvcj5LaG9v

LEouUC48L2F1dGhvcj48YXV0aG9yPktub3dsdG9uLEwuTS48L2F1dGhvcj48YXV0aG9yPktvYnVz

aW5neWUsTy48L2F1dGhvcj48YXV0aG9yPktvcmFudGVuZyxBLjwvYXV0aG9yPjxhdXRob3I+S3Jp

c2huYW11cnRoaSxSLjwvYXV0aG9yPjxhdXRob3I+TGlwbmljayxNLjwvYXV0aG9yPjxhdXRob3I+

TGlwc2h1bHR6LFMuRS48L2F1dGhvcj48YXV0aG9yPk9obm8sUy5MLjwvYXV0aG9yPjxhdXRob3I+

TWFid2VpamFubyxKLjwvYXV0aG9yPjxhdXRob3I+TWFjSW50eXJlLE0uRi48L2F1dGhvcj48YXV0

aG9yPk1hbGxpbmdlcixMLjwvYXV0aG9yPjxhdXRob3I+TWFyY2gsTC48L2F1dGhvcj48YXV0aG9y

Pk1hcmtzLEcuQi48L2F1dGhvcj48YXV0aG9yPk1hcmtzLFIuPC9hdXRob3I+PGF1dGhvcj5NYXRz

dW1vcmksQS48L2F1dGhvcj48YXV0aG9yPk1hdHpvcG91bG9zLFIuPC9hdXRob3I+PGF1dGhvcj5N

YXlvc2ksQi5NLjwvYXV0aG9yPjxhdXRob3I+TWNBbnVsdHksSi5ILjwvYXV0aG9yPjxhdXRob3I+

TWNEZXJtb3R0LE0uTS48L2F1dGhvcj48YXV0aG9yPk1jR3JhdGgsSi48L2F1dGhvcj48YXV0aG9y

Pk1lbnNhaCxHLkEuPC9hdXRob3I+PGF1dGhvcj5NZXJyaW1hbixULlIuPC9hdXRob3I+PGF1dGhv

cj5NaWNoYXVkLEMuPC9hdXRob3I+PGF1dGhvcj5NaWxsZXIsTS48L2F1dGhvcj48YXV0aG9yPk1p

bGxlcixULlIuPC9hdXRob3I+PGF1dGhvcj5Nb2NrLEMuPC9hdXRob3I+PGF1dGhvcj5Nb2N1bWJp

LEEuTy48L2F1dGhvcj48YXV0aG9yPk1va2RhZCxBLkEuPC9hdXRob3I+PGF1dGhvcj5Nb3JhbixB

LjwvYXV0aG9yPjxhdXRob3I+TXVsaG9sbGFuZCxLLjwvYXV0aG9yPjxhdXRob3I+TmFpcixNLk4u

PC9hdXRob3I+PGF1dGhvcj5OYWxkaSxMLjwvYXV0aG9yPjxhdXRob3I+TmFyYXlhbixLLk0uPC9h

dXRob3I+PGF1dGhvcj5OYXNzZXJpLEsuPC9hdXRob3I+PGF1dGhvcj5Ob3JtYW4sUC48L2F1dGhv

cj48YXV0aG9yPk8mYXBvcztEb25uZWxsLE0uPC9hdXRob3I+PGF1dGhvcj5PbWVyLFMuQi48L2F1

dGhvcj48YXV0aG9yPk9ydGJsYWQsSy48L2F1dGhvcj48YXV0aG9yPk9zYm9ybmUsUi48L2F1dGhv

cj48YXV0aG9yPk96Z2VkaXosRC48L2F1dGhvcj48YXV0aG9yPlBhaGFyaSxCLjwvYXV0aG9yPjxh

dXRob3I+UGFuZGlhbixKLkQuPC9hdXRob3I+PGF1dGhvcj5SaXZlcm8sQS5QLjwvYXV0aG9yPjxh

dXRob3I+UGFkaWxsYSxSLlAuPC9hdXRob3I+PGF1dGhvcj5QZXJlei1SdWl6LEYuPC9hdXRob3I+

PGF1dGhvcj5QZXJpY28sTi48L2F1dGhvcj48YXV0aG9yPlBoaWxsaXBzLEQuPC9hdXRob3I+PGF1

dGhvcj5QaWVyY2UsSy48L2F1dGhvcj48YXV0aG9yPlBvcGUsQy5BLixJSUk8L2F1dGhvcj48YXV0

aG9yPlBvcnJpbmksRS48L2F1dGhvcj48YXV0aG9yPlBvdXJtYWxlayxGLjwvYXV0aG9yPjxhdXRo

b3I+UmFqdSxNLjwvYXV0aG9yPjxhdXRob3I+UmFuZ2FuYXRoYW4sRC48L2F1dGhvcj48YXV0aG9y

PlJlaG0sSi5ULjwvYXV0aG9yPjxhdXRob3I+UmVpbixELkIuPC9hdXRob3I+PGF1dGhvcj5SZW11

enppLEcuPC9hdXRob3I+PGF1dGhvcj5SaXZhcmEsRi5QLjwvYXV0aG9yPjxhdXRob3I+Um9iZXJ0

cyxULjwvYXV0aG9yPjxhdXRob3I+RGUgTGVvbixGLlIuPC9hdXRob3I+PGF1dGhvcj5Sb3NlbmZl

bGQsTC5DLjwvYXV0aG9yPjxhdXRob3I+UnVzaHRvbixMLjwvYXV0aG9yPjxhdXRob3I+U2FjY28s

Ui5MLjwvYXV0aG9yPjxhdXRob3I+U2Fsb21vbixKLkEuPC9hdXRob3I+PGF1dGhvcj5TYW1wc29u

LFUuPC9hdXRob3I+PGF1dGhvcj5TYW5tYW4sRS48L2F1dGhvcj48YXV0aG9yPlNjaHdlYmVsLEQu

Qy48L2F1dGhvcj48YXV0aG9yPlNlZ3VpLUdvbWV6LE0uPC9hdXRob3I+PGF1dGhvcj5TaGVwYXJk

LEQuUy48L2F1dGhvcj48YXV0aG9yPlNpbmdoLEQuPC9hdXRob3I+PGF1dGhvcj5TaW5nbGV0b24s

Si48L2F1dGhvcj48YXV0aG9yPlNsaXdhLEsuPC9hdXRob3I+PGF1dGhvcj5TbWl0aCxFLjwvYXV0

aG9yPjxhdXRob3I+U3RlZXIsQS48L2F1dGhvcj48YXV0aG9yPlRheWxvcixKLkEuPC9hdXRob3I+

PGF1dGhvcj5UaG9tYXMsQi48L2F1dGhvcj48YXV0aG9yPlRsZXlqZWgsSS5NLjwvYXV0aG9yPjxh

dXRob3I+VG93YmluLEouQS48L2F1dGhvcj48YXV0aG9yPlRydWVsc2VuLFQuPC9hdXRob3I+PGF1

dGhvcj5VbmR1cnJhZ2EsRS5BLjwvYXV0aG9yPjxhdXRob3I+VmVua2V0YXN1YnJhbWFuaWFuLE4u

PC9hdXRob3I+PGF1dGhvcj5WaWpheWFrdW1hcixMLjwvYXV0aG9yPjxhdXRob3I+Vm9zLFQuPC9h

dXRob3I+PGF1dGhvcj5XYWduZXIsRy5SLjwvYXV0aG9yPjxhdXRob3I+V2FuZyxNLjwvYXV0aG9y

PjxhdXRob3I+V2FuZyxXLjwvYXV0aG9yPjxhdXRob3I+V2F0dCxLLjwvYXV0aG9yPjxhdXRob3I+

V2VpbnN0b2NrLE0uQS48L2F1dGhvcj48YXV0aG9yPldlaW50cmF1YixSLjwvYXV0aG9yPjxhdXRo

b3I+V2lsa2luc29uLEouRC48L2F1dGhvcj48YXV0aG9yPldvb2xmLEEuRC48L2F1dGhvcj48YXV0

aG9yPld1bGYsUy48L2F1dGhvcj48YXV0aG9yPlllaCxQLkguPC9hdXRob3I+PGF1dGhvcj5ZaXAs

UC48L2F1dGhvcj48YXV0aG9yPlphYmV0aWFuLEEuPC9hdXRob3I+PGF1dGhvcj5aaGVuZyxaLkou

PC9hdXRob3I+PGF1dGhvcj5Mb3BleixBLkQuPC9hdXRob3I+PGF1dGhvcj5NdXJyYXksQy5KLjwv

YXV0aG9yPjxhdXRob3I+QWxNYXpyb2EsTS5BLjwvYXV0aG9yPjxhdXRob3I+TWVtaXNoLFouQS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+R2xvYmFsIGFu

ZCByZWdpb25hbCBtb3J0YWxpdHkgZnJvbSAyMzUgY2F1c2VzIG9mIGRlYXRoIGZvciAyMCBhZ2Ug

Z3JvdXBzIGluIDE5OTAgYW5kIDIwMTA6IGEgc3lzdGVtYXRpYyBhbmFseXNpcyBmb3IgdGhlIEds

b2JhbCBCdXJkZW4gb2YgRGlzZWFzZSBTdHVkeSAyMDEwPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5MYW5jZXQuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjA5NS0yMTI4PC9wYWdl

cz48dm9sdW1lPjM4MDwvdm9sdW1lPjxudW1iZXI+OTg1OTwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MTk4MDwv

a2V5d29yZD48a2V5d29yZD5BQ1VURTwva2V5d29yZD48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3

b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3b3JkPjxrZXl3b3JkPmFmcmljYTwva2V5d29yZD48a2V5

d29yZD5BR0U8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3Jk

PkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkFQUFJPQUNIRVM8L2tleXdvcmQ+PGtleXdvcmQ+

QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTTUVOVDwva2V5d29yZD48a2V5d29yZD5B

dXRvcHN5PC9rZXl3b3JkPjxrZXl3b3JkPkJST05DSFVTPC9rZXl3b3JkPjxrZXl3b3JkPmNhdXNl

IG9mIGRlYXRoPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxk

LFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNI

Uk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jb21wbGljYXRpb25zPC9rZXl3b3Jk

PjxrZXl3b3JkPkNPTkdFTklUQUw8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5DT1VHSDwva2V5d29yZD48a2V5d29yZD5ERUFUSDwva2V5d29yZD48a2V5d29yZD5ERUFU

SFM8L2tleXdvcmQ+PGtleXdvcmQ+REVDQURFUzwva2V5d29yZD48a2V5d29yZD5ERUNSRUFTRUQ8

L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+RElT

RUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5ESVNPUkRF

UlM8L2tleXdvcmQ+PGtleXdvcmQ+RElTVFJJQlVUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVQSURF

TUlPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5FVkFMVUFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPmZhbGw8

L2tleXdvcmQ+PGtleXdvcmQ+RkFNSUxZPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29y

ZD48a2V5d29yZD5nbG9iYWw8L2tleXdvcmQ+PGtleXdvcmQ+R1JPV1RIPC9rZXl3b3JkPjxrZXl3

b3JkPkhFQUxUSDwva2V5d29yZD48a2V5d29yZD5IZWFsdGggUG9saWN5PC9rZXl3b3JkPjxrZXl3

b3JkPkhFQVJUPC9rZXl3b3JkPjxrZXl3b3JkPkhFVEVST0dFTkVJVFk8L2tleXdvcmQ+PGtleXdv

cmQ+aGlzdG9yeTwva2V5d29yZD48a2V5d29yZD5IT1NQSVRBTDwva2V5d29yZD48a2V5d29yZD5I

T1NQSVRBTFM8L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9r

ZXl3b3JkPjxrZXl3b3JkPmluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tl

eXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPkluZmFudCxOZXdib3JuPC9r

ZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlvbjwva2V5d29yZD48a2V5d29yZD5JTkZFQ1RJT05TPC9r

ZXl3b3JkPjxrZXl3b3JkPmluanVyaWVzPC9rZXl3b3JkPjxrZXl3b3JkPklOSlVSWTwva2V5d29y

ZD48a2V5d29yZD5LaWRuZXk8L2tleXdvcmQ+PGtleXdvcmQ+TEFSR0U8L2tleXdvcmQ+PGtleXdv

cmQ+TGl2ZXI8L2tleXdvcmQ+PGtleXdvcmQ+bGl2ZXIgY2lycmhvc2lzPC9rZXl3b3JkPjxrZXl3

b3JkPkxPV0VSPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8

L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5tZWxhbm9tYTwva2V5d29y

ZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NT0RFTDwva2V5d29yZD48a2V5d29y

ZD5NT0RFTFM8L2tleXdvcmQ+PGtleXdvcmQ+TU9SVEFMSVRZPC9rZXl3b3JkPjxrZXl3b3JkPk5B

VFVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+TkVPTkFUQUw8L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVS

Uzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QT1BVTEFU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBSRVZBTEVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9O

QVJZPC9rZXl3b3JkPjxrZXl3b3JkPlJBVEU8L2tleXdvcmQ+PGtleXdvcmQ+UkFURVM8L2tleXdv

cmQ+PGtleXdvcmQ+UkVHSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPnJpc2U8L2tleXdvcmQ+PGtleXdvcmQ+cmlzazwva2V5d29yZD48a2V5d29yZD5S

aXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U2V4IEZhY3RvcnM8L2tleXdvcmQ+PGtleXdv

cmQ+c3RhdGlzdGljcyAmYW1wOyBudW1lcmljYWwgZGF0YTwva2V5d29yZD48a2V5d29yZD5TVFJB

VEVHSUVTPC9rZXl3b3JkPjxrZXl3b3JkPlN0cm9rZTwva2V5d29yZD48a2V5d29yZD5TVFVESUVT

PC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlN1aWNpZGU8L2tleXdv

cmQ+PGtleXdvcmQ+U1VSVkVZPC9rZXl3b3JkPjxrZXl3b3JkPlRyYWNoZWE8L2tleXdvcmQ+PGtl

eXdvcmQ+dHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPnR1YmVyY3Vsb3Npczwva2V5d29yZD48a2V5

d29yZD5UV088L2tleXdvcmQ+PGtleXdvcmQ+VVNFPC9rZXl3b3JkPjxrZXl3b3JkPlZBUklBVElP

Tjwva2V5d29yZD48a2V5d29yZD5WQVNDVUxBUjwva2V5d29yZD48a2V5d29yZD5WYXNjdWxhciBE

aXNlYXNlczwva2V5d29yZD48a2V5d29yZD5WSVRBTDwva2V5d29yZD48a2V5d29yZD5XaG9vcGlu

ZyBDb3VnaDwva2V5d29yZD48a2V5d29yZD5Xb3JsZCBIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+

V09STERXSURFPC9rZXl3b3JkPjxrZXl3b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xMi8xNS8yMDEyPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkxPWkFOTzIwMTI8L2xhYmVsPjx1cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Mb3phbm88L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE3NzE8L1JlY051bT48RGlzcGxheVRleHQ+WzEzXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTc3MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTc3MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+TG96YW5vLFIuPC9hdXRob3I+PGF1dGhvcj5OYWdoYXZpLE0uPC9hdXRob3I+PGF1dGhvcj5G

b3JlbWFuLEsuPC9hdXRob3I+PGF1dGhvcj5MaW0sUy48L2F1dGhvcj48YXV0aG9yPlNoaWJ1eWEs

Sy48L2F1dGhvcj48YXV0aG9yPkFib3lhbnMsVi48L2F1dGhvcj48YXV0aG9yPkFicmFoYW0sSi48

L2F1dGhvcj48YXV0aG9yPkFkYWlyLFQuPC9hdXRob3I+PGF1dGhvcj5BZ2dhcndhbCxSLjwvYXV0

aG9yPjxhdXRob3I+QWhuLFMuWS48L2F1dGhvcj48YXV0aG9yPkFsdmFyYWRvLE0uPC9hdXRob3I+

PGF1dGhvcj5BbmRlcnNvbixILlIuPC9hdXRob3I+PGF1dGhvcj5BbmRlcnNvbixMLk0uPC9hdXRo

b3I+PGF1dGhvcj5BbmRyZXdzLEsuRy48L2F1dGhvcj48YXV0aG9yPkF0a2luc29uLEMuPC9hdXRo

b3I+PGF1dGhvcj5CYWRkb3VyLEwuTS48L2F1dGhvcj48YXV0aG9yPkJhcmtlci1Db2xsbyxTLjwv

YXV0aG9yPjxhdXRob3I+QmFydGVscyxELkguPC9hdXRob3I+PGF1dGhvcj5CZWxsLE0uTC48L2F1

dGhvcj48YXV0aG9yPkJlbmphbWluLEUuSi48L2F1dGhvcj48YXV0aG9yPkJlbm5ldHQsRC48L2F1

dGhvcj48YXV0aG9yPkJoYWxsYSxLLjwvYXV0aG9yPjxhdXRob3I+QmlrYm92LEIuPC9hdXRob3I+

PGF1dGhvcj5CaW4sQWJkdWxoYWsgQS48L2F1dGhvcj48YXV0aG9yPkJpcmJlY2ssRy48L2F1dGhv

cj48YXV0aG9yPkJseXRoLEYuPC9hdXRob3I+PGF1dGhvcj5Cb2xsaWdlcixJLjwvYXV0aG9yPjxh

dXRob3I+Qm91Zm91cyxTLjwvYXV0aG9yPjxhdXRob3I+QnVjZWxsbyxDLjwvYXV0aG9yPjxhdXRo

b3I+QnVyY2gsTS48L2F1dGhvcj48YXV0aG9yPkJ1cm5leSxQLjwvYXV0aG9yPjxhdXRob3I+Q2Fy

YXBldGlzLEouPC9hdXRob3I+PGF1dGhvcj5DaGVuLEguPC9hdXRob3I+PGF1dGhvcj5DaG91LEQu

PC9hdXRob3I+PGF1dGhvcj5DaHVnaCxTLlMuPC9hdXRob3I+PGF1dGhvcj5Db2ZmZW5nLEwuRS48

L2F1dGhvcj48YXV0aG9yPkNvbGFuLFMuRC48L2F1dGhvcj48YXV0aG9yPkNvbHF1aG91bixTLjwv

YXV0aG9yPjxhdXRob3I+Q29sc29uLEsuRS48L2F1dGhvcj48YXV0aG9yPkNvbmRvbixKLjwvYXV0

aG9yPjxhdXRob3I+Q29ubm9yLE0uRC48L2F1dGhvcj48YXV0aG9yPkNvb3BlcixMLlQuPC9hdXRo

b3I+PGF1dGhvcj5Db3JyaWVyZSxNLjwvYXV0aG9yPjxhdXRob3I+Q29ydGlub3ZpcyxNLjwvYXV0

aG9yPjxhdXRob3I+ZGUgVmFjY2FybyxLLkMuPC9hdXRob3I+PGF1dGhvcj5Db3VzZXIsVy48L2F1

dGhvcj48YXV0aG9yPkNvd2llLEIuQy48L2F1dGhvcj48YXV0aG9yPkNyaXF1aSxNLkguPC9hdXRo

b3I+PGF1dGhvcj5Dcm9zcyxNLjwvYXV0aG9yPjxhdXRob3I+RGFiaGFka2FyLEsuQy48L2F1dGhv

cj48YXV0aG9yPkRhaG9kd2FsYSxOLjwvYXV0aG9yPjxhdXRob3I+RGUgTGVvLEQuPC9hdXRob3I+

PGF1dGhvcj5EZWdlbmhhcmR0LEwuPC9hdXRob3I+PGF1dGhvcj5EZWxvc3NhbnRvcyxBLjwvYXV0

aG9yPjxhdXRob3I+RGVuZW5iZXJnLEouPC9hdXRob3I+PGF1dGhvcj5EZXMsSmFybGFpcyxELkMu

PC9hdXRob3I+PGF1dGhvcj5EaGFybWFyYXRuZSxTLkQuPC9hdXRob3I+PGF1dGhvcj5Eb3JzZXks

RS5SLjwvYXV0aG9yPjxhdXRob3I+RHJpc2NvbGwsVC48L2F1dGhvcj48YXV0aG9yPkR1YmVyLEgu

PC9hdXRob3I+PGF1dGhvcj5FYmVsLEIuPC9hdXRob3I+PGF1dGhvcj5FcndpbixQLkouPC9hdXRo

b3I+PGF1dGhvcj5Fc3BpbmRvbGEsUC48L2F1dGhvcj48YXV0aG9yPkV6emF0aSxNLjwvYXV0aG9y

PjxhdXRob3I+RmVpZ2luLFYuPC9hdXRob3I+PGF1dGhvcj5GbGF4bWFuLEEuRC48L2F1dGhvcj48

YXV0aG9yPkZvcm91emFuZmFyLE0uSC48L2F1dGhvcj48YXV0aG9yPkZvd2tlcyxGLkcuPC9hdXRo

b3I+PGF1dGhvcj5GcmFua2xpbixSLjwvYXV0aG9yPjxhdXRob3I+RnJhbnNlbixNLjwvYXV0aG9y

PjxhdXRob3I+RnJlZW1hbixNLksuPC9hdXRob3I+PGF1dGhvcj5HYWJyaWVsLFMuRS48L2F1dGhv

cj48YXV0aG9yPkdha2lkb3UsRS48L2F1dGhvcj48YXV0aG9yPkdhc3BhcmksRi48L2F1dGhvcj48

YXV0aG9yPkdpbGx1bSxSLkYuPC9hdXRob3I+PGF1dGhvcj5Hb256YWxlei1NZWRpbmEsRC48L2F1

dGhvcj48YXV0aG9yPkhhbGFzYSxZLkEuPC9hdXRob3I+PGF1dGhvcj5IYXJpbmcsRC48L2F1dGhv

cj48YXV0aG9yPkhhcnJpc29uLEouRS48L2F1dGhvcj48YXV0aG9yPkhhdm1vZWxsZXIsUi48L2F1

dGhvcj48YXV0aG9yPkhheSxSLkouPC9hdXRob3I+PGF1dGhvcj5Ib2VuLEIuPC9hdXRob3I+PGF1

dGhvcj5Ib3RleixQLkouPC9hdXRob3I+PGF1dGhvcj5Ib3ksRC48L2F1dGhvcj48YXV0aG9yPkph

Y29ic2VuLEsuSC48L2F1dGhvcj48YXV0aG9yPkphbWVzLFMuTC48L2F1dGhvcj48YXV0aG9yPkph

c3Jhc2FyaWEsUi48L2F1dGhvcj48YXV0aG9yPkpheWFyYW1hbixTLjwvYXV0aG9yPjxhdXRob3I+

Sm9obnMsTi48L2F1dGhvcj48YXV0aG9yPkthcnRoaWtleWFuLEcuPC9hdXRob3I+PGF1dGhvcj5L

YXNzZWJhdW0sTi48L2F1dGhvcj48YXV0aG9yPktlcmVuLEEuPC9hdXRob3I+PGF1dGhvcj5LaG9v

LEouUC48L2F1dGhvcj48YXV0aG9yPktub3dsdG9uLEwuTS48L2F1dGhvcj48YXV0aG9yPktvYnVz

aW5neWUsTy48L2F1dGhvcj48YXV0aG9yPktvcmFudGVuZyxBLjwvYXV0aG9yPjxhdXRob3I+S3Jp

c2huYW11cnRoaSxSLjwvYXV0aG9yPjxhdXRob3I+TGlwbmljayxNLjwvYXV0aG9yPjxhdXRob3I+

TGlwc2h1bHR6LFMuRS48L2F1dGhvcj48YXV0aG9yPk9obm8sUy5MLjwvYXV0aG9yPjxhdXRob3I+

TWFid2VpamFubyxKLjwvYXV0aG9yPjxhdXRob3I+TWFjSW50eXJlLE0uRi48L2F1dGhvcj48YXV0

aG9yPk1hbGxpbmdlcixMLjwvYXV0aG9yPjxhdXRob3I+TWFyY2gsTC48L2F1dGhvcj48YXV0aG9y

Pk1hcmtzLEcuQi48L2F1dGhvcj48YXV0aG9yPk1hcmtzLFIuPC9hdXRob3I+PGF1dGhvcj5NYXRz

dW1vcmksQS48L2F1dGhvcj48YXV0aG9yPk1hdHpvcG91bG9zLFIuPC9hdXRob3I+PGF1dGhvcj5N

YXlvc2ksQi5NLjwvYXV0aG9yPjxhdXRob3I+TWNBbnVsdHksSi5ILjwvYXV0aG9yPjxhdXRob3I+

TWNEZXJtb3R0LE0uTS48L2F1dGhvcj48YXV0aG9yPk1jR3JhdGgsSi48L2F1dGhvcj48YXV0aG9y

Pk1lbnNhaCxHLkEuPC9hdXRob3I+PGF1dGhvcj5NZXJyaW1hbixULlIuPC9hdXRob3I+PGF1dGhv

cj5NaWNoYXVkLEMuPC9hdXRob3I+PGF1dGhvcj5NaWxsZXIsTS48L2F1dGhvcj48YXV0aG9yPk1p

bGxlcixULlIuPC9hdXRob3I+PGF1dGhvcj5Nb2NrLEMuPC9hdXRob3I+PGF1dGhvcj5Nb2N1bWJp

LEEuTy48L2F1dGhvcj48YXV0aG9yPk1va2RhZCxBLkEuPC9hdXRob3I+PGF1dGhvcj5Nb3JhbixB

LjwvYXV0aG9yPjxhdXRob3I+TXVsaG9sbGFuZCxLLjwvYXV0aG9yPjxhdXRob3I+TmFpcixNLk4u

PC9hdXRob3I+PGF1dGhvcj5OYWxkaSxMLjwvYXV0aG9yPjxhdXRob3I+TmFyYXlhbixLLk0uPC9h

dXRob3I+PGF1dGhvcj5OYXNzZXJpLEsuPC9hdXRob3I+PGF1dGhvcj5Ob3JtYW4sUC48L2F1dGhv

cj48YXV0aG9yPk8mYXBvcztEb25uZWxsLE0uPC9hdXRob3I+PGF1dGhvcj5PbWVyLFMuQi48L2F1

dGhvcj48YXV0aG9yPk9ydGJsYWQsSy48L2F1dGhvcj48YXV0aG9yPk9zYm9ybmUsUi48L2F1dGhv

cj48YXV0aG9yPk96Z2VkaXosRC48L2F1dGhvcj48YXV0aG9yPlBhaGFyaSxCLjwvYXV0aG9yPjxh

dXRob3I+UGFuZGlhbixKLkQuPC9hdXRob3I+PGF1dGhvcj5SaXZlcm8sQS5QLjwvYXV0aG9yPjxh

dXRob3I+UGFkaWxsYSxSLlAuPC9hdXRob3I+PGF1dGhvcj5QZXJlei1SdWl6LEYuPC9hdXRob3I+

PGF1dGhvcj5QZXJpY28sTi48L2F1dGhvcj48YXV0aG9yPlBoaWxsaXBzLEQuPC9hdXRob3I+PGF1

dGhvcj5QaWVyY2UsSy48L2F1dGhvcj48YXV0aG9yPlBvcGUsQy5BLixJSUk8L2F1dGhvcj48YXV0

aG9yPlBvcnJpbmksRS48L2F1dGhvcj48YXV0aG9yPlBvdXJtYWxlayxGLjwvYXV0aG9yPjxhdXRo

b3I+UmFqdSxNLjwvYXV0aG9yPjxhdXRob3I+UmFuZ2FuYXRoYW4sRC48L2F1dGhvcj48YXV0aG9y

PlJlaG0sSi5ULjwvYXV0aG9yPjxhdXRob3I+UmVpbixELkIuPC9hdXRob3I+PGF1dGhvcj5SZW11

enppLEcuPC9hdXRob3I+PGF1dGhvcj5SaXZhcmEsRi5QLjwvYXV0aG9yPjxhdXRob3I+Um9iZXJ0

cyxULjwvYXV0aG9yPjxhdXRob3I+RGUgTGVvbixGLlIuPC9hdXRob3I+PGF1dGhvcj5Sb3NlbmZl

bGQsTC5DLjwvYXV0aG9yPjxhdXRob3I+UnVzaHRvbixMLjwvYXV0aG9yPjxhdXRob3I+U2FjY28s

Ui5MLjwvYXV0aG9yPjxhdXRob3I+U2Fsb21vbixKLkEuPC9hdXRob3I+PGF1dGhvcj5TYW1wc29u

LFUuPC9hdXRob3I+PGF1dGhvcj5TYW5tYW4sRS48L2F1dGhvcj48YXV0aG9yPlNjaHdlYmVsLEQu

Qy48L2F1dGhvcj48YXV0aG9yPlNlZ3VpLUdvbWV6LE0uPC9hdXRob3I+PGF1dGhvcj5TaGVwYXJk

LEQuUy48L2F1dGhvcj48YXV0aG9yPlNpbmdoLEQuPC9hdXRob3I+PGF1dGhvcj5TaW5nbGV0b24s

Si48L2F1dGhvcj48YXV0aG9yPlNsaXdhLEsuPC9hdXRob3I+PGF1dGhvcj5TbWl0aCxFLjwvYXV0

aG9yPjxhdXRob3I+U3RlZXIsQS48L2F1dGhvcj48YXV0aG9yPlRheWxvcixKLkEuPC9hdXRob3I+

PGF1dGhvcj5UaG9tYXMsQi48L2F1dGhvcj48YXV0aG9yPlRsZXlqZWgsSS5NLjwvYXV0aG9yPjxh

dXRob3I+VG93YmluLEouQS48L2F1dGhvcj48YXV0aG9yPlRydWVsc2VuLFQuPC9hdXRob3I+PGF1

dGhvcj5VbmR1cnJhZ2EsRS5BLjwvYXV0aG9yPjxhdXRob3I+VmVua2V0YXN1YnJhbWFuaWFuLE4u

PC9hdXRob3I+PGF1dGhvcj5WaWpheWFrdW1hcixMLjwvYXV0aG9yPjxhdXRob3I+Vm9zLFQuPC9h

dXRob3I+PGF1dGhvcj5XYWduZXIsRy5SLjwvYXV0aG9yPjxhdXRob3I+V2FuZyxNLjwvYXV0aG9y

PjxhdXRob3I+V2FuZyxXLjwvYXV0aG9yPjxhdXRob3I+V2F0dCxLLjwvYXV0aG9yPjxhdXRob3I+

V2VpbnN0b2NrLE0uQS48L2F1dGhvcj48YXV0aG9yPldlaW50cmF1YixSLjwvYXV0aG9yPjxhdXRo

b3I+V2lsa2luc29uLEouRC48L2F1dGhvcj48YXV0aG9yPldvb2xmLEEuRC48L2F1dGhvcj48YXV0

aG9yPld1bGYsUy48L2F1dGhvcj48YXV0aG9yPlllaCxQLkguPC9hdXRob3I+PGF1dGhvcj5ZaXAs

UC48L2F1dGhvcj48YXV0aG9yPlphYmV0aWFuLEEuPC9hdXRob3I+PGF1dGhvcj5aaGVuZyxaLkou

PC9hdXRob3I+PGF1dGhvcj5Mb3BleixBLkQuPC9hdXRob3I+PGF1dGhvcj5NdXJyYXksQy5KLjwv

YXV0aG9yPjxhdXRob3I+QWxNYXpyb2EsTS5BLjwvYXV0aG9yPjxhdXRob3I+TWVtaXNoLFouQS48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+R2xvYmFsIGFu

ZCByZWdpb25hbCBtb3J0YWxpdHkgZnJvbSAyMzUgY2F1c2VzIG9mIGRlYXRoIGZvciAyMCBhZ2Ug

Z3JvdXBzIGluIDE5OTAgYW5kIDIwMTA6IGEgc3lzdGVtYXRpYyBhbmFseXNpcyBmb3IgdGhlIEds

b2JhbCBCdXJkZW4gb2YgRGlzZWFzZSBTdHVkeSAyMDEwPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PkxhbmNldC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5MYW5jZXQuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjA5NS0yMTI4PC9wYWdl

cz48dm9sdW1lPjM4MDwvdm9sdW1lPjxudW1iZXI+OTg1OTwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MTk4MDwv

a2V5d29yZD48a2V5d29yZD5BQ1VURTwva2V5d29yZD48a2V5d29yZD5BZG9sZXNjZW50PC9rZXl3

b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3b3JkPjxrZXl3b3JkPmFmcmljYTwva2V5d29yZD48a2V5

d29yZD5BR0U8L2tleXdvcmQ+PGtleXdvcmQ+QWdlIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

QWdlZDwva2V5d29yZD48a2V5d29yZD5BZ2VkLDgwIGFuZCBvdmVyPC9rZXl3b3JkPjxrZXl3b3Jk

PkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkFQUFJPQUNIRVM8L2tleXdvcmQ+PGtleXdvcmQ+

QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTTUVOVDwva2V5d29yZD48a2V5d29yZD5B

dXRvcHN5PC9rZXl3b3JkPjxrZXl3b3JkPkJST05DSFVTPC9rZXl3b3JkPjxrZXl3b3JkPmNhdXNl

IG9mIGRlYXRoPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxkPC9rZXl3b3JkPjxrZXl3b3JkPkNoaWxk

LFByZXNjaG9vbDwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNI

Uk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jb21wbGljYXRpb25zPC9rZXl3b3Jk

PjxrZXl3b3JkPkNPTkdFTklUQUw8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5DT1VHSDwva2V5d29yZD48a2V5d29yZD5ERUFUSDwva2V5d29yZD48a2V5d29yZD5ERUFU

SFM8L2tleXdvcmQ+PGtleXdvcmQ+REVDQURFUzwva2V5d29yZD48a2V5d29yZD5ERUNSRUFTRUQ8

L2tleXdvcmQ+PGtleXdvcmQ+RGlhYmV0ZXMgTWVsbGl0dXM8L2tleXdvcmQ+PGtleXdvcmQ+RElT

RUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5ESVNPUkRF

UlM8L2tleXdvcmQ+PGtleXdvcmQ+RElTVFJJQlVUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVQSURF

TUlPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5FVkFMVUFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPmZhbGw8

L2tleXdvcmQ+PGtleXdvcmQ+RkFNSUxZPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29y

ZD48a2V5d29yZD5nbG9iYWw8L2tleXdvcmQ+PGtleXdvcmQ+R1JPV1RIPC9rZXl3b3JkPjxrZXl3

b3JkPkhFQUxUSDwva2V5d29yZD48a2V5d29yZD5IZWFsdGggUG9saWN5PC9rZXl3b3JkPjxrZXl3

b3JkPkhFQVJUPC9rZXl3b3JkPjxrZXl3b3JkPkhFVEVST0dFTkVJVFk8L2tleXdvcmQ+PGtleXdv

cmQ+aGlzdG9yeTwva2V5d29yZD48a2V5d29yZD5IT1NQSVRBTDwva2V5d29yZD48a2V5d29yZD5I

T1NQSVRBTFM8L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9r

ZXl3b3JkPjxrZXl3b3JkPmluY2lkZW5jZTwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tl

eXdvcmQ+PGtleXdvcmQ+SW5mYW50PC9rZXl3b3JkPjxrZXl3b3JkPkluZmFudCxOZXdib3JuPC9r

ZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlvbjwva2V5d29yZD48a2V5d29yZD5JTkZFQ1RJT05TPC9r

ZXl3b3JkPjxrZXl3b3JkPmluanVyaWVzPC9rZXl3b3JkPjxrZXl3b3JkPklOSlVSWTwva2V5d29y

ZD48a2V5d29yZD5LaWRuZXk8L2tleXdvcmQ+PGtleXdvcmQ+TEFSR0U8L2tleXdvcmQ+PGtleXdv

cmQ+TGl2ZXI8L2tleXdvcmQ+PGtleXdvcmQ+bGl2ZXIgY2lycmhvc2lzPC9rZXl3b3JkPjxrZXl3

b3JkPkxPV0VSPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8

L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5tZWxhbm9tYTwva2V5d29y

ZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5

d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5NT0RFTDwva2V5d29yZD48a2V5d29y

ZD5NT0RFTFM8L2tleXdvcmQ+PGtleXdvcmQ+TU9SVEFMSVRZPC9rZXl3b3JkPjxrZXl3b3JkPk5B

VFVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+TkVPTkFUQUw8L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVS

Uzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QT1BVTEFU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBSRVZBTEVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9O

QVJZPC9rZXl3b3JkPjxrZXl3b3JkPlJBVEU8L2tleXdvcmQ+PGtleXdvcmQ+UkFURVM8L2tleXdv

cmQ+PGtleXdvcmQ+UkVHSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPnJpc2U8L2tleXdvcmQ+PGtleXdvcmQ+cmlzazwva2V5d29yZD48a2V5d29yZD5S

aXNrIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+U2V4IEZhY3RvcnM8L2tleXdvcmQ+PGtleXdv

cmQ+c3RhdGlzdGljcyAmYW1wOyBudW1lcmljYWwgZGF0YTwva2V5d29yZD48a2V5d29yZD5TVFJB

VEVHSUVTPC9rZXl3b3JkPjxrZXl3b3JkPlN0cm9rZTwva2V5d29yZD48a2V5d29yZD5TVFVESUVT

PC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlN1aWNpZGU8L2tleXdv

cmQ+PGtleXdvcmQ+U1VSVkVZPC9rZXl3b3JkPjxrZXl3b3JkPlRyYWNoZWE8L2tleXdvcmQ+PGtl

eXdvcmQ+dHJlbmRzPC9rZXl3b3JkPjxrZXl3b3JkPnR1YmVyY3Vsb3Npczwva2V5d29yZD48a2V5

d29yZD5UV088L2tleXdvcmQ+PGtleXdvcmQ+VVNFPC9rZXl3b3JkPjxrZXl3b3JkPlZBUklBVElP

Tjwva2V5d29yZD48a2V5d29yZD5WQVNDVUxBUjwva2V5d29yZD48a2V5d29yZD5WYXNjdWxhciBE

aXNlYXNlczwva2V5d29yZD48a2V5d29yZD5WSVRBTDwva2V5d29yZD48a2V5d29yZD5XaG9vcGlu

ZyBDb3VnaDwva2V5d29yZD48a2V5d29yZD5Xb3JsZCBIZWFsdGg8L2tleXdvcmQ+PGtleXdvcmQ+

V09STERXSURFPC9rZXl3b3JkPjxrZXl3b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xMi8xNS8yMDEyPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkxPWkFOTzIwMTI8L2xhYmVsPjx1cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [13]. In developed countries the predominant risk factor for developing COPD is cigarette smoking and it now affects women as often as men, reflecting the equal prevalence of smoking. In low and middle income countries COPD is often seen in non-smokers and due to wood smoke (biomass) exposure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWx2aTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

Y051bT4xMDg2MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTRdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwODYyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5OTIiPjEwODYyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5TYWx2aSxTLlMuPC9hdXRob3I+PGF1dGhvcj5CYXJuZXMsUC5KLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlIGluIG5vbi1zbW9rZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNl

dC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5j

ZXQuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzMzLTc0MzwvcGFnZXM+PHZvbHVt

ZT4zNzQ8L3ZvbHVtZT48bnVtYmVyPjk2OTE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBp

biBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjM8L2tleXdvcmQ+PGtl

eXdvcmQ+QUlSPC9rZXl3b3JkPjxrZXl3b3JkPmFpciBwb2xsdXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hc3M8L2tleXdvcmQ+PGtleXdvcmQ+Q0hJ

TERIT09EPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05J

QyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+RGV2

ZWxvcGluZyBDb3VudHJpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5

d29yZD5EVVNUPC9rZXl3b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UE9TVVJFPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNUT1JT

PC9rZXl3b3JkPjxrZXl3b3JkPkdBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPmhpc3Rvcnk8L2tleXdv

cmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPklORkVDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+

TU9SQklESVRZPC9rZXl3b3JkPjxrZXl3b3JkPk1PUlRBTElUWTwva2V5d29yZD48a2V5d29yZD5u

b24tc21va2luZzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29y

ZD5PQ0NVUEFUSU9OQUw8L2tleXdvcmQ+PGtleXdvcmQ+b2NjdXBhdGlvbmFsIGV4cG9zdXJlPC9r

ZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBPTExVVElPTjwva2V5

d29yZD48a2V5d29yZD5QT1BVTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5

d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFDVDwva2V5d29yZD48a2V5d29yZD5yZXNwaXJh

dG9yeSB0cmFjdCBpbmZlY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlJldmlldzwva2V5d29yZD48

a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5

d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnRv

YmFjY288L2tleXdvcmQ+PGtleXdvcmQ+dHViZXJjdWxvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPldP

UkxEV0lERTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWIt

ZGF0ZXM+PGRhdGU+OC8yOS8yMDA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlNB

TFZJMjAwOUE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWx2aTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

Y051bT4xMDg2MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTRdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwODYyPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5OTIiPjEwODYyPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5TYWx2aSxTLlMuPC9hdXRob3I+PGF1dGhvcj5CYXJuZXMsUC5KLjwvYXV0aG9yPjwvYXV0aG9y

cz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlIGluIG5vbi1zbW9rZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkxhbmNl

dC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5j

ZXQuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NzMzLTc0MzwvcGFnZXM+PHZvbHVt

ZT4zNzQ8L3ZvbHVtZT48bnVtYmVyPjk2OTE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBp

biBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjM8L2tleXdvcmQ+PGtl

eXdvcmQ+QUlSPC9rZXl3b3JkPjxrZXl3b3JkPmFpciBwb2xsdXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21hc3M8L2tleXdvcmQ+PGtleXdvcmQ+Q0hJ

TERIT09EPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05J

QyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+RGV2

ZWxvcGluZyBDb3VudHJpZXM8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5

d29yZD5EVVNUPC9rZXl3b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UE9TVVJFPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNUT1JT

PC9rZXl3b3JkPjxrZXl3b3JkPkdBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPmhpc3Rvcnk8L2tleXdv

cmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPklORkVDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+

TU9SQklESVRZPC9rZXl3b3JkPjxrZXl3b3JkPk1PUlRBTElUWTwva2V5d29yZD48a2V5d29yZD5u

b24tc21va2luZzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29y

ZD5PQ0NVUEFUSU9OQUw8L2tleXdvcmQ+PGtleXdvcmQ+b2NjdXBhdGlvbmFsIGV4cG9zdXJlPC9r

ZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBPTExVVElPTjwva2V5

d29yZD48a2V5d29yZD5QT1BVTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5

d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFDVDwva2V5d29yZD48a2V5d29yZD5yZXNwaXJh

dG9yeSB0cmFjdCBpbmZlY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlJldmlldzwva2V5d29yZD48

a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlJpc2sgRmFjdG9yczwva2V5d29yZD48a2V5

d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnRv

YmFjY288L2tleXdvcmQ+PGtleXdvcmQ+dHViZXJjdWxvc2lzPC9rZXl3b3JkPjxrZXl3b3JkPldP

UkxEV0lERTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5PC95ZWFyPjxwdWIt

ZGF0ZXM+PGRhdGU+OC8yOS8yMDA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlNB

TFZJMjAwOUE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [14]. There are clearly different clinical phenotypes of COPD, with some patients having predominantly small airway disease, whereas others have mainly increased alveolar space and destruction (emphysema). Other differences include age of onset, rate of progression, frequency of exacerbations and the association with other diseases, such as chronic cardiovascular and metabolic diseases (comorbidities). Although attempts have been made to segregate COPD patients into different clusters based on clinical and radiological characteristics, but it has been difficult to identify these phenotypes in different populations and there has been no link to underlying disease mechanisms (endotypes) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXN0YWxkaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

PFJlY051bT4xMjc2MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTUsIDE2XTwvRGlzcGxheVRleHQ+

PHJlY29yZD48cmVjLW51bWJlcj4xMjc2MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGlt

ZXN0YW1wPSIxNDU5NDM0OTQ1Ij4xMjc2MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+Q2FzdGFsZGksIFAuIEouPC9hdXRob3I+PGF1dGhvcj5EeSwgSi48L2F1dGhvcj48

YXV0aG9yPlJvc3MsIEouPC9hdXRob3I+PGF1dGhvcj5DaGFuZywgWS48L2F1dGhvcj48YXV0aG9y

Pldhc2hrbywgRy4gUi48L2F1dGhvcj48YXV0aG9yPkN1cnJhbi1FdmVyZXR0LCBELjwvYXV0aG9y

PjxhdXRob3I+V2lsbGlhbXMsIEEuPC9hdXRob3I+PGF1dGhvcj5MeW5jaCwgRC4gQS48L2F1dGhv

cj48YXV0aG9yPk1ha2UsIEIuIEouPC9hdXRob3I+PGF1dGhvcj5DcmFwbywgSi4gRC48L2F1dGhv

cj48YXV0aG9yPkJvd2xlciwgUi4gUC48L2F1dGhvcj48YXV0aG9yPlJlZ2FuLCBFLiBBLjwvYXV0

aG9yPjxhdXRob3I+SG9rYW5zb24sIEouIEUuPC9hdXRob3I+PGF1dGhvcj5LaW5uZXksIEcuIEwu

PC9hdXRob3I+PGF1dGhvcj5IYW4sIE0uIEsuPC9hdXRob3I+PGF1dGhvcj5Tb2xlciwgWC48L2F1

dGhvcj48YXV0aG9yPlJhbXNkZWxsLCBKLiBXLjwvYXV0aG9yPjxhdXRob3I+QmFyciwgUi4gRy48

L2F1dGhvcj48YXV0aG9yPkZvcmVtYW4sIE0uPC9hdXRob3I+PGF1dGhvcj52YW4gQmVlaywgRS48

L2F1dGhvcj48YXV0aG9yPkNhc2FidXJpLCBSLjwvYXV0aG9yPjxhdXRob3I+Q3JpbmVyLCBHLiBK

LjwvYXV0aG9yPjxhdXRob3I+THV0eiwgUy4gTS48L2F1dGhvcj48YXV0aG9yPlJlbm5hcmQsIFMu

IEkuPC9hdXRob3I+PGF1dGhvcj5TYW50b3JpY28sIFMuPC9hdXRob3I+PGF1dGhvcj5TY2l1cmJh

LCBGLiBDLjwvYXV0aG9yPjxhdXRob3I+RGVNZW8sIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5IZXJz

aCwgQy4gUC48L2F1dGhvcj48YXV0aG9yPlNpbHZlcm1hbiwgRS4gSy48L2F1dGhvcj48YXV0aG9y

PkNobywgTS4gSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5DaGFubmluZyBEaXZpc2lvbiBvZiBOZXR3b3JrIE1lZGljaW5lLCBCcmlnaGFtIGFuZCBXb21l

biZhcG9zO3MgSG9zcGl0YWwsICwgQm9zdG9uLCBNYXNzYWNodXNldHRzLCBVU0EuPC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2x1c3RlciBhbmFseXNpcyBpbiB0aGUgQ09QREdlbmUgc3R1

ZHkgaWRlbnRpZmllcyBzdWJ0eXBlcyBvZiBzbW9rZXJzIHdpdGggZGlzdGluY3QgcGF0dGVybnMg

b2YgYWlyd2F5IGRpc2Vhc2UgYW5kIGVtcGh5c2VtYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5U

aG9yYXg8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRob3JheDwvYWx0LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L2FsdC1w

ZXJpb2RpY2FsPjxwYWdlcz40MTUtMjI8L3BhZ2VzPjx2b2x1bWU+Njk8L3ZvbHVtZT48bnVtYmVy

PjU8L251bWJlcj48ZWRpdGlvbj4yMDE0LzAyLzI1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5DbHVzdGVyIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5Gb2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qR2VuZXRpYyBQcmVkaXNw

b3NpdGlvbiB0byBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm9tZS1XaWRlIEFzc29jaWF0

aW9uIFN0dWR5LyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PlBoZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5QdWxtb25hcnkgRGlzZWFzZSwgQ2hyb25pYyBP

YnN0cnVjdGl2ZS9kaWFnbm9zaXMvKmdlbmV0aWNzL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5QdWxtb25hcnkgRW1waHlzZW1hL2RpYWdub3Npcy8qZ2VuZXRpY3MvcGh5c2lvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48

a2V5d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjxrZXl3b3JkPlNtb2tp

bmcvKmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5TcGlyb21ldHJ5PC9rZXl3b3Jk

PjxrZXl3b3JkPlRvbW9ncmFwaHksIFgtUmF5IENvbXB1dGVkPC9rZXl3b3JkPjxrZXl3b3JkPkNP

UEQgZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkVtcGh5c2VtYTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDA0MC02Mzc2PC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI0NTYzMTk0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0MDA0MzM4

PC9jdXN0b20yPjxjdXN0b202Pk5JSE1TNTczODQwPC9jdXN0b202PjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMTM2L3Rob3JheGpubC0yMDEzLTIwMzYwMTwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5CdXJnZWw8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNOdW0+MTE5MjA8L1JlY051bT48

cmVjb3JkPjxyZWMtbnVtYmVyPjExOTIwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1l

c3RhbXA9IjEzOTcxMzc0MTQiPjExOTIwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5CdXJnZWwsIFAuIFIuPC9hdXRob3I+PGF1dGhvcj5QYWlsbGFzc2V1ciwgSi4gTC48

L2F1dGhvcj48YXV0aG9yPkNhaWxsYXVkLCBELjwvYXV0aG9yPjxhdXRob3I+VGlsbGllLUxlYmxv

bmQsIEkuPC9hdXRob3I+PGF1dGhvcj5DaGFuZXosIFAuPC9hdXRob3I+PGF1dGhvcj5Fc2NhbWls

bGEsIFIuPC9hdXRob3I+PGF1dGhvcj5Db3VydC1Gb3J0dW5lLCBJLjwvYXV0aG9yPjxhdXRob3I+

UGVyZXosIFQuPC9hdXRob3I+PGF1dGhvcj5DYXJyZSwgUC48L2F1dGhvcj48YXV0aG9yPlJvY2hl

LCBOLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNlcnZp

Y2UgZGUgUG5ldW1vbG9naWUsIEhvcGl0YWwgQ29jaGluLCBBc3Npc3RhbmNlIFB1YmxpcXVlIEhv

cGl0YXV4IGRlIFBhcmlzLCAyNyBydWUgZHUgRmF1Ym91cmcgU3QgSmFjcXVlcywgNzU2NzkgUGFy

aXMgQ2VkZXggMTQsIEZyYW5jZS4gcGllcnJlLXJlZ2lzLmJ1cmdlbEBjY2guYXBocC5mcjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsaW5pY2FsIENPUEQgcGhlbm90eXBlczogYSBub3Zl

bCBhcHByb2FjaCB1c2luZyBwcmluY2lwYWwgY29tcG9uZW50IGFuZCBjbHVzdGVyIGFuYWx5c2Vz

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBSZXNwaXIgSjwvc2Vjb25kYXJ5LXRpdGxlPjxh

bHQtdGl0bGU+VGhlIEV1cm9wZWFuIHJlc3BpcmF0b3J5IGpvdXJuYWw8L2FsdC10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIgUmVzcGlyIEo8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz41MzEtOTwvcGFnZXM+PHZvbHVtZT4zNjwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMDEvMTY8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2x1c3RlciBBbmFseXNpczwva2V5d29yZD48a2V5d29y

ZD5Db21vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD5Dcm9zcy1TZWN0aW9uYWwgU3R1ZGllczwv

a2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UGhlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPlByaW5jaXBhbCBDb21wb25lbnQgQW5h

bHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1

Y3RpdmUvY2xhc3NpZmljYXRpb24vKmRpYWdub3Npcy8qdGhlcmFweTwva2V5d29yZD48a2V5d29y

ZD5QdWxtb25hcnkgTWVkaWNpbmUvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBE

ZXNpZ248L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRh

dGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5MDMtMTkzNjwv

aXNibj48YWNjZXNzaW9uLW51bT4yMDA3NTA0NTwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODMvMDkwMzE5MzYuMDAxNzUxMDk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUt

ZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRl

PjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXN0YWxkaTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

PFJlY051bT4xMjc2MTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTUsIDE2XTwvRGlzcGxheVRleHQ+

PHJlY29yZD48cmVjLW51bWJlcj4xMjc2MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGlt

ZXN0YW1wPSIxNDU5NDM0OTQ1Ij4xMjc2MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+Q2FzdGFsZGksIFAuIEouPC9hdXRob3I+PGF1dGhvcj5EeSwgSi48L2F1dGhvcj48

YXV0aG9yPlJvc3MsIEouPC9hdXRob3I+PGF1dGhvcj5DaGFuZywgWS48L2F1dGhvcj48YXV0aG9y

Pldhc2hrbywgRy4gUi48L2F1dGhvcj48YXV0aG9yPkN1cnJhbi1FdmVyZXR0LCBELjwvYXV0aG9y

PjxhdXRob3I+V2lsbGlhbXMsIEEuPC9hdXRob3I+PGF1dGhvcj5MeW5jaCwgRC4gQS48L2F1dGhv

cj48YXV0aG9yPk1ha2UsIEIuIEouPC9hdXRob3I+PGF1dGhvcj5DcmFwbywgSi4gRC48L2F1dGhv

cj48YXV0aG9yPkJvd2xlciwgUi4gUC48L2F1dGhvcj48YXV0aG9yPlJlZ2FuLCBFLiBBLjwvYXV0

aG9yPjxhdXRob3I+SG9rYW5zb24sIEouIEUuPC9hdXRob3I+PGF1dGhvcj5LaW5uZXksIEcuIEwu

PC9hdXRob3I+PGF1dGhvcj5IYW4sIE0uIEsuPC9hdXRob3I+PGF1dGhvcj5Tb2xlciwgWC48L2F1

dGhvcj48YXV0aG9yPlJhbXNkZWxsLCBKLiBXLjwvYXV0aG9yPjxhdXRob3I+QmFyciwgUi4gRy48

L2F1dGhvcj48YXV0aG9yPkZvcmVtYW4sIE0uPC9hdXRob3I+PGF1dGhvcj52YW4gQmVlaywgRS48

L2F1dGhvcj48YXV0aG9yPkNhc2FidXJpLCBSLjwvYXV0aG9yPjxhdXRob3I+Q3JpbmVyLCBHLiBK

LjwvYXV0aG9yPjxhdXRob3I+THV0eiwgUy4gTS48L2F1dGhvcj48YXV0aG9yPlJlbm5hcmQsIFMu

IEkuPC9hdXRob3I+PGF1dGhvcj5TYW50b3JpY28sIFMuPC9hdXRob3I+PGF1dGhvcj5TY2l1cmJh

LCBGLiBDLjwvYXV0aG9yPjxhdXRob3I+RGVNZW8sIEQuIEwuPC9hdXRob3I+PGF1dGhvcj5IZXJz

aCwgQy4gUC48L2F1dGhvcj48YXV0aG9yPlNpbHZlcm1hbiwgRS4gSy48L2F1dGhvcj48YXV0aG9y

PkNobywgTS4gSC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVz

cz5DaGFubmluZyBEaXZpc2lvbiBvZiBOZXR3b3JrIE1lZGljaW5lLCBCcmlnaGFtIGFuZCBXb21l

biZhcG9zO3MgSG9zcGl0YWwsICwgQm9zdG9uLCBNYXNzYWNodXNldHRzLCBVU0EuPC9hdXRoLWFk

ZHJlc3M+PHRpdGxlcz48dGl0bGU+Q2x1c3RlciBhbmFseXNpcyBpbiB0aGUgQ09QREdlbmUgc3R1

ZHkgaWRlbnRpZmllcyBzdWJ0eXBlcyBvZiBzbW9rZXJzIHdpdGggZGlzdGluY3QgcGF0dGVybnMg

b2YgYWlyd2F5IGRpc2Vhc2UgYW5kIGVtcGh5c2VtYTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5U

aG9yYXg8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRob3JheDwvYWx0LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L2FsdC1w

ZXJpb2RpY2FsPjxwYWdlcz40MTUtMjI8L3BhZ2VzPjx2b2x1bWU+Njk8L3ZvbHVtZT48bnVtYmVy

PjU8L251bWJlcj48ZWRpdGlvbj4yMDE0LzAyLzI1PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5DbHVzdGVyIEFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5

d29yZD5Gb2xsb3ctVXAgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qR2VuZXRpYyBQcmVkaXNw

b3NpdGlvbiB0byBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbm9tZS1XaWRlIEFzc29jaWF0

aW9uIFN0dWR5LyptZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5

d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PlBoZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5QdWxtb25hcnkgRGlzZWFzZSwgQ2hyb25pYyBP

YnN0cnVjdGl2ZS9kaWFnbm9zaXMvKmdlbmV0aWNzL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48

a2V5d29yZD5QdWxtb25hcnkgRW1waHlzZW1hL2RpYWdub3Npcy8qZ2VuZXRpY3MvcGh5c2lvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlJldHJvc3BlY3RpdmUgU3R1ZGllczwva2V5d29yZD48

a2V5d29yZD5TZXZlcml0eSBvZiBJbGxuZXNzIEluZGV4PC9rZXl3b3JkPjxrZXl3b3JkPlNtb2tp

bmcvKmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5TcGlyb21ldHJ5PC9rZXl3b3Jk

PjxrZXl3b3JkPlRvbW9ncmFwaHksIFgtUmF5IENvbXB1dGVkPC9rZXl3b3JkPjxrZXl3b3JkPkNP

UEQgZXBpZGVtaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkVtcGh5c2VtYTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWF5PC9kYXRl

PjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDA0MC02Mzc2PC9pc2JuPjxhY2Nlc3Npb24tbnVt

PjI0NTYzMTk0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0MDA0MzM4

PC9jdXN0b20yPjxjdXN0b202Pk5JSE1TNTczODQwPC9jdXN0b202PjxlbGVjdHJvbmljLXJlc291

cmNlLW51bT4xMC4xMTM2L3Rob3JheGpubC0yMDEzLTIwMzYwMTwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5CdXJnZWw8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNOdW0+MTE5MjA8L1JlY051bT48

cmVjb3JkPjxyZWMtbnVtYmVyPjExOTIwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1l

c3RhbXA9IjEzOTcxMzc0MTQiPjExOTIwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5CdXJnZWwsIFAuIFIuPC9hdXRob3I+PGF1dGhvcj5QYWlsbGFzc2V1ciwgSi4gTC48

L2F1dGhvcj48YXV0aG9yPkNhaWxsYXVkLCBELjwvYXV0aG9yPjxhdXRob3I+VGlsbGllLUxlYmxv

bmQsIEkuPC9hdXRob3I+PGF1dGhvcj5DaGFuZXosIFAuPC9hdXRob3I+PGF1dGhvcj5Fc2NhbWls

bGEsIFIuPC9hdXRob3I+PGF1dGhvcj5Db3VydC1Gb3J0dW5lLCBJLjwvYXV0aG9yPjxhdXRob3I+

UGVyZXosIFQuPC9hdXRob3I+PGF1dGhvcj5DYXJyZSwgUC48L2F1dGhvcj48YXV0aG9yPlJvY2hl

LCBOLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPlNlcnZp

Y2UgZGUgUG5ldW1vbG9naWUsIEhvcGl0YWwgQ29jaGluLCBBc3Npc3RhbmNlIFB1YmxpcXVlIEhv

cGl0YXV4IGRlIFBhcmlzLCAyNyBydWUgZHUgRmF1Ym91cmcgU3QgSmFjcXVlcywgNzU2NzkgUGFy

aXMgQ2VkZXggMTQsIEZyYW5jZS4gcGllcnJlLXJlZ2lzLmJ1cmdlbEBjY2guYXBocC5mcjwvYXV0

aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsaW5pY2FsIENPUEQgcGhlbm90eXBlczogYSBub3Zl

bCBhcHByb2FjaCB1c2luZyBwcmluY2lwYWwgY29tcG9uZW50IGFuZCBjbHVzdGVyIGFuYWx5c2Vz

PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBSZXNwaXIgSjwvc2Vjb25kYXJ5LXRpdGxlPjxh

bHQtdGl0bGU+VGhlIEV1cm9wZWFuIHJlc3BpcmF0b3J5IGpvdXJuYWw8L2FsdC10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIgUmVzcGlyIEo8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz41MzEtOTwvcGFnZXM+PHZvbHVtZT4zNjwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxlZGl0aW9uPjIwMTAvMDEvMTY8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2x1c3RlciBBbmFseXNpczwva2V5d29yZD48a2V5d29y

ZD5Db21vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD5Dcm9zcy1TZWN0aW9uYWwgU3R1ZGllczwv

a2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UGhlbm90eXBlPC9rZXl3b3JkPjxrZXl3b3JkPlByaW5jaXBhbCBDb21wb25lbnQgQW5h

bHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1

Y3RpdmUvY2xhc3NpZmljYXRpb24vKmRpYWdub3Npcy8qdGhlcmFweTwva2V5d29yZD48a2V5d29y

ZD5QdWxtb25hcnkgTWVkaWNpbmUvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBE

ZXNpZ248L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRh

dGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5MDMtMTkzNjwv

aXNibj48YWNjZXNzaW9uLW51bT4yMDA3NTA0NTwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+

PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODMvMDkwMzE5MzYuMDAxNzUxMDk8L2VsZWN0

cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUt

ZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRl

PjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [15, 16].Unlike asthma, the inflammation in COPD is predominantly localized to peripheral airways and lung parenchyma ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2016</Year><RecNum>12787</RecNum><DisplayText>[17]</DisplayText><record><rec-number>12787</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1461164910">12787</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, P.J.</author></authors></contributors><titles><title>Inflammatory mechanisms in COPD</title><secondary-title>J Allergy Clin Immunol</secondary-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>16-27</pages><volume>138</volume><number>1</number><dates><year>2016</year></dates><urls></urls></record></Cite></EndNote>[17] and is also associated with systemic inflammation ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2014</Year><RecNum>11886</RecNum><DisplayText>[18]</DisplayText><record><rec-number>11886</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1392812879">11886</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, P. J.</author></authors></contributors><auth-address>National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. Electronic address: p.j.barnes@imperial.ac.uk.</auth-address><titles><title>Cellular and Molecular Mechanisms of Chronic Obstructive Pulmonary Disease</title><secondary-title>Clin Chest Med</secondary-title><alt-title>Clinics in chest medicine</alt-title></titles><periodical><full-title>Clin Chest Med</full-title></periodical><pages>71-86</pages><volume>35</volume><number>1</number><edition>2014/02/11</edition><dates><year>2014</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0272-5231</isbn><accession-num>24507838</accession-num><urls></urls><electronic-resource-num>10.1016/m.2013.10.004</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[18]. In contrast to asthma, the predominant causes of airways obstruction are small airway narrowing due to fibrosis and collapse of peripheral airways due to loss of elasticity in the lung parenchyma, which leads to air trapping, which are irreversible mechanisms (Fig. 2). However, there is superimposed cholinergic contraction of small airways (“cholinergic tone”), which is reversible. Mucus hypersecretion may also contribute to airway obstruction as mucus occupies the airway lumen and tends to be retained because of ciliary dysfunction. The airway obstruction in COPD is usually progressive with accelerated decline in lung function over many years, whereas in asthma it does not usually progress. Even in mild disease there is obstruction and loss of peripheral airways PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0Rvbm91Z2g8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

PjxSZWNOdW0+MTE0NDE8L1JlY051bT48RGlzcGxheVRleHQ+WzE5XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMTQ0MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc5MDAxIj4xMTQ0MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+TWNEb25vdWdoLEouRS48L2F1dGhvcj48YXV0aG9yPll1YW4sUi48L2F1dGhvcj48YXV0

aG9yPlN1enVraSxNLjwvYXV0aG9yPjxhdXRob3I+U2V5ZWRuZWphZCxOLjwvYXV0aG9yPjxhdXRo

b3I+RWxsaW90dCxXLk0uPC9hdXRob3I+PGF1dGhvcj5TYW5jaGV6LFAuRy48L2F1dGhvcj48YXV0

aG9yPldyaWdodCxBLkMuPC9hdXRob3I+PGF1dGhvcj5HZWZ0ZXIsVy5CLjwvYXV0aG9yPjxhdXRo

b3I+TGl0emt5LEwuPC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+

UGFyZSxQLkQuPC9hdXRob3I+PGF1dGhvcj5TaW4sRC5ELjwvYXV0aG9yPjxhdXRob3I+UGllcmNl

LFIuQS48L2F1dGhvcj48YXV0aG9yPldvb2RzLEouQy48L2F1dGhvcj48YXV0aG9yPk1jV2lsbGlh

bXMsQS5NLjwvYXV0aG9yPjxhdXRob3I+TWF5byxKLlIuPC9hdXRob3I+PGF1dGhvcj5MYW0sUy5D

LjwvYXV0aG9yPjxhdXRob3I+Q29vcGVyLEouRC48L2F1dGhvcj48YXV0aG9yPkhvZ2csSi5DLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5TbWFsbC1haXJ3

YXkgb2JzdHJ1Y3Rpb24gYW5kIGVtcGh5c2VtYSBpbiBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4uRW5nbC5KIE1lZC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OLkVuZ2wuSiBNZWQu

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTU2Ny0xNTc1PC9wYWdlcz48dm9sdW1l

PjM2NTwvdm9sdW1lPjxudW1iZXI+MTc8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjE8L2tleXdvcmQ+PGtleXdv

cmQ+Mjwva2V5d29yZD48a2V5d29yZD4zPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29y

ZD48a2V5d29yZD5BaXJ3YXkgUmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9r

ZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPkJyb25jaGlvbGVzPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElW

RTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFIExVTkcgRElTRUFTRTwva2V5

d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPkNPTVBBUklTT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29y

ZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJTUVOU0lPTlM8L2tleXdvcmQ+PGtl

eXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FTVBIWVNFTUE8L2tleXdvcmQ+PGtleXdv

cmQ+Z2xvYmFsPC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8

L2tleXdvcmQ+PGtleXdvcmQ+SE9TUElUQUw8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+

PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklTT0xBVEVEPC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+bHVuZyB0cmFuc3BsYW50YXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdv

cmQ+TUVBU1VSRTwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0

aG9kczwva2V5d29yZD48a2V5d29yZD5OQVJST1dJTkc8L2tleXdvcmQ+PGtleXdvcmQ+TkFUSU9O

QUw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJV

Q1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBI

RVJBTDwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNF

RDwva2V5d29yZD48a2V5d29yZD5SRURVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05T

SElQPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0lTVEFO

Q0U8L2tleXdvcmQ+PGtleXdvcmQ+U0NBTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0lURVM8L2tleXdv

cmQ+PGtleXdvcmQ+U01BTEw8L2tleXdvcmQ+PGtleXdvcmQ+VE9NT0dSQVBIWTwva2V5d29yZD48

a2V5d29yZD5UUkFOU1BMQU5UQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+VmFuY291dmVyPC9rZXl3

b3JkPjxrZXl3b3JkPlZPTFVNRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEx

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTAvMjcvMjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxsYWJlbD5NQ0RPTk9VR0gyMDExPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0Rvbm91Z2g8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

PjxSZWNOdW0+MTE0NDE8L1JlY051bT48RGlzcGxheVRleHQ+WzE5XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMTQ0MTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc5MDAxIj4xMTQ0MTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+TWNEb25vdWdoLEouRS48L2F1dGhvcj48YXV0aG9yPll1YW4sUi48L2F1dGhvcj48YXV0

aG9yPlN1enVraSxNLjwvYXV0aG9yPjxhdXRob3I+U2V5ZWRuZWphZCxOLjwvYXV0aG9yPjxhdXRo

b3I+RWxsaW90dCxXLk0uPC9hdXRob3I+PGF1dGhvcj5TYW5jaGV6LFAuRy48L2F1dGhvcj48YXV0

aG9yPldyaWdodCxBLkMuPC9hdXRob3I+PGF1dGhvcj5HZWZ0ZXIsVy5CLjwvYXV0aG9yPjxhdXRo

b3I+TGl0emt5LEwuPC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+

UGFyZSxQLkQuPC9hdXRob3I+PGF1dGhvcj5TaW4sRC5ELjwvYXV0aG9yPjxhdXRob3I+UGllcmNl

LFIuQS48L2F1dGhvcj48YXV0aG9yPldvb2RzLEouQy48L2F1dGhvcj48YXV0aG9yPk1jV2lsbGlh

bXMsQS5NLjwvYXV0aG9yPjxhdXRob3I+TWF5byxKLlIuPC9hdXRob3I+PGF1dGhvcj5MYW0sUy5D

LjwvYXV0aG9yPjxhdXRob3I+Q29vcGVyLEouRC48L2F1dGhvcj48YXV0aG9yPkhvZ2csSi5DLjwv

YXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5TbWFsbC1haXJ3

YXkgb2JzdHJ1Y3Rpb24gYW5kIGVtcGh5c2VtYSBpbiBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4uRW5nbC5KIE1lZC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OLkVuZ2wuSiBNZWQu

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTU2Ny0xNTc1PC9wYWdlcz48dm9sdW1l

PjM2NTwvdm9sdW1lPjxudW1iZXI+MTc8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjE8L2tleXdvcmQ+PGtleXdv

cmQ+Mjwva2V5d29yZD48a2V5d29yZD4zPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29y

ZD48a2V5d29yZD5BaXJ3YXkgUmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9r

ZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPkJyb25jaGlvbGVzPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElW

RTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFIExVTkcgRElTRUFTRTwva2V5

d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPkNPTVBBUklTT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29y

ZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJTUVOU0lPTlM8L2tleXdvcmQ+PGtl

eXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FTVBIWVNFTUE8L2tleXdvcmQ+PGtleXdv

cmQ+Z2xvYmFsPC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8

L2tleXdvcmQ+PGtleXdvcmQ+SE9TUElUQUw8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+

PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklTT0xBVEVEPC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+bHVuZyB0cmFuc3BsYW50YXRpb248L2tleXdv

cmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdv

cmQ+TUVBU1VSRTwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0

aG9kczwva2V5d29yZD48a2V5d29yZD5OQVJST1dJTkc8L2tleXdvcmQ+PGtleXdvcmQ+TkFUSU9O

QUw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJV

Q1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBI

RVJBTDwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNF

RDwva2V5d29yZD48a2V5d29yZD5SRURVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05T

SElQPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0lTVEFO

Q0U8L2tleXdvcmQ+PGtleXdvcmQ+U0NBTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0lURVM8L2tleXdv

cmQ+PGtleXdvcmQ+U01BTEw8L2tleXdvcmQ+PGtleXdvcmQ+VE9NT0dSQVBIWTwva2V5d29yZD48

a2V5d29yZD5UUkFOU1BMQU5UQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+VmFuY291dmVyPC9rZXl3

b3JkPjxrZXl3b3JkPlZPTFVNRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEx

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTAvMjcvMjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxsYWJlbD5NQ0RPTk9VR0gyMDExPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [19] and serial computed tomography scans suggest that small airway obstruction usually precedes the development of emphysema PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxiYW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE3Mzc8L1JlY051bT48RGlzcGxheVRleHQ+WzIwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTczNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTczNzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+R2FsYmFuLEMuSi48L2F1dGhvcj48YXV0aG9yPkhhbixNLksuPC9hdXRob3I+PGF1dGhvcj5C

b2VzLEouTC48L2F1dGhvcj48YXV0aG9yPkNodWdodGFpLEsuQS48L2F1dGhvcj48YXV0aG9yPk1l

eWVyLEMuUi48L2F1dGhvcj48YXV0aG9yPkpvaG5zb24sVC5ELjwvYXV0aG9yPjxhdXRob3I+R2Fs

YmFuLFMuPC9hdXRob3I+PGF1dGhvcj5SZWhlbXR1bGxhLEEuPC9hdXRob3I+PGF1dGhvcj5LYXpl

cm9vbmksRS5BLjwvYXV0aG9yPjxhdXRob3I+TWFydGluZXosRi5KLjwvYXV0aG9yPjxhdXRob3I+

Um9zcyxCLkQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkNvbXB1dGVkIHRvbW9ncmFwaHktYmFzZWQgYmlvbWFya2VyIHByb3ZpZGVzIHVuaXF1ZSBzaWdu

YXR1cmUgZm9yIGRpYWdub3NpcyBvZiBDT1BEIHBoZW5vdHlwZXMgYW5kIGRpc2Vhc2UgcHJvZ3Jl

c3Npb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IE1lZC48L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQgTWVkLjwvZnVsbC10aXRsZT48L3Bl

cmlvZGljYWw+PHBhZ2VzPjE3MTEtMTcxNTwvcGFnZXM+PHZvbHVtZT4xODwvdm9sdW1lPjxudW1i

ZXI+MTE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdv

cmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmlj

IG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPmNsaW5pY2Fs

PC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+REVURUNUSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPkRJQUdOT1NJUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3Jk

PjxrZXl3b3JkPmRpc2Vhc2UgcHJvZ3Jlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RElTVFJJQlVU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVNUEhZU0VNQTwva2V5d29yZD48a2V5d29yZD5FVklERU5D

RTwva2V5d29yZD48a2V5d29yZD5GVU5DVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPklORElWSURV

QUxTPC9rZXl3b3JkPjxrZXl3b3JkPm1pY2hpZ2FuPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNU

SVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBIRU5PVFlQ

RTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8

L2tleXdvcmQ+PGtleXdvcmQ+U0VWRVJJVFk8L2tleXdvcmQ+PGtleXdvcmQ+U01BTEw8L2tleXdv

cmQ+PGtleXdvcmQ+U1BFQ0lGSUM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48

a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJUWVBFPC9rZXl3b3JkPjxrZXl3b3Jk

PnN1YnR5cGVzPC9rZXl3b3JkPjxrZXl3b3JkPlRPTU9HUkFQSFk8L2tleXdvcmQ+PGtleXdvcmQ+

VFJFQVRNRU5UPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4xMS8yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkdB

TEJBTjIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxiYW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE3Mzc8L1JlY051bT48RGlzcGxheVRleHQ+WzIwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTczNzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTczNzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+R2FsYmFuLEMuSi48L2F1dGhvcj48YXV0aG9yPkhhbixNLksuPC9hdXRob3I+PGF1dGhvcj5C

b2VzLEouTC48L2F1dGhvcj48YXV0aG9yPkNodWdodGFpLEsuQS48L2F1dGhvcj48YXV0aG9yPk1l

eWVyLEMuUi48L2F1dGhvcj48YXV0aG9yPkpvaG5zb24sVC5ELjwvYXV0aG9yPjxhdXRob3I+R2Fs

YmFuLFMuPC9hdXRob3I+PGF1dGhvcj5SZWhlbXR1bGxhLEEuPC9hdXRob3I+PGF1dGhvcj5LYXpl

cm9vbmksRS5BLjwvYXV0aG9yPjxhdXRob3I+TWFydGluZXosRi5KLjwvYXV0aG9yPjxhdXRob3I+

Um9zcyxCLkQuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkNvbXB1dGVkIHRvbW9ncmFwaHktYmFzZWQgYmlvbWFya2VyIHByb3ZpZGVzIHVuaXF1ZSBzaWdu

YXR1cmUgZm9yIGRpYWdub3NpcyBvZiBDT1BEIHBoZW5vdHlwZXMgYW5kIGRpc2Vhc2UgcHJvZ3Jl

c3Npb248L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IE1lZC48L3NlY29uZGFyeS10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQgTWVkLjwvZnVsbC10aXRsZT48L3Bl

cmlvZGljYWw+PHBhZ2VzPjE3MTEtMTcxNTwvcGFnZXM+PHZvbHVtZT4xODwvdm9sdW1lPjxudW1i

ZXI+MTE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9r

ZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdv

cmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmlj

IG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPmNsaW5pY2Fs

PC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+REVURUNUSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPkRJQUdOT1NJUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3Jk

PjxrZXl3b3JkPmRpc2Vhc2UgcHJvZ3Jlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RElTVFJJQlVU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVNUEhZU0VNQTwva2V5d29yZD48a2V5d29yZD5FVklERU5D

RTwva2V5d29yZD48a2V5d29yZD5GVU5DVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPklORElWSURV

QUxTPC9rZXl3b3JkPjxrZXl3b3JkPm1pY2hpZ2FuPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNU

SVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBIRU5PVFlQ

RTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8

L2tleXdvcmQ+PGtleXdvcmQ+U0VWRVJJVFk8L2tleXdvcmQ+PGtleXdvcmQ+U01BTEw8L2tleXdv

cmQ+PGtleXdvcmQ+U1BFQ0lGSUM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48

a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJUWVBFPC9rZXl3b3JkPjxrZXl3b3Jk

PnN1YnR5cGVzPC9rZXl3b3JkPjxrZXl3b3JkPlRPTU9HUkFQSFk8L2tleXdvcmQ+PGtleXdvcmQ+

VFJFQVRNRU5UPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4xMS8yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkdB

TEJBTjIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [20]. Longitudinal studies of COPD populations have demonstrated that only about 50% of patients with COPD have accelerated decline in lung function, and the others have a normal age-related decline but start from a lower value, which is likely to be due to impaired lung growth either prenatally or during childhood PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nZTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT4xMjQxOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMjFdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEyNDE5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjE0NDMwMDk2MjgiPjEyNDE5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5MYW5nZSwgUC48L2F1dGhvcj48YXV0aG9yPkNlbGxpLCBCLjwvYXV0aG9yPjxhdXRob3I+QWd1

c3RpLCBBLjwvYXV0aG9yPjxhdXRob3I+Qm9qZSBKZW5zZW4sIEcuPC9hdXRob3I+PGF1dGhvcj5E

aXZvLCBNLjwvYXV0aG9yPjxhdXRob3I+RmFuZXIsIFIuPC9hdXRob3I+PGF1dGhvcj5HdWVycmEs

IFMuPC9hdXRob3I+PGF1dGhvcj5NYXJvdHQsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW5l

eiwgRi4gRC48L2F1dGhvcj48YXV0aG9yPk1hcnRpbmV6LUNhbWJsb3IsIFAuPC9hdXRob3I+PGF1

dGhvcj5NZWVrLCBQLjwvYXV0aG9yPjxhdXRob3I+T3dlbiwgQy4gQS48L2F1dGhvcj48YXV0aG9y

PlBldGVyc2VuLCBILjwvYXV0aG9yPjxhdXRob3I+UGludG8tUGxhdGEsIFYuPC9hdXRob3I+PGF1

dGhvcj5TY2hub2hyLCBQLjwvYXV0aG9yPjxhdXRob3I+U29vZCwgQS48L2F1dGhvcj48YXV0aG9y

PlNvcmlhbm8sIEouIEIuPC9hdXRob3I+PGF1dGhvcj5UZXNmYWlnemksIFkuPC9hdXRob3I+PGF1

dGhvcj5WZXN0Ym8sIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RnJvbSB0aGUgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGgsIFNlY3Rpb24gb2YgU29j

aWFsIE1lZGljaW5lIChQLkwuKSwgUmVzcGlyYXRvcnkgU2VjdGlvbiwgSHZpZG92cmUgSG9zcGl0

YWwgKFAuTC4pLCBDb3BlbmhhZ2VuIENpdHkgSGVhcnQgU3R1ZHksIEZyZWRlcmlrc2JlcmcgSG9z

cGl0YWwgKFAuTC4sIEcuQi5KLiwgSi5MLk0uLCBQLlMuKSwgYW5kIHRoZSBEZXBhcnRtZW50IG9m

IFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHZW50b2Z0ZSBIb3NwaXRhbCAoSi5WLiksIENvcGVuaGFn

ZW4gVW5pdmVyc2l0eSwgQ29wZW5oYWdlbiwgYW5kIFVuaXZlcnNpdHkgb2YgU291dGhlcm4gRGVu

bWFyaywgT2RlbnNlIChHLkIuSi4pIC0gYWxsIGluIERlbm1hcms7IEJyaWdoYW0gYW5kIFdvbWVu

JmFwb3M7cyBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9zdG9uIChCLkMuLCBN

LkQuLCBDLkEuTy4sIFYuUC4tUC4pOyBTZXJ2ZWkgZGUgUG5ldW1vbG9naWEsIFRob3JheCBJbnN0

aXR1dGUsIEhvc3BpdGFsIENsaW5pYywgSW5zdGl0dXQgZCZhcG9zO0ludmVzdGlnYWNpb25zIEJp

b21lZGlxdWVzIEF1Z3VzdCBQaSBpIFN1bnllciwgVW5pdmVyc2l0eSBvZiBCYXJjZWxvbmEgKEEu

QS4pLCBhbmQgRnVuZGFjaW8gQ2xpbmljIHBlciBhIGxhIFJlY2VyY2EgQmlvbWVkaWNhIChSLkYu

KSAtIGJvdGggaW4gQmFyY2Vsb25hOyBDZW50cm8gZGUgSW52ZXN0aWdhY2lvbiBCaW9tZWRpY2Eg

ZW4gUmVkIGRlIEVuZmVybWVkYWRlcyBSZXNwaXJhdG9yaWFzIChBLkEuLCBSLkYuKSBhbmQgSW5z

dGl0dXRvIGRlIEludmVzdGlnYWNpb24gSG9zcGl0YWwgVW5pdmVyc2l0YXJpbyBkZSBsYSBQcmlu

Y2VzYSwgVW5pdmVyc2lkYWQgQXV0b25vbWEgZGUgTWFkcmlkIChVQU0pLCBDYXRlZHJhIFVBTS1M

aW5kZSAoSi5CLlMuKSAtIGJvdGggaW4gTWFkcmlkOyBBcml6b25hIFJlc3BpcmF0b3J5IENlbnRl

ciwgVW5pdmVyc2l0eSBvZiBBcml6b25hLCBUdWNzb24gKFMuRy4sIEYuRC5NLik7IFVuaXZlcnNp

ZGFkIEF1dG9ub21hIGRlIENoaWxlLCBTYW50aWFnbywgQ2hpbGUgKFAuTS4tQy4pOyBVbml2ZXJz

aXR5IG9mIENvbG9yYWRvLCBEZW52ZXIsIERlbnZlciAoUC5NLik7IExvdmVsYWNlIFJlc3BpcmF0

b3J5IFJlc2VhcmNoIEluc3RpdHV0ZSAoSC5QLiwgWS5ULikgYW5kIFVuaXZlcnNpdHkgb2YgTmV3

IE1leGljbyAoQS5TLikgLSBib3RoIGluIEFsYnVxdWVycXVlOyBhbmQgdGhlIFJlc3BpcmF0b3J5

IGFuZCBBbGxlcmd5IFJlc2VhcmNoIEdyb3VwLCBNYW5jaGVzdGVyIEFjYWRlbWljIEhlYWx0aCBT

Y2llbmNlIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBNYW5jaGVzdGVyLCBNYW5jaGVzdGVyLCBVbml0

ZWQgS2luZ2RvbSAoSi5WLikuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+THVuZy1mdW5j

dGlvbiB0cmFqZWN0b3JpZXMgbGVhZGluZyB0byBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFy

eSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2Fs

dC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTEtMjI8L3BhZ2VzPjx2b2x1bWU+MzczPC92

b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGVkaXRpb24+MjAxNS8wNy8xNTwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5

d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qRGlzZWFzZSBQcm9ncmVzc2lv

bjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+KkZvcmNlZCBFeHBp

cmF0b3J5IFZvbHVtZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QdWxt

b25hcnkgRGlzZWFzZSwgQ2hyb25pYyBPYnN0cnVjdGl2ZS9ldGlvbG9neS8qcGh5c2lvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlNtb2tpbmcvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwgOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjAwMjgtNDc5MzwvaXNibj48YWNjZXNzaW9uLW51bT4yNjE1NDc4NjwvYWNjZXNzaW9uLW51

bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTQx

MTUzMjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5O

TE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nZTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT4xMjQxOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMjFdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEyNDE5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjE0NDMwMDk2MjgiPjEyNDE5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5MYW5nZSwgUC48L2F1dGhvcj48YXV0aG9yPkNlbGxpLCBCLjwvYXV0aG9yPjxhdXRob3I+QWd1

c3RpLCBBLjwvYXV0aG9yPjxhdXRob3I+Qm9qZSBKZW5zZW4sIEcuPC9hdXRob3I+PGF1dGhvcj5E

aXZvLCBNLjwvYXV0aG9yPjxhdXRob3I+RmFuZXIsIFIuPC9hdXRob3I+PGF1dGhvcj5HdWVycmEs

IFMuPC9hdXRob3I+PGF1dGhvcj5NYXJvdHQsIEouIEwuPC9hdXRob3I+PGF1dGhvcj5NYXJ0aW5l

eiwgRi4gRC48L2F1dGhvcj48YXV0aG9yPk1hcnRpbmV6LUNhbWJsb3IsIFAuPC9hdXRob3I+PGF1

dGhvcj5NZWVrLCBQLjwvYXV0aG9yPjxhdXRob3I+T3dlbiwgQy4gQS48L2F1dGhvcj48YXV0aG9y

PlBldGVyc2VuLCBILjwvYXV0aG9yPjxhdXRob3I+UGludG8tUGxhdGEsIFYuPC9hdXRob3I+PGF1

dGhvcj5TY2hub2hyLCBQLjwvYXV0aG9yPjxhdXRob3I+U29vZCwgQS48L2F1dGhvcj48YXV0aG9y

PlNvcmlhbm8sIEouIEIuPC9hdXRob3I+PGF1dGhvcj5UZXNmYWlnemksIFkuPC9hdXRob3I+PGF1

dGhvcj5WZXN0Ym8sIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFk

ZHJlc3M+RnJvbSB0aGUgSW5zdGl0dXRlIG9mIFB1YmxpYyBIZWFsdGgsIFNlY3Rpb24gb2YgU29j

aWFsIE1lZGljaW5lIChQLkwuKSwgUmVzcGlyYXRvcnkgU2VjdGlvbiwgSHZpZG92cmUgSG9zcGl0

YWwgKFAuTC4pLCBDb3BlbmhhZ2VuIENpdHkgSGVhcnQgU3R1ZHksIEZyZWRlcmlrc2JlcmcgSG9z

cGl0YWwgKFAuTC4sIEcuQi5KLiwgSi5MLk0uLCBQLlMuKSwgYW5kIHRoZSBEZXBhcnRtZW50IG9m

IFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHZW50b2Z0ZSBIb3NwaXRhbCAoSi5WLiksIENvcGVuaGFn

ZW4gVW5pdmVyc2l0eSwgQ29wZW5oYWdlbiwgYW5kIFVuaXZlcnNpdHkgb2YgU291dGhlcm4gRGVu

bWFyaywgT2RlbnNlIChHLkIuSi4pIC0gYWxsIGluIERlbm1hcms7IEJyaWdoYW0gYW5kIFdvbWVu

JmFwb3M7cyBIb3NwaXRhbCwgSGFydmFyZCBNZWRpY2FsIFNjaG9vbCwgQm9zdG9uIChCLkMuLCBN

LkQuLCBDLkEuTy4sIFYuUC4tUC4pOyBTZXJ2ZWkgZGUgUG5ldW1vbG9naWEsIFRob3JheCBJbnN0

aXR1dGUsIEhvc3BpdGFsIENsaW5pYywgSW5zdGl0dXQgZCZhcG9zO0ludmVzdGlnYWNpb25zIEJp

b21lZGlxdWVzIEF1Z3VzdCBQaSBpIFN1bnllciwgVW5pdmVyc2l0eSBvZiBCYXJjZWxvbmEgKEEu

QS4pLCBhbmQgRnVuZGFjaW8gQ2xpbmljIHBlciBhIGxhIFJlY2VyY2EgQmlvbWVkaWNhIChSLkYu

KSAtIGJvdGggaW4gQmFyY2Vsb25hOyBDZW50cm8gZGUgSW52ZXN0aWdhY2lvbiBCaW9tZWRpY2Eg

ZW4gUmVkIGRlIEVuZmVybWVkYWRlcyBSZXNwaXJhdG9yaWFzIChBLkEuLCBSLkYuKSBhbmQgSW5z

dGl0dXRvIGRlIEludmVzdGlnYWNpb24gSG9zcGl0YWwgVW5pdmVyc2l0YXJpbyBkZSBsYSBQcmlu

Y2VzYSwgVW5pdmVyc2lkYWQgQXV0b25vbWEgZGUgTWFkcmlkIChVQU0pLCBDYXRlZHJhIFVBTS1M

aW5kZSAoSi5CLlMuKSAtIGJvdGggaW4gTWFkcmlkOyBBcml6b25hIFJlc3BpcmF0b3J5IENlbnRl

ciwgVW5pdmVyc2l0eSBvZiBBcml6b25hLCBUdWNzb24gKFMuRy4sIEYuRC5NLik7IFVuaXZlcnNp

ZGFkIEF1dG9ub21hIGRlIENoaWxlLCBTYW50aWFnbywgQ2hpbGUgKFAuTS4tQy4pOyBVbml2ZXJz

aXR5IG9mIENvbG9yYWRvLCBEZW52ZXIsIERlbnZlciAoUC5NLik7IExvdmVsYWNlIFJlc3BpcmF0

b3J5IFJlc2VhcmNoIEluc3RpdHV0ZSAoSC5QLiwgWS5ULikgYW5kIFVuaXZlcnNpdHkgb2YgTmV3

IE1leGljbyAoQS5TLikgLSBib3RoIGluIEFsYnVxdWVycXVlOyBhbmQgdGhlIFJlc3BpcmF0b3J5

IGFuZCBBbGxlcmd5IFJlc2VhcmNoIEdyb3VwLCBNYW5jaGVzdGVyIEFjYWRlbWljIEhlYWx0aCBT

Y2llbmNlIENlbnRyZSwgVW5pdmVyc2l0eSBvZiBNYW5jaGVzdGVyLCBNYW5jaGVzdGVyLCBVbml0

ZWQgS2luZ2RvbSAoSi5WLikuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+THVuZy1mdW5j

dGlvbiB0cmFqZWN0b3JpZXMgbGVhZGluZyB0byBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFy

eSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8L2Fs

dC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTEtMjI8L3BhZ2VzPjx2b2x1bWU+MzczPC92

b2x1bWU+PG51bWJlcj4yPC9udW1iZXI+PGVkaXRpb24+MjAxNS8wNy8xNTwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5

d29yZD5Db2hvcnQgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD4qRGlzZWFzZSBQcm9ncmVzc2lv

bjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+KkZvcmNlZCBFeHBp

cmF0b3J5IFZvbHVtZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+

TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QdWxt

b25hcnkgRGlzZWFzZSwgQ2hyb25pYyBPYnN0cnVjdGl2ZS9ldGlvbG9neS8qcGh5c2lvcGF0aG9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPlNtb2tpbmcvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPllvdW5nIEFkdWx0PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWwgOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxp

c2JuPjAwMjgtNDc5MzwvaXNibj48YWNjZXNzaW9uLW51bT4yNjE1NDc4NjwvYWNjZXNzaW9uLW51

bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTQx

MTUzMjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5O

TE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3Jl

Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [21]. This suggests that in some patients with COPD the disease starts in early life ADDIN EN.CITE <EndNote><Cite><Author>Martinez</Author><Year>2016</Year><RecNum>12915</RecNum><DisplayText>[22]</DisplayText><record><rec-number>12915</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1480423602">12915</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez, F. D.</author></authors></contributors><auth-address>From the Asthma and Airway Disease Research Center, University of Arizona, Tucson.</auth-address><titles><title>Early-life origins of chronic obstructive pulmonary disease</title><secondary-title>N Engl J Med</secondary-title><alt-title>The New England journal of medicine</alt-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>871-8</pages><volume>375</volume><number>9</number><edition>2016/09/01</edition><keywords><keyword>Adolescent</keyword><keyword>Age of Onset</keyword><keyword>Air Pollution/adverse effects</keyword><keyword>Asthma/complications</keyword><keyword>Bronchopulmonary Dysplasia/complications</keyword><keyword>Child</keyword><keyword>Female</keyword><keyword>Forced Expiratory Volume</keyword><keyword>Humans</keyword><keyword>Infant, Premature</keyword><keyword>Lung/physiology</keyword><keyword>Pneumonia/complications</keyword><keyword>Pregnancy</keyword><keyword>Prenatal Exposure Delayed Effects</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*etiology/genetics/physiopathology</keyword><keyword>Respiratory Mechanics/*genetics</keyword><keyword>Smoking/adverse effects</keyword></keywords><dates><year>2016</year><pub-dates><date>Sep 1</date></pub-dates></dates><isbn>0028-4793</isbn><accession-num>27579637</accession-num><urls></urls><electronic-resource-num>10.1056/NEJMra1603287</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[22].In COPD there is an increase in neutrophils and macrophages in the airway lumen and greater numbers of macrophages, T-lymphocytes and B-lymphocytes in the airway wall and parenchyma QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\0ACOSIO2009A)Cosio, Saetta, et al. 2009 COSIO2009A /id\00)\00 QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\0DBRUSSELLE2011.Brusselle, Joos, et al. 2011 BRUSSELLE2011 /id\00.\00 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

ZWNOdW0+MTAwNTA8L1JlY051bT48RGlzcGxheVRleHQ+WzIzLTI1XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDA1MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTc5Ij4xMDA1MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+SW1tdW5vbG9neSBvZiBhc3RobWEgYW5kIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVs

bW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IEltbXVub2wgUmV2PC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IEltbXVu

b2wgUmV2PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTgzLTE5MjwvcGFnZXM+PHZv

bHVtZT44PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGht

YTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JT

VFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkg

ZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5Q

VUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwODwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5CQVJORVMyMDA4PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QnJ1c3NlbGxlPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh

cj48UmVjTnVtPjExNDQwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTQ0MDwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZy

cDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxMzc4NDc5MDAxIj4xMTQ0MDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnJ1c3NlbGxlLEcuRy48L2F1dGhvcj48

YXV0aG9yPkpvb3MsRy5GLjwvYXV0aG9yPjxhdXRob3I+QnJhY2tlLEsuUi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmV3IGluc2lnaHRzIGludG8gdGhl

IGltbXVub2xvZ3kgb2YgY2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjEwMTUtMTAyNjwvcGFnZXM+PHZvbHVtZT4zNzg8L3ZvbHVtZT48bnVtYmVyPjk3OTU8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFCTk9STUFMPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWQVRFRDwva2V5d29y

ZD48a2V5d29yZD5BQ1RJVkFURVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNVVEU8L2tleXdvcmQ+PGtl

eXdvcmQ+QWRhcHRpdmUgSW1tdW5pdHk8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5BVVRPQU5USUJPRElFUzwva2V5d29yZD48a2V5d29yZD5hdXRvaW1tdW5lIGRp

c2Vhc2VzPC9rZXl3b3JkPjxrZXl3b3JkPkF1dG9pbW11bml0eTwva2V5d29yZD48a2V5d29yZD5C

LUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Yi1seW1waG9jeXRlczwva2V5d29yZD48a2V5d29yZD5C

YWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5CZWxnaXVtPC9rZXl3b3JkPjxr

ZXl3b3JkPkNENCs8L2tleXdvcmQ+PGtleXdvcmQ+Q0Q4Kzwva2V5d29yZD48a2V5d29yZD5DRUxM

PC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPmNlc3NhdGlvbjwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRF

IFNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+

Q09QRDwva2V5d29yZD48a2V5d29yZD5DeXRvdG94aWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+REVG

RU5DRTwva2V5d29yZD48a2V5d29yZD5ERU5EUklUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVuZHJp

dGljIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkRFVkVMT1BNRU5UPC9rZXl3b3JkPjxrZXl3b3Jk

PkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RFlTUkVHVUxBVElPTjwva2V5d29yZD48a2V5d29y

ZD5FUElUSEVMSUFMPC9rZXl3b3JkPjxrZXl3b3JkPmVwaXRoZWxpYWwgY2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+RVhUUkFDRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5HQVNFUzwva2V5

d29yZD48a2V5d29yZD5IT1NQSVRBTDwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+

PGtleXdvcmQ+SFlQT1hJQTwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+PGtleXdv

cmQ+SW1tdW5pdHksSW5uYXRlPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+

PGtleXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+

SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklORkVDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+

aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5

d29yZD5MZWFkPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9Q

SEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRURJ

Q0lORTwva2V5d29yZD48a2V5d29yZD5NaWNyb1JOQXM8L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNV

TEFSPC9rZXl3b3JkPjxrZXl3b3JkPk5FVzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwv

a2V5d29yZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0

cmVzczwva2V5d29yZD48a2V5d29yZD5QQVJUSUNMRVM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUVEVS

TlM8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFy

eSBEaXNlYXNlLENocm9uaWMgT2JzdHJ1Y3RpdmU8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8

L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlJFQ09HTklUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPlJFTEVBU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVTUElSQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+cmVzcGlyYXRvcnkg

dHJhY3QgaW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5

d29yZD5SRVNQT05TRVM8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5d29yZD48a2V5d29yZD5T

TU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnNtb2tpbmcg

Y2Vzc2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29yZD48a2V5d29yZD5zdHJl

c3M8L2tleXdvcmQ+PGtleXdvcmQ+U1lORFJPTUU8L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29y

ZD48a2V5d29yZD5UIENFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29yZD48a2V5

d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VGgxNzwva2V5d29yZD48a2V5d29yZD50aGVy

YXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRSSUdHRVJJTkc8L2tleXdvcmQ+PGtleXdvcmQ+VklSQUw8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjkvMTAvMjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CUlVTU0VMTEUy

MDExPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+SG9n

ZzwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJlY051bT44ODM1PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj44ODM1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NTkiPjg4MzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhv

Z2csSi5DLjwvYXV0aG9yPjxhdXRob3I+Q2h1LEYuPC9hdXRob3I+PGF1dGhvcj5VdG9rYXBhcmNo

LFMuPC9hdXRob3I+PGF1dGhvcj5Xb29kcyxSLjwvYXV0aG9yPjxhdXRob3I+RWxsaW90dCxXLk0u

PC9hdXRob3I+PGF1dGhvcj5CdXphdHUsTC48L2F1dGhvcj48YXV0aG9yPkNoZXJuaWFjayxSLk0u

PC9hdXRob3I+PGF1dGhvcj5Sb2dlcnMsUi5NLjwvYXV0aG9yPjxhdXRob3I+U2NpdXJiYSxGLkMu

PC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+UGFyZSxQLkQuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBuYXR1cmUg

b2Ygc21hbGwtYWlyd2F5IG9ic3RydWN0aW9uIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9u

YXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TiBFbmdsIEogTWVkPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjY0NS0yNjUzPC9wYWdlcz48dm9sdW1lPjM1

MDwvdm9sdW1lPjxudW1iZXI+MjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdvcmQ+

MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPjM8L2tleXdvcmQ+PGtleXdv

cmQ+QUNDVU1VTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48a2V5d29yZD5CLUNFTEw8L2tleXdvcmQ+PGtleXdv

cmQ+Q0Q0PC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q0hBTkdFUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3Jk

PjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBP

QlNUUlVDVElWRSBMVU5HIERJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGFzc2lmaWNhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPVVBMRUQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdv

cmQ+RUZGRUNUUzwva2V5d29yZD48a2V5d29yZD5FVk9MVVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

RVhQT1NVUkU8L2tleXdvcmQ+PGtleXdvcmQ+RVhVREFURVM8L2tleXdvcmQ+PGtleXdvcmQ+R0FT

RVM8L2tleXdvcmQ+PGtleXdvcmQ+Z2xvYmFsPC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdv

cmQ+PGtleXdvcmQ+SEVBTFRIPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVORTwva2V5d29yZD48a2V5

d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5JTkNS

RUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmlu

ZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5MT05HIFRFUk08L2tleXdvcmQ+PGtleXdvcmQ+

TE9ORy1URVJNPC9rZXl3b3JkPjxrZXl3b3JkPkxVTUVOPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8

L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdl

czwva2V5d29yZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NVUNPVVM8L2tleXdvcmQ+PGtl

eXdvcmQ+bmV1dHJvcGhpbDwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElPTjwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5QQVJUSUNMRVM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+

PGtleXdvcmQ+UE9MWU1PUlBIT05VQ0xFQVI8L2tleXdvcmQ+PGtleXdvcmQ+UFJPQkxFTTwva2V5

d29yZD48a2V5d29yZD5QdWJsaWMgSGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwv

a2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48

a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5USVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+

Vk9MVU1FPC9rZXl3b3JkPjxrZXl3b3JkPldBTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjQvMjAwNDwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5IT0dHMjAwNDwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

ZWNOdW0+MTAwNTA8L1JlY051bT48RGlzcGxheVRleHQ+WzIzLTI1XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDA1MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTc5Ij4xMDA1MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+SW1tdW5vbG9neSBvZiBhc3RobWEgYW5kIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVs

bW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IEltbXVub2wgUmV2PC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IEltbXVu

b2wgUmV2PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTgzLTE5MjwvcGFnZXM+PHZv

bHVtZT44PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGht

YTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JT

VFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkg

ZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5Q

VUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwODwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5CQVJORVMyMDA4PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNv

cmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QnJ1c3NlbGxlPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh

cj48UmVjTnVtPjExNDQwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTQ0MDwvcmVjLW51

bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZy

cDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxMzc4NDc5MDAxIj4xMTQ0MDwva2V5Pjwv

Zm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlw

ZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QnJ1c3NlbGxlLEcuRy48L2F1dGhvcj48

YXV0aG9yPkpvb3MsRy5GLjwvYXV0aG9yPjxhdXRob3I+QnJhY2tlLEsuUi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmV3IGluc2lnaHRzIGludG8gdGhl

IGltbXVub2xvZ3kgb2YgY2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5MYW5jZXQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+TGFuY2V0LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBh

Z2VzPjEwMTUtMTAyNjwvcGFnZXM+PHZvbHVtZT4zNzg8L3ZvbHVtZT48bnVtYmVyPjk3OTU8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFCTk9STUFMPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWQVRFRDwva2V5d29y

ZD48a2V5d29yZD5BQ1RJVkFURVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNVVEU8L2tleXdvcmQ+PGtl

eXdvcmQ+QWRhcHRpdmUgSW1tdW5pdHk8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5BVVRPQU5USUJPRElFUzwva2V5d29yZD48a2V5d29yZD5hdXRvaW1tdW5lIGRp

c2Vhc2VzPC9rZXl3b3JkPjxrZXl3b3JkPkF1dG9pbW11bml0eTwva2V5d29yZD48a2V5d29yZD5C

LUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Yi1seW1waG9jeXRlczwva2V5d29yZD48a2V5d29yZD5C

YWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5CZWxnaXVtPC9rZXl3b3JkPjxr

ZXl3b3JkPkNENCs8L2tleXdvcmQ+PGtleXdvcmQ+Q0Q4Kzwva2V5d29yZD48a2V5d29yZD5DRUxM

PC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPmNlc3NhdGlvbjwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRF

IFNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPmNvbXBsaWNhdGlvbnM8L2tleXdvcmQ+PGtleXdvcmQ+

Q09QRDwva2V5d29yZD48a2V5d29yZD5DeXRvdG94aWNpdHk8L2tleXdvcmQ+PGtleXdvcmQ+REVG

RU5DRTwva2V5d29yZD48a2V5d29yZD5ERU5EUklUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVuZHJp

dGljIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkRFVkVMT1BNRU5UPC9rZXl3b3JkPjxrZXl3b3Jk

PkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RFlTUkVHVUxBVElPTjwva2V5d29yZD48a2V5d29y

ZD5FUElUSEVMSUFMPC9rZXl3b3JkPjxrZXl3b3JkPmVwaXRoZWxpYWwgY2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+RVhUUkFDRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5HQVNFUzwva2V5

d29yZD48a2V5d29yZD5IT1NQSVRBTDwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+

PGtleXdvcmQ+SFlQT1hJQTwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+PGtleXdv

cmQ+SW1tdW5pdHksSW5uYXRlPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+

PGtleXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+

SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklORkVDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+

aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5

d29yZD5MZWFkPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9Q

SEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRURJ

Q0lORTwva2V5d29yZD48a2V5d29yZD5NaWNyb1JOQXM8L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNV

TEFSPC9rZXl3b3JkPjxrZXl3b3JkPk5FVzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwv

a2V5d29yZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0

cmVzczwva2V5d29yZD48a2V5d29yZD5QQVJUSUNMRVM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUVEVS

TlM8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFy

eSBEaXNlYXNlLENocm9uaWMgT2JzdHJ1Y3RpdmU8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8

L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlJFQ09HTklUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPlJFTEVBU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVTUElSQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+cmVzcGlyYXRvcnkg

dHJhY3QgaW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5

d29yZD5SRVNQT05TRVM8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5d29yZD48a2V5d29yZD5T

TU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnNtb2tpbmcg

Y2Vzc2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29yZD48a2V5d29yZD5zdHJl

c3M8L2tleXdvcmQ+PGtleXdvcmQ+U1lORFJPTUU8L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29y

ZD48a2V5d29yZD5UIENFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29yZD48a2V5

d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VGgxNzwva2V5d29yZD48a2V5d29yZD50aGVy

YXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRSSUdHRVJJTkc8L2tleXdvcmQ+PGtleXdvcmQ+VklSQUw8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjkvMTAvMjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CUlVTU0VMTEUy

MDExPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+SG9n

ZzwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJlY051bT44ODM1PC9SZWNOdW0+PHJlY29yZD48

cmVjLW51bWJlcj44ODM1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NTkiPjg4MzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhv

Z2csSi5DLjwvYXV0aG9yPjxhdXRob3I+Q2h1LEYuPC9hdXRob3I+PGF1dGhvcj5VdG9rYXBhcmNo

LFMuPC9hdXRob3I+PGF1dGhvcj5Xb29kcyxSLjwvYXV0aG9yPjxhdXRob3I+RWxsaW90dCxXLk0u

PC9hdXRob3I+PGF1dGhvcj5CdXphdHUsTC48L2F1dGhvcj48YXV0aG9yPkNoZXJuaWFjayxSLk0u

PC9hdXRob3I+PGF1dGhvcj5Sb2dlcnMsUi5NLjwvYXV0aG9yPjxhdXRob3I+U2NpdXJiYSxGLkMu

PC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+UGFyZSxQLkQuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBuYXR1cmUg

b2Ygc21hbGwtYWlyd2F5IG9ic3RydWN0aW9uIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9u

YXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TiBFbmdsIEogTWVkPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjY0NS0yNjUzPC9wYWdlcz48dm9sdW1lPjM1

MDwvdm9sdW1lPjxudW1iZXI+MjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdvcmQ+

MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPjM8L2tleXdvcmQ+PGtleXdv

cmQ+QUNDVU1VTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48a2V5d29yZD5CLUNFTEw8L2tleXdvcmQ+PGtleXdv

cmQ+Q0Q0PC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q0hBTkdFUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3Jk

PjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBP

QlNUUlVDVElWRSBMVU5HIERJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGFzc2lmaWNhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPVVBMRUQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdv

cmQ+RUZGRUNUUzwva2V5d29yZD48a2V5d29yZD5FVk9MVVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

RVhQT1NVUkU8L2tleXdvcmQ+PGtleXdvcmQ+RVhVREFURVM8L2tleXdvcmQ+PGtleXdvcmQ+R0FT

RVM8L2tleXdvcmQ+PGtleXdvcmQ+Z2xvYmFsPC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdv

cmQ+PGtleXdvcmQ+SEVBTFRIPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVORTwva2V5d29yZD48a2V5

d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5JTkNS

RUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmlu

ZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5MT05HIFRFUk08L2tleXdvcmQ+PGtleXdvcmQ+

TE9ORy1URVJNPC9rZXl3b3JkPjxrZXl3b3JkPkxVTUVOPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8

L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdl

czwva2V5d29yZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NVUNPVVM8L2tleXdvcmQ+PGtl

eXdvcmQ+bmV1dHJvcGhpbDwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElPTjwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5QQVJUSUNMRVM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+

PGtleXdvcmQ+UE9MWU1PUlBIT05VQ0xFQVI8L2tleXdvcmQ+PGtleXdvcmQ+UFJPQkxFTTwva2V5

d29yZD48a2V5d29yZD5QdWJsaWMgSGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwv

a2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48

a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5USVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+

Vk9MVU1FPC9rZXl3b3JkPjxrZXl3b3JkPldBTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjQvMjAwNDwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5IT0dHMjAwNDwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [23-25]. The inflammatory response in COPD involves both innate and adaptive immune responses, linked through the activation of dendritic cells ADDIN EN.CITE <EndNote><Cite><Author>Givi</Author><Year>2012</Year><RecNum>12764</RecNum><DisplayText>[26]</DisplayText><record><rec-number>12764</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1459445364">12764</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Givi, M. E.</author><author>Redegeld, F. A.</author><author>Folkerts, G.</author><author>Mortaz, E.</author></authors></contributors><auth-address>Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.</auth-address><titles><title>Dendritic cells in pathogenesis of COPD</title><secondary-title>Curr Pharm Des</secondary-title><alt-title>Current pharmaceutical design</alt-title></titles><periodical><full-title>Curr Pharm Des</full-title><abbr-1>Current pharmaceutical design</abbr-1></periodical><alt-periodical><full-title>Curr Pharm Des</full-title><abbr-1>Current pharmaceutical design</abbr-1></alt-periodical><pages>2329-35</pages><volume>18</volume><number>16</number><edition>2012/03/07</edition><keywords><keyword>Dendritic Cells/*immunology</keyword><keyword>Emphysema/immunology</keyword><keyword>Humans</keyword><keyword>Inflammation/immunology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*immunology</keyword></keywords><dates><year>2012</year></dates><isbn>1381-6128</isbn><accession-num>22390696</accession-num><urls></urls><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[26]. A similar pattern of inflammation is found in smokers without airflow limitation, but is amplified in COPD through mechanisms not yet fully determined.INFLAMMATORY CELLS Many inflammatory cells are recruited from the blood into the lungs in asthma and COPD under the direction of locally released chemotactic factors. Structural cells in the lungs, including epithelial cells, endothelial cells and fibroblasts, also release inflammatory mediators and actively participate in the inflammatory process. In both asthma and COPD the inflammatory response involves innate immunity (eosinophils, neutrophils, macrophages, mast cells, natural killer cells, γ-T-cells, innate lymphoid cells and dendritic cells) and adaptive immunity (T- and B-lymphocytes).Mast cellsMast cells are key effector cells in asthma through their release of multiple bronchoconstrictor mediators, such as histamine, cysteinyl-leukotrienes (Cys-LT) and prostaglandin(PG)-D2 ADDIN EN.CITE <EndNote><Cite><Author>Arthur</Author><Year>2016</Year><RecNum>12927</RecNum><DisplayText>[27]</DisplayText><record><rec-number>12927</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482417979">12927</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Arthur, G.</author><author>Bradding, P.</author></authors></contributors><auth-address>Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, England.&#xD;Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, England. Electronic address: pb46@le.ac.uk.</auth-address><titles><title>New developments in mast cell biology: clinical Implications</title><secondary-title>Chest</secondary-title><alt-title>Chest</alt-title></titles><periodical><full-title>Chest</full-title></periodical><alt-periodical><full-title>Chest</full-title></alt-periodical><pages>680-93</pages><volume>150</volume><number>3</number><edition>2016/06/19</edition><keywords><keyword>Copd</keyword><keyword>asthma</keyword><keyword>pulmonary fibrosis</keyword><keyword>pulmonary hypertension</keyword></keywords><dates><year>2016</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0012-3692</isbn><accession-num>27316557</accession-num><urls></urls><electronic-resource-num>10.1016/j.chest.2016.06.009</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[27]. In allergic asthma mast cells are sensitized by binding of IgE to surface high affinity IgE-receptors (FcεR1) so that they can be triggered by allergens, which cross-link IgE receptors, or by changes in osmolality, for example after the hyperventilation of exercise PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxsaTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTcxNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMjhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjExNzE0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0NzkwMDUiPjExNzE0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5HYWxsaSxTLkouPC9hdXRob3I+PGF1dGhvcj5Uc2FpLE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPklnRSBhbmQgbWFzdCBjZWxscyBpbiBhbGxlcmdp

YyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBNZWQuPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IE1lZC48L2Z1bGwtdGl0bGU+

PC9wZXJpb2RpY2FsPjxwYWdlcz42OTMtNzA0PC9wYWdlcz48dm9sdW1lPjE4PC92b2x1bWU+PG51

bWJlcj41PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+QUNUSU9OUzwv

a2V5d29yZD48a2V5d29yZD5BQ1VURTwva2V5d29yZD48a2V5d29yZD5BTExFUkdFTlM8L2tleXdv

cmQ+PGtleXdvcmQ+QUxMRVJHSUM8L2tleXdvcmQ+PGtleXdvcmQ+QW5hcGh5bGF4aXM8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BTlRJQk9ESUVTPC9rZXl3b3Jk

PjxrZXl3b3JkPkFOVElCT0RZPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5

d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIQU5H

RVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DT01QTEVYRVM8

L2tleXdvcmQ+PGtleXdvcmQ+ZGlmZmljdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tl

eXdvcmQ+PGtleXdvcmQ+RElTT1JERVJTPC9rZXl3b3JkPjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPkZVTkNUSU9OUzwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtl

eXdvcmQ+SFlQRVJTRU5TSVRJVklUWTwva2V5d29yZD48a2V5d29yZD5JZ0U8L2tleXdvcmQ+PGtl

eXdvcmQ+SUdFLURFUEVOREVOVDwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+PGtl

eXdvcmQ+SU1NVU5PR0xPQlVMSU48L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PR0xPQlVMSU4gRTwv

a2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3Jk

PjxrZXl3b3JkPklOREVQRU5ERU5UPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5

d29yZD48a2V5d29yZD5MQVJHRTwva2V5d29yZD48a2V5d29yZD5MT05HIFRFUk08L2tleXdvcmQ+

PGtleXdvcmQ+TE9ORy1URVJNPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdv

cmQ+TUFTVCBDRUxMPC9rZXl3b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdv

cmQ+TUVESUNJTkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3Jk

PlBBVEhPUEhZU0lPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5QQVRIT1BIWVNJT0xPR1k8L2tl

eXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UkVBQ1RJT05TPC9rZXl3

b3JkPjxrZXl3b3JkPlJlY2VwdG9ycyxJZ0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVHVUxBVElPTjwv

a2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRVM8L2tl

eXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtl

eXdvcmQ+Uk9MRVM8L2tleXdvcmQ+PGtleXdvcmQ+U0NIT09MPC9rZXl3b3JkPjxrZXl3b3JkPlRJ

U1NVRTwva2V5d29yZD48a2V5d29yZD5VU0E8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvNC8yMDEyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPkdBTExJMjAxMjwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxsaTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTcxNDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMjhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjExNzE0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0NzkwMDUiPjExNzE0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5HYWxsaSxTLkouPC9hdXRob3I+PGF1dGhvcj5Uc2FpLE0uPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPklnRSBhbmQgbWFzdCBjZWxscyBpbiBhbGxlcmdp

YyBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5hdCBNZWQuPC9zZWNvbmRhcnktdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0IE1lZC48L2Z1bGwtdGl0bGU+

PC9wZXJpb2RpY2FsPjxwYWdlcz42OTMtNzA0PC9wYWdlcz48dm9sdW1lPjE4PC92b2x1bWU+PG51

bWJlcj41PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0

aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+QUNUSU9OUzwv

a2V5d29yZD48a2V5d29yZD5BQ1VURTwva2V5d29yZD48a2V5d29yZD5BTExFUkdFTlM8L2tleXdv

cmQ+PGtleXdvcmQ+QUxMRVJHSUM8L2tleXdvcmQ+PGtleXdvcmQ+QW5hcGh5bGF4aXM8L2tleXdv

cmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BTlRJQk9ESUVTPC9rZXl3b3Jk

PjxrZXl3b3JkPkFOVElCT0RZPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5

d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIQU5H

RVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DT01QTEVYRVM8

L2tleXdvcmQ+PGtleXdvcmQ+ZGlmZmljdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tl

eXdvcmQ+PGtleXdvcmQ+RElTT1JERVJTPC9rZXl3b3JkPjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3

b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPkZVTkNUSU9OUzwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtl

eXdvcmQ+SFlQRVJTRU5TSVRJVklUWTwva2V5d29yZD48a2V5d29yZD5JZ0U8L2tleXdvcmQ+PGtl

eXdvcmQ+SUdFLURFUEVOREVOVDwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+PGtl

eXdvcmQ+SU1NVU5PR0xPQlVMSU48L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PR0xPQlVMSU4gRTwv

a2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3Jk

PjxrZXl3b3JkPklOREVQRU5ERU5UPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5

d29yZD48a2V5d29yZD5MQVJHRTwva2V5d29yZD48a2V5d29yZD5MT05HIFRFUk08L2tleXdvcmQ+

PGtleXdvcmQ+TE9ORy1URVJNPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdv

cmQ+TUFTVCBDRUxMPC9rZXl3b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdv

cmQ+TUVESUNJTkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3Jk

PlBBVEhPUEhZU0lPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5QQVRIT1BIWVNJT0xPR1k8L2tl

eXdvcmQ+PGtleXdvcmQ+cGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UkVBQ1RJT05TPC9rZXl3

b3JkPjxrZXl3b3JkPlJlY2VwdG9ycyxJZ0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVHVUxBVElPTjwv

a2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRVM8L2tl

eXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtl

eXdvcmQ+Uk9MRVM8L2tleXdvcmQ+PGtleXdvcmQ+U0NIT09MPC9rZXl3b3JkPjxrZXl3b3JkPlRJ

U1NVRTwva2V5d29yZD48a2V5d29yZD5VU0E8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvNC8yMDEyPC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPkdBTExJMjAxMjwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [28]. Mucosal mast cells are recruited to the surface of the airways in asthma by stem-cell factor (SCF) released from epithelial cells, which acts on c-Kit receptors expressed on mast cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWJlcjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4xMDEzMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMjldPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwMTMzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5ODEiPjEwMTMzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5SZWJlcixMLjwvYXV0aG9yPjxhdXRob3I+RGEgU2lsdmEsQy5BLjwvYXV0aG9yPjxhdXRob3I+

RnJvc3NhcmQsTi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0

bGU+U3RlbSBjZWxsIGZhY3RvciBhbmQgaXRzIHJlY2VwdG9yIGMtS2l0IGFzIHRhcmdldHMgZm9y

IGluZmxhbW1hdG9yeSBkaXNlYXNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FdXIgSiBQaGFy

bWFjb2wuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

RXVyIEogUGhhcm1hY29sLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMyNy0zNDA8

L3BhZ2VzPjx2b2x1bWU+NTMzPC92b2x1bWU+PG51bWJlcj4xLTM8L251bWJlcj48cmVwcmludC1l

ZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFD

VElWQVRFRDwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFD

VElWQVRPUjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPkFE

SEVTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+YW50YWdvbmlzdHMg

JmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5BbnRpLWluZmxhbW1hdG9yeSBhZ2Vu

dHM8L2tleXdvcmQ+PGtleXdvcmQ+YXJ0aHJpdGlzLHJoZXVtYXRvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkJJTkRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+Q0VM

TDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5jaGVtb2tpbmVzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkU8L2tleXdv

cmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3b3JkPkRlZ3JhbnVsYXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+ZGVybWF0aXRpczwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5ESVNF

QVNFUzwva2V5d29yZD48a2V5d29yZD5kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1

ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmVvc2lub3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+

RW9zaW5vcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3Jk

PkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RVhUUkFDRUxMVUxBUjwva2V5d29yZD48a2V5

d29yZD5leHRyYWNlbGx1bGFyIG1hdHJpeDwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdv

cmQ+PGtleXdvcmQ+R0VORVJBVElPTjwva2V5d29yZD48a2V5d29yZD5HUk9XVEg8L2tleXdvcmQ+

PGtleXdvcmQ+R3Jvd3RoIGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5IaXN0YW1pbmU8L2tleXdv

cmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3

b3JkPmh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+aW1hdGluaWI8L2tleXdv

cmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklUUk88L2tleXdvcmQ+PGtleXdv

cmQ+SU4gVklWTzwva2V5d29yZD48a2V5d29yZD5JTkZJTFRSQVRJT048L2tleXdvcmQ+PGtleXdv

cmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48

a2V5d29yZD5JTkhJQklUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3Jk

PjxrZXl3b3JkPktJTkFTRTwva2V5d29yZD48a2V5d29yZD5MZWFkPC9rZXl3b3JkPjxrZXl3b3Jk

PkxJR0FORDwva2V5d29yZD48a2V5d29yZD5NQVNUPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1QgQ0VM

TDwva2V5d29yZD48a2V5d29yZD5tYXN0IGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPk1BVFJJWDwv

a2V5d29yZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ0U8L2tleXdv

cmQ+PGtleXdvcmQ+TW9kZWxzLE1vbGVjdWxhcjwva2V5d29yZD48a2V5d29yZD5NVUxUSVBMRTwv

a2V5d29yZD48a2V5d29yZD5QQVRIV0FZPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhXQVlTPC9rZXl3

b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QSE9TUEhPTElQQVNF

PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9saXBhc2UgQzwva2V5d29yZD48a2V5d29yZD5waXBl

cmF6aW5lczwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tleXdvcmQ+PGtleXdvcmQ+UFJP

RFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QUk9JTkZMQU1NQVRPUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIENvbmZvcm1hdGlvbjwva2V5d29y

ZD48a2V5d29yZD5Qcm90ZWluIEtpbmFzZSBJbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlBy

b3RvLU9uY29nZW5lIFByb3RlaW5zIGMta2l0PC9rZXl3b3JkPjxrZXl3b3JkPnB5cmltaWRpbmVz

PC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJFTEVBU0U8L2tl

eXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPnNpZ25hbCB0cmFuc2R1Y3Rp

b248L2tleXdvcmQ+PGtleXdvcmQ+U1RBVDwva2V5d29yZD48a2V5d29yZD5TdGVtIENlbGwgRmFj

dG9yPC9rZXl3b3JkPjxrZXl3b3JkPlNUUlVDVFVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VU

PC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcGV1

dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5UUkFOU0NSSVBUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PlRSQU5TRFVDRVJTPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT4zLzgvMjAwNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJl

bD5SRUJFUjIwMDZBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWJlcjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT4xMDEzMzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMjldPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwMTMzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5ODEiPjEwMTMzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5SZWJlcixMLjwvYXV0aG9yPjxhdXRob3I+RGEgU2lsdmEsQy5BLjwvYXV0aG9yPjxhdXRob3I+

RnJvc3NhcmQsTi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0

bGU+U3RlbSBjZWxsIGZhY3RvciBhbmQgaXRzIHJlY2VwdG9yIGMtS2l0IGFzIHRhcmdldHMgZm9y

IGluZmxhbW1hdG9yeSBkaXNlYXNlczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FdXIgSiBQaGFy

bWFjb2wuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

RXVyIEogUGhhcm1hY29sLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjMyNy0zNDA8

L3BhZ2VzPjx2b2x1bWU+NTMzPC92b2x1bWU+PG51bWJlcj4xLTM8L251bWJlcj48cmVwcmludC1l

ZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFD

VElWQVRFRDwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFD

VElWQVRPUjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPkFE

SEVTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+YW50YWdvbmlzdHMg

JmFtcDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5BbnRpLWluZmxhbW1hdG9yeSBhZ2Vu

dHM8L2tleXdvcmQ+PGtleXdvcmQ+YXJ0aHJpdGlzLHJoZXVtYXRvaWQ8L2tleXdvcmQ+PGtleXdv

cmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkJJTkRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+Q0VM

TDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5jaGVtb2tpbmVzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkU8L2tleXdv

cmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3b3JkPkRlZ3JhbnVsYXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+ZGVybWF0aXRpczwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPkRpc2Vhc2UgTW9kZWxzLEFuaW1hbDwva2V5d29yZD48a2V5d29yZD5ESVNF

QVNFUzwva2V5d29yZD48a2V5d29yZD5kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1

ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPmVvc2lub3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+

RW9zaW5vcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3Jk

PkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RVhUUkFDRUxMVUxBUjwva2V5d29yZD48a2V5

d29yZD5leHRyYWNlbGx1bGFyIG1hdHJpeDwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdv

cmQ+PGtleXdvcmQ+R0VORVJBVElPTjwva2V5d29yZD48a2V5d29yZD5HUk9XVEg8L2tleXdvcmQ+

PGtleXdvcmQ+R3Jvd3RoIGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5IaXN0YW1pbmU8L2tleXdv

cmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3

b3JkPmh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+aW1hdGluaWI8L2tleXdv

cmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklUUk88L2tleXdvcmQ+PGtleXdv

cmQ+SU4gVklWTzwva2V5d29yZD48a2V5d29yZD5JTkZJTFRSQVRJT048L2tleXdvcmQ+PGtleXdv

cmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48

a2V5d29yZD5JTkhJQklUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3Jk

PjxrZXl3b3JkPktJTkFTRTwva2V5d29yZD48a2V5d29yZD5MZWFkPC9rZXl3b3JkPjxrZXl3b3Jk

PkxJR0FORDwva2V5d29yZD48a2V5d29yZD5NQVNUPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1QgQ0VM

TDwva2V5d29yZD48a2V5d29yZD5tYXN0IGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPk1BVFJJWDwv

a2V5d29yZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ0U8L2tleXdv

cmQ+PGtleXdvcmQ+TW9kZWxzLE1vbGVjdWxhcjwva2V5d29yZD48a2V5d29yZD5NVUxUSVBMRTwv

a2V5d29yZD48a2V5d29yZD5QQVRIV0FZPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhXQVlTPC9rZXl3

b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5QSE9TUEhPTElQQVNF

PC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaG9saXBhc2UgQzwva2V5d29yZD48a2V5d29yZD5waXBl

cmF6aW5lczwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tleXdvcmQ+PGtleXdvcmQ+UFJP

RFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QUk9JTkZMQU1NQVRPUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5Qcm90ZWluIENvbmZvcm1hdGlvbjwva2V5d29y

ZD48a2V5d29yZD5Qcm90ZWluIEtpbmFzZSBJbmhpYml0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlBy

b3RvLU9uY29nZW5lIFByb3RlaW5zIGMta2l0PC9rZXl3b3JkPjxrZXl3b3JkPnB5cmltaWRpbmVz

PC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJFTEVBU0U8L2tl

eXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPnNpZ25hbCB0cmFuc2R1Y3Rp

b248L2tleXdvcmQ+PGtleXdvcmQ+U1RBVDwva2V5d29yZD48a2V5d29yZD5TdGVtIENlbGwgRmFj

dG9yPC9rZXl3b3JkPjxrZXl3b3JkPlNUUlVDVFVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VU

PC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcGV1

dGljIHVzZTwva2V5d29yZD48a2V5d29yZD5UUkFOU0NSSVBUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PlRSQU5TRFVDRVJTPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+

PHB1Yi1kYXRlcz48ZGF0ZT4zLzgvMjAwNjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJl

bD5SRUJFUjIwMDZBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT4A

ADDIN EN.CITE.DATA [29]. Mast cells also release several cytokines linked to allergic inflammation, including IL-4, IL-5 and IL-13, as well as growth factors and neurotrophins, which appear to be important in the late response to allergens. The presence of mast cells in the airway smooth muscle has been linked to AHR PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmlnaHRsaW5nPC9BdXRob3I+PFllYXI+MjAwMjwvWWVh

cj48UmVjTnVtPjc4NzQ8L1JlY051bT48RGlzcGxheVRleHQ+WzMwXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj43ODc0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5NDMiPjc4NzQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkJyaWdodGxpbmcsQy5FLjwvYXV0aG9yPjxhdXRob3I+QnJhZGRpbmcsUC48L2F1dGhvcj48

YXV0aG9yPlN5bW9uLEYuQS48L2F1dGhvcj48YXV0aG9yPkhvbGdhdGUsUy5ULjwvYXV0aG9yPjxh

dXRob3I+V2FyZGxhdyxBLkouPC9hdXRob3I+PGF1dGhvcj5QYXZvcmQsSS5ELjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5NYXN0LWNlbGwgaW5maWx0cmF0

aW9uIG9mIGFpcndheSBzbW9vdGggbXVzY2xlIGluIGFzdGhtYTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5OLkVuZ2wuSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OLkVuZ2wuSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4x

Njk5LTE3MDU8L3BhZ2VzPjx2b2x1bWU+MzQ2PC92b2x1bWU+PG51bWJlcj4yMjwvbnVtYmVyPjxy

ZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+MTE8L2tleXdvcmQ+PGtleXdvcmQ+QURVTFQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxP

Vzwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5IHNtb290

aCBtdXNjbGU8L2tleXdvcmQ+PGtleXdvcmQ+QU5BTFlTSVM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0

aG1hPC9rZXl3b3JkPjxrZXl3b3JkPmJhc2VtZW50IG1lbWJyYW5lPC9rZXl3b3JkPjxrZXl3b3Jk

PkJJT1BTWTwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hJPC9rZXl3b3JkPjxrZXl3b3JkPkJST05D

SElUSVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5

d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5DT01QQVJJ

U09OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5D

RTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPmVvc2lub3BoaWw8

L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhpbGlhPC9rZXl3b3JkPjxrZXl3b3JkPkVPU0lOT1BI

SUxJQzwva2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsczwva2V5d29yZD48a2V5d29yZD5GZW1h

bGU8L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tl

eXdvcmQ+PGtleXdvcmQ+aHlwZXJyZXNwb25zaXZlbmVzczwva2V5d29yZD48a2V5d29yZD5JTU1V

Tk9ISVNUT0NIRU1JQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+PGtl

eXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5MT1dFUjwva2V5d29yZD48a2V5d29yZD5N

QUxFPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVNQlJBTkU8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+

PGtleXdvcmQ+TWlkZGxlIEFnZTwva2V5d29yZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtl

eXdvcmQ+bXVzY2xlLHNtb290aDwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29y

ZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+

UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5SZWZlcmVuY2UgVmFsdWVzPC9rZXl3b3JkPjxrZXl3b3JkPlNNT09USDwva2V5d29yZD48

a2V5d29yZD5TbW9vdGggbXVzY2xlPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3Jk

PjxrZXl3b3JkPlNVQk1VQ09TQUw8L2tleXdvcmQ+PGtleXdvcmQ+c3VwcG9ydCxub24tdS5zLmdv

diZhcG9zO3Q8L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tl

eXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29yZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+

PGtleXdvcmQ+VEhJQ0tFTklORzwva2V5d29yZD48a2V5d29yZD5UV088L2tleXdvcmQ+PGtleXdv

cmQ+VU5JVEVEPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRCBTVEFURVM8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMzAvMjAwMjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CUklHSFRMSU5HMjAwMjwvbGFiZWw+PHVy

bHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmlnaHRsaW5nPC9BdXRob3I+PFllYXI+MjAwMjwvWWVh

cj48UmVjTnVtPjc4NzQ8L1JlY051bT48RGlzcGxheVRleHQ+WzMwXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj43ODc0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5NDMiPjc4NzQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkJyaWdodGxpbmcsQy5FLjwvYXV0aG9yPjxhdXRob3I+QnJhZGRpbmcsUC48L2F1dGhvcj48

YXV0aG9yPlN5bW9uLEYuQS48L2F1dGhvcj48YXV0aG9yPkhvbGdhdGUsUy5ULjwvYXV0aG9yPjxh

dXRob3I+V2FyZGxhdyxBLkouPC9hdXRob3I+PGF1dGhvcj5QYXZvcmQsSS5ELjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5NYXN0LWNlbGwgaW5maWx0cmF0

aW9uIG9mIGFpcndheSBzbW9vdGggbXVzY2xlIGluIGFzdGhtYTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5OLkVuZ2wuSiBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OLkVuZ2wuSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4x

Njk5LTE3MDU8L3BhZ2VzPjx2b2x1bWU+MzQ2PC92b2x1bWU+PG51bWJlcj4yMjwvbnVtYmVyPjxy

ZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+MTE8L2tleXdvcmQ+PGtleXdvcmQ+QURVTFQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxP

Vzwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5IHNtb290

aCBtdXNjbGU8L2tleXdvcmQ+PGtleXdvcmQ+QU5BTFlTSVM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0

aG1hPC9rZXl3b3JkPjxrZXl3b3JkPmJhc2VtZW50IG1lbWJyYW5lPC9rZXl3b3JkPjxrZXl3b3Jk

PkJJT1BTWTwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hJPC9rZXl3b3JkPjxrZXl3b3JkPkJST05D

SElUSVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5

d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5DT01QQVJJ

U09OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5D

RTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPmVvc2lub3BoaWw8

L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhpbGlhPC9rZXl3b3JkPjxrZXl3b3JkPkVPU0lOT1BI

SUxJQzwva2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsczwva2V5d29yZD48a2V5d29yZD5GZW1h

bGU8L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tl

eXdvcmQ+PGtleXdvcmQ+aHlwZXJyZXNwb25zaXZlbmVzczwva2V5d29yZD48a2V5d29yZD5JTU1V

Tk9ISVNUT0NIRU1JQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+PGtl

eXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5MT1dFUjwva2V5d29yZD48a2V5d29yZD5N

QUxFPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVNQlJBTkU8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+

PGtleXdvcmQ+TWlkZGxlIEFnZTwva2V5d29yZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtl

eXdvcmQ+bXVzY2xlLHNtb290aDwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29y

ZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+

UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5

d29yZD5SZWZlcmVuY2UgVmFsdWVzPC9rZXl3b3JkPjxrZXl3b3JkPlNNT09USDwva2V5d29yZD48

a2V5d29yZD5TbW9vdGggbXVzY2xlPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3Jk

PjxrZXl3b3JkPlNVQk1VQ09TQUw8L2tleXdvcmQ+PGtleXdvcmQ+c3VwcG9ydCxub24tdS5zLmdv

diZhcG9zO3Q8L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tl

eXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29yZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+

PGtleXdvcmQ+VEhJQ0tFTklORzwva2V5d29yZD48a2V5d29yZD5UV088L2tleXdvcmQ+PGtleXdv

cmQ+VU5JVEVEPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRCBTVEFURVM8L2tleXdvcmQ+PC9rZXl3

b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMzAvMjAwMjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CUklHSFRMSU5HMjAwMjwvbGFiZWw+PHVy

bHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [30]. Mast cells also release several proteases, of which tryptase and chymase are mast cell specific ADDIN EN.CITE <EndNote><Cite><Author>Caughey</Author><Year>2016</Year><RecNum>12928</RecNum><DisplayText>[31]</DisplayText><record><rec-number>12928</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482418559">12928</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Caughey, G. H.</author></authors></contributors><auth-address>Cardiovascular Research Institute, School of Medicine, University of California at San Francisco, CA, United States; Department of Medicine, School of Medicine, University of California at San Francisco, CA, United States; Veterans Affairs Medical Center, San Francisco, CA, United States. Electronic address: George.Caughey@ucsf.edu.</auth-address><titles><title>Mast cell proteases as pharmacological targets</title><secondary-title>Eur J Pharmacol</secondary-title><alt-title>European journal of pharmacology</alt-title></titles><periodical><full-title>Eur J Pharmacol</full-title></periodical><pages>44-55</pages><volume>778</volume><edition>2015/05/11</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Mast Cells/drug effects/*enzymology</keyword><keyword>Molecular Targeted Therapy/*methods</keyword><keyword>Peptide Hydrolases/chemistry/*metabolism</keyword><keyword>Basophil</keyword><keyword>Carboxypeptidase A3</keyword><keyword>Cathepsin C</keyword><keyword>Cathepsin G</keyword><keyword>Cathepsin L</keyword><keyword>Chymase</keyword><keyword>Dipeptidylpeptidase I</keyword><keyword>Mast cell</keyword><keyword>Protease</keyword><keyword>Tryptase</keyword></keywords><dates><year>2016</year><pub-dates><date>May 05</date></pub-dates></dates><isbn>0014-2999</isbn><accession-num>25958181</accession-num><urls></urls><custom2>PMC4636979</custom2><custom6>NIHMS688969</custom6><electronic-resource-num>10.1016/j.ejphar.2015.04.045</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[31]. Tryptase is proinflammatory and may contribute to AHR is asthma, whereas chymase is profibrotic through the activation of transforming growth factor(TGF)-β.Mast cells do not seem to play a significant role in COPD, which may explain the lack of variable airway narrowing in this disease, in marked contrast to asthma. Increased numbers of mast cells have been described in COPD patients with centrilobular emphysema, where the increased mast cell number in airway smooth muscle is related to AHR PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxsYXJpbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT4xMjkyOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMzJdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyOTI5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0ODI0MTkzNDQiPjEyOTI5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5CYWxsYXJpbiwgQS48L2F1dGhvcj48YXV0aG9yPkJhenphbiwgRS48L2F1dGhvcj48YXV0

aG9yPlplbnRlbm8sIFIuIEguPC9hdXRob3I+PGF1dGhvcj5UdXJhdG8sIEcuPC9hdXRob3I+PGF1

dGhvcj5CYXJhbGRvLCBTLjwvYXV0aG9yPjxhdXRob3I+WmFub3ZlbGxvLCBELjwvYXV0aG9yPjxh

dXRob3I+TXV0dGksIEUuPC9hdXRob3I+PGF1dGhvcj5Ib2dnLCBKLiBDLjwvYXV0aG9yPjxhdXRo

b3I+U2FldHRhLCBNLjwvYXV0aG9yPjxhdXRob3I+Q29zaW8sIE0uIEcuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDYXJkaWFjLCBU

aG9yYWNpYywgYW5kIFZhc2N1bGFyIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFBhZG92YSwgUGFk

b3ZhLCBJdGFseS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NYXN0IGNlbGwgaW5maWx0

cmF0aW9uIGRpc2NyaW1pbmF0ZXMgYmV0d2VlbiBoaXN0b3BhdGhvbG9naWNhbCBwaGVub3R5cGVz

IG9mIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQt

dGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiByZXNwaXJhdG9yeSBhbmQgY3JpdGljYWwgY2FyZSBt

ZWRpY2luZTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEog

UmVzcGlyIENyaXQgQ2FyZSBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMzMt

OTwvcGFnZXM+PHZvbHVtZT4xODY8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlvbj4y

MDEyLzA2LzA5PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vaGlzdG9jaGVtaXN0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24v

Y29tcGxpY2F0aW9ucy9pbW11bm9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5MdW5n

L2ltbXVub2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NYXN0IENlbGxzLyppbW11bm9sb2d5Lyp1bHRyYXN0cnVjdHVyZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QaGVub3R5cGU8L2tleXdv

cmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IEFsdmVvbGkvaW1tdW5vbG9neS91bHRyYXN0cnVjdHVyZTwv

a2V5d29yZD48a2V5d29yZD5QdWxtb25hcnkgRGlzZWFzZSwgQ2hyb25pYyBPYnN0cnVjdGl2ZS9j

b21wbGljYXRpb25zLyppbW11bm9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QdWxt

b25hcnkgRW1waHlzZW1hL2NvbXBsaWNhdGlvbnMvaW1tdW5vbG9neS9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+UmVzcGlyYXRvcnkgRnVuY3Rpb24gVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+

U21va2luZy9pbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWcgMDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xMDczLTQ0OXg8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjI2NzkwMDk8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTY0L3JjY20uMjAx

MTEyLTIxNDJPQzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFn

ZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWxsYXJpbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

PFJlY051bT4xMjkyOTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMzJdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyOTI5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0ODI0MTkzNDQiPjEyOTI5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5CYWxsYXJpbiwgQS48L2F1dGhvcj48YXV0aG9yPkJhenphbiwgRS48L2F1dGhvcj48YXV0

aG9yPlplbnRlbm8sIFIuIEguPC9hdXRob3I+PGF1dGhvcj5UdXJhdG8sIEcuPC9hdXRob3I+PGF1

dGhvcj5CYXJhbGRvLCBTLjwvYXV0aG9yPjxhdXRob3I+WmFub3ZlbGxvLCBELjwvYXV0aG9yPjxh

dXRob3I+TXV0dGksIEUuPC9hdXRob3I+PGF1dGhvcj5Ib2dnLCBKLiBDLjwvYXV0aG9yPjxhdXRo

b3I+U2FldHRhLCBNLjwvYXV0aG9yPjxhdXRob3I+Q29zaW8sIE0uIEcuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBDYXJkaWFjLCBU

aG9yYWNpYywgYW5kIFZhc2N1bGFyIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIFBhZG92YSwgUGFk

b3ZhLCBJdGFseS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5NYXN0IGNlbGwgaW5maWx0

cmF0aW9uIGRpc2NyaW1pbmF0ZXMgYmV0d2VlbiBoaXN0b3BhdGhvbG9naWNhbCBwaGVub3R5cGVz

IG9mIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQt

dGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiByZXNwaXJhdG9yeSBhbmQgY3JpdGljYWwgY2FyZSBt

ZWRpY2luZTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEog

UmVzcGlyIENyaXQgQ2FyZSBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMzMt

OTwvcGFnZXM+PHZvbHVtZT4xODY8L3ZvbHVtZT48bnVtYmVyPjM8L251bWJlcj48ZWRpdGlvbj4y

MDEyLzA2LzA5PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vaGlzdG9jaGVtaXN0cnkvbWV0aG9kczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb24v

Y29tcGxpY2F0aW9ucy9pbW11bm9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5MdW5n

L2ltbXVub2xvZ3kvdWx0cmFzdHJ1Y3R1cmU8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29y

ZD48a2V5d29yZD5NYXN0IENlbGxzLyppbW11bm9sb2d5Lyp1bHRyYXN0cnVjdHVyZTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QaGVub3R5cGU8L2tleXdv

cmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IEFsdmVvbGkvaW1tdW5vbG9neS91bHRyYXN0cnVjdHVyZTwv

a2V5d29yZD48a2V5d29yZD5QdWxtb25hcnkgRGlzZWFzZSwgQ2hyb25pYyBPYnN0cnVjdGl2ZS9j

b21wbGljYXRpb25zLyppbW11bm9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5QdWxt

b25hcnkgRW1waHlzZW1hL2NvbXBsaWNhdGlvbnMvaW1tdW5vbG9neS9wYXRob2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+UmVzcGlyYXRvcnkgRnVuY3Rpb24gVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+

U21va2luZy9pbW11bm9sb2d5PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5BdWcgMDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48

aXNibj4xMDczLTQ0OXg8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjI2NzkwMDk8L2FjY2Vzc2lvbi1u

dW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTY0L3JjY20uMjAx

MTEyLTIxNDJPQzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFn

ZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [32]. It is possible that mast cells are linked to increased fibrosis in small airways.Macrophages Macrophages are largely derived from blood monocytes which traffic to the lungs and differentiate locally. There is heterogeneity of macrophages, with some macrophages having a proinflammatory profile, whereas others are anti-inflammatory, promote tissue repair and are more phagocytic PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JhbGVzLU5lYnJlZGE8L0F1dGhvcj48WWVhcj4yMDE1

PC9ZZWFyPjxSZWNOdW0+MTI5MzE8L1JlY051bT48RGlzcGxheVRleHQ+WzMzXTwvRGlzcGxheVRl

eHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMjkzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIg

dGltZXN0YW1wPSIxNDgyNDIzMTAyIj4xMjkzMTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+TW9yYWxlcy1OZWJyZWRhLCBMLjwvYXV0aG9yPjxhdXRob3I+TWlzaGFyaW4s

IEEuIFYuPC9hdXRob3I+PGF1dGhvcj5QZXJsbWFuLCBILjwvYXV0aG9yPjxhdXRob3I+QnVkaW5n

ZXIsIEcuIFIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

RGVwdCBvZiBNZWRpY2luZSwgRGl2aXNpb24gb2YgUHVsbW9uYXJ5IGFuZCBDcml0aWNhbCBDYXJl

IE1lZGljaW5lLCBOb3J0aHdlc3Rlcm4gVW5pdmVyc2l0eSwgRmVpbmJlcmcgU2Nob29sIG9mIE1l

ZGljaW5lLCBDaGljYWdvLCBJTCwgVVNBLiYjeEQ7RGVwdCBvZiBNZWRpY2luZSwgRGl2aXNpb24g

b2YgUmhldW1hdG9sb2d5LCBOb3J0aHdlc3Rlcm4gVW5pdmVyc2l0eSwgRmVpbmJlcmcgU2Nob29s

IG9mIE1lZGljaW5lLCBDaGljYWdvLCBJTCwgVVNBLiYjeEQ7RGVwdCBvZiBNZWRpY2luZSwgRGl2

aXNpb24gb2YgUHVsbW9uYXJ5IGFuZCBDcml0aWNhbCBDYXJlIE1lZGljaW5lLCBOb3J0aHdlc3Rl

cm4gVW5pdmVyc2l0eSwgRmVpbmJlcmcgU2Nob29sIG9mIE1lZGljaW5lLCBDaGljYWdvLCBJTCwg

VVNBIHMtYnVkaW5nQG5vcnRod2VzdGVybi5lZHUuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+VGhlIGhldGVyb2dlbmVpdHkgb2YgbHVuZyBtYWNyb3BoYWdlcyBpbiB0aGUgc3VzY2VwdGli

aWxpdHkgdG8gZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FdXIgUmVzcGlyIFJldjwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+RXVyb3BlYW4gcmVzcGlyYXRvcnkgcmV2aWV3IDog

YW4gb2ZmaWNpYWwgam91cm5hbCBvZiB0aGUgRXVyb3BlYW4gUmVzcGlyYXRvcnkgU29jaWV0eTwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkV1ciBSZXNwaXIgUmV2

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTA1LTk8L3BhZ2VzPjx2b2x1bWU+MjQ8

L3ZvbHVtZT48bnVtYmVyPjEzNzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDkvMDI8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBEaWZmZXJl

bnRpYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBTZWxmIFJlbmV3YWw8L2tleXdvcmQ+PGtl

eXdvcmQ+KkNlbGx1bGFyIE1pY3JvZW52aXJvbm1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFz

ZSBTdXNjZXB0aWJpbGl0eTwva2V5d29yZD48a2V5d29yZD5FcGlnZW5lc2lzLCBHZW5ldGljPC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD4qTHVuZy9pbW11bm9sb2d5

L21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmcgRGlzZWFzZXMvZGlh

Z25vc2lzLypldGlvbG9neS9nZW5ldGljcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Kk1hY3JvcGhhZ2VzLCBBbHZlb2xhci9pbW11bm9sb2d5L21ldGFib2xpc20vcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBoZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5SaXNr

IEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5MDUtOTE4

MDwvaXNibj48YWNjZXNzaW9uLW51bT4yNjMyNDgxMjwvYWNjZXNzaW9uLW51bT48dXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODMvMTYwMDA2MTcuMDAzMS0yMDE1PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVt

b3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JhbGVzLU5lYnJlZGE8L0F1dGhvcj48WWVhcj4yMDE1

PC9ZZWFyPjxSZWNOdW0+MTI5MzE8L1JlY051bT48RGlzcGxheVRleHQ+WzMzXTwvRGlzcGxheVRl

eHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMjkzMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIg

dGltZXN0YW1wPSIxNDgyNDIzMTAyIj4xMjkzMTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+TW9yYWxlcy1OZWJyZWRhLCBMLjwvYXV0aG9yPjxhdXRob3I+TWlzaGFyaW4s

IEEuIFYuPC9hdXRob3I+PGF1dGhvcj5QZXJsbWFuLCBILjwvYXV0aG9yPjxhdXRob3I+QnVkaW5n

ZXIsIEcuIFIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

RGVwdCBvZiBNZWRpY2luZSwgRGl2aXNpb24gb2YgUHVsbW9uYXJ5IGFuZCBDcml0aWNhbCBDYXJl

IE1lZGljaW5lLCBOb3J0aHdlc3Rlcm4gVW5pdmVyc2l0eSwgRmVpbmJlcmcgU2Nob29sIG9mIE1l

ZGljaW5lLCBDaGljYWdvLCBJTCwgVVNBLiYjeEQ7RGVwdCBvZiBNZWRpY2luZSwgRGl2aXNpb24g

b2YgUmhldW1hdG9sb2d5LCBOb3J0aHdlc3Rlcm4gVW5pdmVyc2l0eSwgRmVpbmJlcmcgU2Nob29s

IG9mIE1lZGljaW5lLCBDaGljYWdvLCBJTCwgVVNBLiYjeEQ7RGVwdCBvZiBNZWRpY2luZSwgRGl2

aXNpb24gb2YgUHVsbW9uYXJ5IGFuZCBDcml0aWNhbCBDYXJlIE1lZGljaW5lLCBOb3J0aHdlc3Rl

cm4gVW5pdmVyc2l0eSwgRmVpbmJlcmcgU2Nob29sIG9mIE1lZGljaW5lLCBDaGljYWdvLCBJTCwg

VVNBIHMtYnVkaW5nQG5vcnRod2VzdGVybi5lZHUuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0

bGU+VGhlIGhldGVyb2dlbmVpdHkgb2YgbHVuZyBtYWNyb3BoYWdlcyBpbiB0aGUgc3VzY2VwdGli

aWxpdHkgdG8gZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FdXIgUmVzcGlyIFJldjwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+RXVyb3BlYW4gcmVzcGlyYXRvcnkgcmV2aWV3IDog

YW4gb2ZmaWNpYWwgam91cm5hbCBvZiB0aGUgRXVyb3BlYW4gUmVzcGlyYXRvcnkgU29jaWV0eTwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkV1ciBSZXNwaXIgUmV2

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTA1LTk8L3BhZ2VzPjx2b2x1bWU+MjQ8

L3ZvbHVtZT48bnVtYmVyPjEzNzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDkvMDI8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBEaWZmZXJl

bnRpYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBTZWxmIFJlbmV3YWw8L2tleXdvcmQ+PGtl

eXdvcmQ+KkNlbGx1bGFyIE1pY3JvZW52aXJvbm1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+RGlzZWFz

ZSBTdXNjZXB0aWJpbGl0eTwva2V5d29yZD48a2V5d29yZD5FcGlnZW5lc2lzLCBHZW5ldGljPC9r

ZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD4qTHVuZy9pbW11bm9sb2d5

L21ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmcgRGlzZWFzZXMvZGlh

Z25vc2lzLypldGlvbG9neS9nZW5ldGljcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+Kk1hY3JvcGhhZ2VzLCBBbHZlb2xhci9pbW11bm9sb2d5L21ldGFib2xpc20vcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBoZW5vdHlwZTwva2V5d29yZD48a2V5d29yZD5SaXNr

IEZhY3RvcnM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNTwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPlNlcDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjA5MDUtOTE4

MDwvaXNibj48YWNjZXNzaW9uLW51bT4yNjMyNDgxMjwvYWNjZXNzaW9uLW51bT48dXJscz48L3Vy

bHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExODMvMTYwMDA2MTcuMDAzMS0yMDE1PC9l

bGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVt

b3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [33]. There is plasticity between these phenotypes that may be lost in disease. However, although distinct macrophage phenotypes (M1, M2) have been described in mice, these do not apply to humans and there is currently a lack of markers to distinguish different types of macrophage reliably ADDIN EN.CITE <EndNote><Cite><Author>Chana</Author><Year>2014</Year><RecNum>11864</RecNum><DisplayText>[34]</DisplayText><record><rec-number>11864</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1387795672">11864</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chana, K. K.</author><author>Fenwick, P. S.</author><author>Nicholson, A. G.</author><author>Barnes, P. J.</author><author>Donnelly, L. E.</author></authors></contributors><auth-address>Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.</auth-address><titles><title>Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease</title><secondary-title>J Allergy Clin Immunol</secondary-title><alt-title>The Journal of allergy and clinical immunology</alt-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>207-216</pages><volume>133</volume><edition>2013/11/02</edition><dates><year>2014</year><pub-dates><date>Oct 28</date></pub-dates></dates><isbn>0091-6749</isbn><accession-num>24176116</accession-num><urls></urls><electronic-resource-num>10.1016/j.jaci.2013.08.044</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[34]. The role of macrophages in asthma is currently uncertain as they may have proinflammatory or anti-inflammatory effects. Macrophages may be activated by allergens via low-affinity IgE receptors (FcεRII). Macrophages have the capacity to initiate a type of inflammatory response via the release of a certain pattern of cytokines, but these cells also release anti-inflammatory mediators, such as IL-10. There is some evidence that IL-10 secretion may be reduced in patients with severe asthma ADDIN EN.CITE <EndNote><Cite><Author>Tomita</Author><Year>2002</Year><RecNum>7774</RecNum><DisplayText>[35]</DisplayText><record><rec-number>7774</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478941">7774</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tomita,K.</author><author>Lim,S.</author><author>Hanazawa,T.</author><author>Usmani,O.</author><author>Stirling,R.</author><author>Chung,K.F.</author><author>Barnes,P.J.</author><author>Adcock,I.M.</author></authors></contributors><titles><title>Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma</title><secondary-title>Clin Immunol</secondary-title></titles><periodical><full-title>Clin Immunol</full-title></periodical><pages>258-266</pages><volume>102</volume><number>3</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Asthma</keyword><keyword>asthmatic</keyword><keyword>ASTHMATICS</keyword><keyword>BLOOD</keyword><keyword>CELL</keyword><keyword>CELLS</keyword><keyword>CONTROL</keyword><keyword>CULTURE</keyword><keyword>DECREASED</keyword><keyword>FLOW</keyword><keyword>Flow Cytometry</keyword><keyword>HETEROGENEITY</keyword><keyword>IL-10</keyword><keyword>IL-12</keyword><keyword>IN</keyword><keyword>INCREASE</keyword><keyword>INTERLEUKIN</keyword><keyword>INTRACELLULAR</keyword><keyword>MILD</keyword><keyword>MONOCYTE</keyword><keyword>Monocytes</keyword><keyword>MONONUCLEAR</keyword><keyword>normal</keyword><keyword>PATIENTS</keyword><keyword>PERIPHERAL</keyword><keyword>PERSISTENT</keyword><keyword>PRODUCTION</keyword><keyword>RELEASE</keyword><keyword>SEVERE</keyword><keyword>staining</keyword><keyword>STIMULATION</keyword><keyword>SUBJECTS</keyword><keyword>SYNTHESIS</keyword><keyword>UNITED</keyword><keyword>UNITED STATES</keyword><keyword>USA</keyword></keywords><dates><year>2002</year><pub-dates><date>3/2002</date></pub-dates></dates><label>TOMITA2002</label><urls></urls></record></Cite></EndNote>[35]. In COPD macrophages appear to play a major role in orchestrating the inflammatory response (Fig. 3) ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2004</Year><RecNum>8660</RecNum><DisplayText>[36]</DisplayText><record><rec-number>8660</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478956">8660</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes,P.J.</author></authors></contributors><titles><title>Macrophages as orchestrators of COPD</title><secondary-title>J COPD</secondary-title></titles><periodical><full-title>J COPD</full-title></periodical><pages>59-70</pages><volume>1</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Macrophages</keyword><keyword>MACROPHAGE</keyword><keyword>COPD</keyword></keywords><dates><year>2004</year><pub-dates><date>2004</date></pub-dates></dates><label>BARNES2004</label><urls></urls></record></Cite></EndNote>[36]. There is a marked increase in macrophage numbers in airways, lung parenchyma, BAL fluid and sputum of COPD patients, which is likely to be due to increased recruitment of monocytes from the circulation in response to the chemokines CCL2 and CXCL1, which are increased in sputum and BAL of patients with COPD ADDIN EN.CITE <EndNote><Cite><Author>Traves</Author><Year>2002</Year><RecNum>7167</RecNum><DisplayText>[37]</DisplayText><record><rec-number>7167</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478931">7167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Traves,S.L.</author><author>Culpitt,S.</author><author>Russell,R.E.K.</author><author>Barnes,P.J.</author><author>Donnelly,L.E.</author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Elevated levels of the chemokines GRO-</style><style face="normal" font="Symbol" charset="2" size="100%">a</style><style face="normal" font="default" size="100%"> and MCP-1 in sputum samples from COPD patients</style></title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>590-595</pages><volume>57</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>BLOOD</keyword><keyword>CELL</keyword><keyword>chemokines</keyword><keyword>Chemotaxis</keyword><keyword>COPD</keyword><keyword>IL-8</keyword><keyword>IN</keyword><keyword>MCP-1</keyword><keyword>MONONUCLEAR</keyword><keyword>PATIENTS</keyword><keyword>PERIPHERAL</keyword><keyword>SPUTUM</keyword></keywords><dates><year>2002</year><pub-dates><date>2002</date></pub-dates></dates><label>TRAVES2002</label><urls></urls></record></Cite></EndNote>[37]. In addition, monocytes from COPD patients show a greater chemotactic response to CXCL1 than cells from normal smokers and non-smokers, which appears to be due to greater CXCR2 receptor turnover PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmF2ZXM8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+ODc0NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMzhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjg3NDc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk1OCI+ODc0Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

VHJhdmVzLFMuTC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLFMuSi48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5Eb25uZWxseSxMLkUuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNwZWNpZmljIENYQyBidXQgbm90IENDIGNo

ZW1va2luZXMgY2F1c2UgZWxldmF0ZWQgbW9ub2N5dGUgbWlncmF0aW9uIGluIENPUEQ6IGEgcm9s

ZSBmb3IgQ1hDUjI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBMZXVrb2MuQmlvbC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIExldWtvYy5CaW9s

LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQ0MS00NTA8L3BhZ2VzPjx2b2x1bWU+

NzY8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxPVzwv

a2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29y

ZD48a2V5d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVEFHT05JU1Q8L2tleXdvcmQ+PGtleXdvcmQ+QU5UQUdPTklT

VFM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdvcmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29y

ZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSEFOR0VTPC9rZXl3b3JkPjxrZXl3b3JkPmNo

ZW1va2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hlbW90YXhpczwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNI

Uk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0lSQ1VMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5

d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5FTkhB

TkNFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RP

Ujwva2V5d29yZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5

PC9rZXl3b3JkPjxrZXl3b3JkPkhPU1Q8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORklMVFJBVElPTjwva2V5d29yZD48

a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3

b3JkPjxrZXl3b3JkPklORkxVWDwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbiA4PC9rZXl3

b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOLTg8L2tleXdvcmQ+PGtleXdvcmQ+SVJSRVZFUlNJQkxF

PC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtleXdvcmQ+TEVVS09DWVRFPC9rZXl3

b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdv

cmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5

d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRURJQVRFRDwva2V5d29yZD48a2V5d29yZD5N

SUdSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+TU9OT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+TW9u

b2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPk1PTk9OVUNMRUFSPC9rZXl3b3JkPjxrZXl3b3JkPk5V

TUJFUlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVQVElERTwva2V5d29yZD48a2V5d29yZD5QRVJJUEhF

UkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9URUlO

PC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwv

a2V5d29yZD48a2V5d29yZD5SZWNlcHRvciBleHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJl

Y2VwdG9yczwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UElSQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UE9OU0VTPC9rZXl3b3JkPjxrZXl3b3JkPnJpc2s8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5

d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3Jk

PjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdv

cmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRVM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMjAvMjAwNDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5UUkFWRVMyMDA0PC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmF2ZXM8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+ODc0NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMzhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjg3NDc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk1OCI+ODc0Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

VHJhdmVzLFMuTC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLFMuSi48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5Eb25uZWxseSxMLkUuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNwZWNpZmljIENYQyBidXQgbm90IENDIGNo

ZW1va2luZXMgY2F1c2UgZWxldmF0ZWQgbW9ub2N5dGUgbWlncmF0aW9uIGluIENPUEQ6IGEgcm9s

ZSBmb3IgQ1hDUjI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBMZXVrb2MuQmlvbC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIExldWtvYy5CaW9s

LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQ0MS00NTA8L3BhZ2VzPjx2b2x1bWU+

NzY8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxPVzwv

a2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29y

ZD48a2V5d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVEFHT05JU1Q8L2tleXdvcmQ+PGtleXdvcmQ+QU5UQUdPTklT

VFM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdvcmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29y

ZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSEFOR0VTPC9rZXl3b3JkPjxrZXl3b3JkPmNo

ZW1va2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hlbW90YXhpczwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNI

Uk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0lSQ1VMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5

d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5FTkhB

TkNFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RP

Ujwva2V5d29yZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5

PC9rZXl3b3JkPjxrZXl3b3JkPkhPU1Q8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORklMVFJBVElPTjwva2V5d29yZD48

a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3

b3JkPjxrZXl3b3JkPklORkxVWDwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbiA4PC9rZXl3

b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOLTg8L2tleXdvcmQ+PGtleXdvcmQ+SVJSRVZFUlNJQkxF

PC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtleXdvcmQ+TEVVS09DWVRFPC9rZXl3

b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdv

cmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5

d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRURJQVRFRDwva2V5d29yZD48a2V5d29yZD5N

SUdSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+TU9OT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+TW9u

b2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPk1PTk9OVUNMRUFSPC9rZXl3b3JkPjxrZXl3b3JkPk5V

TUJFUlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVQVElERTwva2V5d29yZD48a2V5d29yZD5QRVJJUEhF

UkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9URUlO

PC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwv

a2V5d29yZD48a2V5d29yZD5SZWNlcHRvciBleHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJl

Y2VwdG9yczwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UElSQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UE9OU0VTPC9rZXl3b3JkPjxrZXl3b3JkPnJpc2s8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5

d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3Jk

PjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdv

cmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRVM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMjAvMjAwNDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5UUkFWRVMyMDA0PC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [38]. In general, it is likely that “M1-like” proinflammatory macrophages predominate in COPD but further phenotyping is needed in the future ADDIN EN.CITE <EndNote><Cite><Author>Chana</Author><Year>2014</Year><RecNum>11864</RecNum><DisplayText>[34]</DisplayText><record><rec-number>11864</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1387795672">11864</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chana, K. K.</author><author>Fenwick, P. S.</author><author>Nicholson, A. G.</author><author>Barnes, P. J.</author><author>Donnelly, L. E.</author></authors></contributors><auth-address>Airway Disease, National Heart and Lung Institute, Imperial College London, London, United Kingdom.</auth-address><titles><title>Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease</title><secondary-title>J Allergy Clin Immunol</secondary-title><alt-title>The Journal of allergy and clinical immunology</alt-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>207-216</pages><volume>133</volume><edition>2013/11/02</edition><dates><year>2014</year><pub-dates><date>Oct 28</date></pub-dates></dates><isbn>0091-6749</isbn><accession-num>24176116</accession-num><urls></urls><electronic-resource-num>10.1016/j.jaci.2013.08.044</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[34]. M2 macrophage markers, such as CD163 are increased in COPD lungs and a subset of “M2-like” skewed macrophages may contribute to defective remodelling in COPD ADDIN EN.CITE <EndNote><Cite><Author>Vlahos</Author><Year>2014</Year><RecNum>12960</RecNum><DisplayText>[39]</DisplayText><record><rec-number>12960</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1488284606">12960</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vlahos, R.</author><author>Bozinovski, S.</author></authors></contributors><auth-address>Department of Pharmacology and Therapeutics, Lung Health Research Centre, The University of Melbourne , Parkville, VIC , Australia.</auth-address><titles><title>Role of alveolar macrophages in chronic obstructive pulmonary disease</title><secondary-title>Front Immunol</secondary-title><alt-title>Frontiers in immunology</alt-title></titles><periodical><full-title>Front Immunol</full-title><abbr-1>Frontiers in immunology</abbr-1></periodical><alt-periodical><full-title>Front Immunol</full-title><abbr-1>Frontiers in immunology</abbr-1></alt-periodical><pages>435</pages><volume>5</volume><edition>2014/10/14</edition><keywords><keyword>alveolar macrophage</keyword><keyword>chronic obstructive pulmonary disease</keyword><keyword>efferocytosis</keyword><keyword>lung inflammation</keyword><keyword>oxidative stress</keyword><keyword>resolution</keyword></keywords><dates><year>2014</year></dates><isbn>1664-3224</isbn><accession-num>25309536</accession-num><urls></urls><custom2>PMC4160089</custom2><electronic-resource-num>10.3389/fimmu.2014.00435</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[39]. Activated macrophages from COPD patients release more inflammatory mediators (IL-1β, IL-6, TNF-, CXCL1, CXCL8, CCL2, LTB4) and reactive oxygen species (ROS) than normal macrophages PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DdWxwaXR0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48

UmVjTnVtPjgwOTE8L1JlY051bT48RGlzcGxheVRleHQ+WzQwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj44MDkxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NDYiPjgwOTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRob3I+Um9nZXJzLEQuRi48L2F1dGhvcj48YXV0aG9y

PlNoYWgsUC48L2F1dGhvcj48YXV0aG9yPmRlIE1hdG9zLEMuPC9hdXRob3I+PGF1dGhvcj5SdXNz

ZWxsLFIuRS48L2F1dGhvcj48YXV0aG9yPkRvbm5lbGx5LEwuRS48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkltcGFpcmVkIGluaGliaXRpb24gYnkgZGV4YW1ldGhhc29uZSBvZiBjeXRva2luZSByZWxlYXNl

IGJ5IGFsdmVvbGFyIG1hY3JvcGhhZ2VzIGZyb20gcGF0aWVudHMgd2l0aCBjaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVz

cGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MjQtMzE8L3BhZ2VzPjx2b2x1bWU+MTY3PC92b2x1bWU+PG51bWJlcj4xPC9u

dW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD4xNTwva2V5d29yZD48a2V5d29yZD4yMjM5MDU1NDwva2V5d29yZD48a2V5

d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdlPC9rZXl3

b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hPQUxW

RU9MQVIgTEFWQUdFPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0hS

T05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3

b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdv

cmQ+Q0lHQVJFVFRFPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURSBTTU9LRTwva2V5d29yZD48

a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lEPC9rZXl3b3JkPjxr

ZXl3b3JkPkNvcnRpY29zdGVyb2lkczwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29y

ZD48a2V5d29yZD5kZXhhbWV0aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRklDQUNZPC9rZXl3b3JkPjxr

ZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5HTS1DU0Y8L2tleXdvcmQ+PGtleXdvcmQ+

R1JBTlVMT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+R3JhbnVsb2N5dGUgTWFjcm9waGFnZSBDb2xv

bnkgU3RpbXVsYXRpbmcgRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtl

eXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5D

UkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVDwva2V5d29yZD48a2V5d29yZD5J

TkhJQklUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3Jk

PkxBVkFHRTwva2V5d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1h

Y3JvcGhhZ2UgQ29sb255IFN0aW11bGF0aW5nIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5NYWNy

b3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRURJVU08L2tleXdvcmQ+PGtleXdvcmQ+Tjwva2V5

d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29y

ZD48a2V5d29yZD5SRVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFD

VDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3

b3JkPjxrZXl3b3JkPlNUSU1VTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+U1RJTVVMQVRJTkc8L2tl

eXdvcmQ+PGtleXdvcmQ+VFJBQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5UPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzEv

MjAwMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5DVUxQSVRUMjAwMzwvbGFiZWw+

PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DdWxwaXR0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48

UmVjTnVtPjgwOTE8L1JlY051bT48RGlzcGxheVRleHQ+WzQwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj44MDkxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NDYiPjgwOTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRob3I+Um9nZXJzLEQuRi48L2F1dGhvcj48YXV0aG9y

PlNoYWgsUC48L2F1dGhvcj48YXV0aG9yPmRlIE1hdG9zLEMuPC9hdXRob3I+PGF1dGhvcj5SdXNz

ZWxsLFIuRS48L2F1dGhvcj48YXV0aG9yPkRvbm5lbGx5LEwuRS48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkltcGFpcmVkIGluaGliaXRpb24gYnkgZGV4YW1ldGhhc29uZSBvZiBjeXRva2luZSByZWxlYXNl

IGJ5IGFsdmVvbGFyIG1hY3JvcGhhZ2VzIGZyb20gcGF0aWVudHMgd2l0aCBjaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVz

cGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MjQtMzE8L3BhZ2VzPjx2b2x1bWU+MTY3PC92b2x1bWU+PG51bWJlcj4xPC9u

dW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD4xNTwva2V5d29yZD48a2V5d29yZD4yMjM5MDU1NDwva2V5d29yZD48a2V5

d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdlPC9rZXl3

b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hPQUxW

RU9MQVIgTEFWQUdFPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0hS

T05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3

b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdv

cmQ+Q0lHQVJFVFRFPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURSBTTU9LRTwva2V5d29yZD48

a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lEPC9rZXl3b3JkPjxr

ZXl3b3JkPkNvcnRpY29zdGVyb2lkczwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29y

ZD48a2V5d29yZD5kZXhhbWV0aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRklDQUNZPC9rZXl3b3JkPjxr

ZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5HTS1DU0Y8L2tleXdvcmQ+PGtleXdvcmQ+

R1JBTlVMT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+R3JhbnVsb2N5dGUgTWFjcm9waGFnZSBDb2xv

bnkgU3RpbXVsYXRpbmcgRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtl

eXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5D

UkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVDwva2V5d29yZD48a2V5d29yZD5J

TkhJQklUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3Jk

PkxBVkFHRTwva2V5d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1h

Y3JvcGhhZ2UgQ29sb255IFN0aW11bGF0aW5nIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5NYWNy

b3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRURJVU08L2tleXdvcmQ+PGtleXdvcmQ+Tjwva2V5

d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29y

ZD48a2V5d29yZD5SRVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFD

VDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3

b3JkPjxrZXl3b3JkPlNUSU1VTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+U1RJTVVMQVRJTkc8L2tl

eXdvcmQ+PGtleXdvcmQ+VFJBQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5UPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzEv

MjAwMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5DVUxQSVRUMjAwMzwvbGFiZWw+

PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [40], as well as elastolytic enzymes, including MMP-2, MMP-9, MMP-12, cathepsins K, L and S PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdXNzZWxsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjc5NTQ8L1JlY051bT48RGlzcGxheVRleHQ+WzQxXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj43OTU0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NDQiPjc5NTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlJ1c3NlbGwsUi5FLjwvYXV0aG9yPjxhdXRob3I+VGhvcmxleSxBLjwvYXV0aG9yPjxhdXRob3I+

Q3VscGl0dCxTLlYuPC9hdXRob3I+PGF1dGhvcj5Eb2RkLFMuPC9hdXRob3I+PGF1dGhvcj5Eb25u

ZWxseSxMLkUuPC9hdXRob3I+PGF1dGhvcj5EZW1hdHRvcyxDLjwvYXV0aG9yPjxhdXRob3I+Rml0

emdlcmFsZCxNLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx2ZW9sYXIgbWFjcm9waGFnZS1tZWRpYXRl

ZCBlbGFzdG9seXNpczogcm9sZXMgb2YgbWF0cml4IG1ldGFsbG9wcm90ZWluYXNlcywgY3lzdGVp

bmUsIGFuZCBzZXJpbmUgcHJvdGVhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGh5

c2lvbCBMdW5nIENlbGwgTW9sIFBoeXNpb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFBoeXNpb2wgTHVuZyBDZWxsIE1vbCBQaHlzaW9sPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+TDg2Ny1MODczPC9wYWdlcz48dm9sdW1lPjI4

Mzwvdm9sdW1lPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwv

a2V5d29yZD48a2V5d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNy

b3BoYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05J

QyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURTwva2V5d29yZD48a2V5d29y

ZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNVTFRVUkU8L2tleXdvcmQ+PGtleXdvcmQ+Q3lzdGVp

bmU8L2tleXdvcmQ+PGtleXdvcmQ+REVDUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVO

Q0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FbGFzdGluPC9r

ZXl3b3JkPjxrZXl3b3JkPkVOWllNRTwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgSW5oaWJpdG9y

czwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SUzwva2V5

d29yZD48a2V5d29yZD5IRUFMVEhZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3

b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1I8L2tleXdvcmQ+PGtleXdv

cmQ+SU5ISUJJVE9SUzwva2V5d29yZD48a2V5d29yZD5JTlZFU1RJR0FUSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29y

ZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5N

QVRSSVg8L2tleXdvcmQ+PGtleXdvcmQ+bWF0cml4IG1ldGFsbG9wcm90ZWluYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hdHJpeCBNZXRhbGxvcHJvdGVpbmFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUVE

SUFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YWxsb3Byb3RlaW5hc2VzPC9rZXl3b3JkPjxrZXl3

b3JkPk1NUDwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5Q

QVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVM

RUFTRTwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFRDwva2V5d29yZD48a2V5d29yZD5ST0xFPC9r

ZXl3b3JkPjxrZXl3b3JkPlJPTEVTPC9rZXl3b3JkPjxrZXl3b3JkPlNFUklORTwva2V5d29yZD48

a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3

b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNVQlNUUkFURTwva2V5d29yZD48a2V5d29y

ZD5VTklURUQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEIFNUQVRFUzwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTAvMjAwMjwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5SVVNTRUxMMjAwMjwvbGFiZWw+PHVybHM+PC91

cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdXNzZWxsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjc5NTQ8L1JlY051bT48RGlzcGxheVRleHQ+WzQxXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj43OTU0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NDQiPjc5NTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlJ1c3NlbGwsUi5FLjwvYXV0aG9yPjxhdXRob3I+VGhvcmxleSxBLjwvYXV0aG9yPjxhdXRob3I+

Q3VscGl0dCxTLlYuPC9hdXRob3I+PGF1dGhvcj5Eb2RkLFMuPC9hdXRob3I+PGF1dGhvcj5Eb25u

ZWxseSxMLkUuPC9hdXRob3I+PGF1dGhvcj5EZW1hdHRvcyxDLjwvYXV0aG9yPjxhdXRob3I+Rml0

emdlcmFsZCxNLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx2ZW9sYXIgbWFjcm9waGFnZS1tZWRpYXRl

ZCBlbGFzdG9seXNpczogcm9sZXMgb2YgbWF0cml4IG1ldGFsbG9wcm90ZWluYXNlcywgY3lzdGVp

bmUsIGFuZCBzZXJpbmUgcHJvdGVhc2VzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUGh5

c2lvbCBMdW5nIENlbGwgTW9sIFBoeXNpb2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFBoeXNpb2wgTHVuZyBDZWxsIE1vbCBQaHlzaW9sPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+TDg2Ny1MODczPC9wYWdlcz48dm9sdW1lPjI4

Mzwvdm9sdW1lPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwv

a2V5d29yZD48a2V5d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNy

b3BoYWdlPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05J

QyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURTwva2V5d29yZD48a2V5d29y

ZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNVTFRVUkU8L2tleXdvcmQ+PGtleXdvcmQ+Q3lzdGVp

bmU8L2tleXdvcmQ+PGtleXdvcmQ+REVDUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVO

Q0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FbGFzdGluPC9r

ZXl3b3JkPjxrZXl3b3JkPkVOWllNRTwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgSW5oaWJpdG9y

czwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SUzwva2V5

d29yZD48a2V5d29yZD5IRUFMVEhZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3

b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1I8L2tleXdvcmQ+PGtleXdv

cmQ+SU5ISUJJVE9SUzwva2V5d29yZD48a2V5d29yZD5JTlZFU1RJR0FUSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29y

ZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5N

QVRSSVg8L2tleXdvcmQ+PGtleXdvcmQ+bWF0cml4IG1ldGFsbG9wcm90ZWluYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPk1hdHJpeCBNZXRhbGxvcHJvdGVpbmFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUVE

SUFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+bWV0YWxsb3Byb3RlaW5hc2VzPC9rZXl3b3JkPjxrZXl3

b3JkPk1NUDwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5Q

QVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVM

RUFTRTwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFRDwva2V5d29yZD48a2V5d29yZD5ST0xFPC9r

ZXl3b3JkPjxrZXl3b3JkPlJPTEVTPC9rZXl3b3JkPjxrZXl3b3JkPlNFUklORTwva2V5d29yZD48

a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3

b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNVQlNUUkFURTwva2V5d29yZD48a2V5d29y

ZD5VTklURUQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEIFNUQVRFUzwva2V5d29yZD48L2tleXdv

cmRzPjxkYXRlcz48eWVhcj4yMDAyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTAvMjAwMjwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5SVVNTRUxMMjAwMjwvbGFiZWw+PHVybHM+PC91

cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [41]. Macrophages demonstrate this difference even when maintained in culture for several days and thus appear to be intrinsically different from the macrophages of normal smokers and non-smoking normal control subjects. The inflammatory proteins that are up-regulated in COPD macrophages are regulated by the transcription factor nuclear factor-B (NF-B) which is activated in alveolar macrophages of COPD patients, particularly during exacerbations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJhbW9yaTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+

PFJlY051bT44MjMzPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls0Ml08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+ODIzMzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQ5Ij44MjMzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5DYXJhbW9yaSxHLjwvYXV0aG9yPjxhdXRob3I+Um9tYWdub2xpLE0uPC9hdXRob3I+PGF1dGhv

cj5DYXNvbGFyaSxQLjwvYXV0aG9yPjxhdXRob3I+QmVsbGV0dGF0byxDLjwvYXV0aG9yPjxhdXRo

b3I+Q2Fzb25pLEcuPC9hdXRob3I+PGF1dGhvcj5Cb3NjaGV0dG8sUC48L2F1dGhvcj48YXV0aG9y

PkZhbixDaHVuZyBLLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48YXV0aG9y

PkFkY29jayxJLk0uPC9hdXRob3I+PGF1dGhvcj5DaWFjY2lhLEEuPC9hdXRob3I+PGF1dGhvcj5G

YWJicmksTC5NLjwvYXV0aG9yPjxhdXRob3I+UGFwaSxBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5OdWNsZWFyIGxvY2FsaXNhdGlvbiBvZiBwNjUgaW4g

c3B1dHVtIG1hY3JvcGhhZ2VzIGJ1dCBub3QgaW4gc3B1dHVtIG5ldXRyb3BoaWxzIGR1cmluZyBD

T1BEIGV4YWNlcmJhdGlvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+VGhvcmF4PC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+VGhvcmF4PC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzQ4LTM1MTwvcGFnZXM+PHZvbHVtZT41ODwvdm9sdW1l

PjxudW1iZXI+NDwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQt

ZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MDwva2V5d29yZD48a2V5d29yZD4xMTwva2V5d29y

ZD48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29y

ZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5D

SFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUg

cHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2xpbmljYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVY

QUNFUkJBVElPTjwva2V5d29yZD48a2V5d29yZD5FWEFDRVJCQVRJT05TPC9rZXl3b3JkPjxrZXl3

b3JkPklNTVVOT1JFQUNUSVZJVFk8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdv

cmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5

d29yZD5MT0NBTElTQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48

a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtl

eXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NT0RFUkFURTwva2V5d29yZD48a2V5d29y

ZD5OQVRVUkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRyb3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1dHJvcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+TlVDTEVBUjwva2V5d29yZD48a2V5d29yZD5P

QlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+

U0lHTkFMPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TVEFCTEU8

L2tleXdvcmQ+PGtleXdvcmQ+c3RhaW5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5

d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAz

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+NC8yMDAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGxhYmVsPkNBUkFNT1JJMjAwMzwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJhbW9yaTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+

PFJlY051bT44MjMzPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls0Ml08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+ODIzMzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQ5Ij44MjMzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5DYXJhbW9yaSxHLjwvYXV0aG9yPjxhdXRob3I+Um9tYWdub2xpLE0uPC9hdXRob3I+PGF1dGhv

cj5DYXNvbGFyaSxQLjwvYXV0aG9yPjxhdXRob3I+QmVsbGV0dGF0byxDLjwvYXV0aG9yPjxhdXRo

b3I+Q2Fzb25pLEcuPC9hdXRob3I+PGF1dGhvcj5Cb3NjaGV0dG8sUC48L2F1dGhvcj48YXV0aG9y

PkZhbixDaHVuZyBLLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48YXV0aG9y

PkFkY29jayxJLk0uPC9hdXRob3I+PGF1dGhvcj5DaWFjY2lhLEEuPC9hdXRob3I+PGF1dGhvcj5G

YWJicmksTC5NLjwvYXV0aG9yPjxhdXRob3I+UGFwaSxBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5OdWNsZWFyIGxvY2FsaXNhdGlvbiBvZiBwNjUgaW4g

c3B1dHVtIG1hY3JvcGhhZ2VzIGJ1dCBub3QgaW4gc3B1dHVtIG5ldXRyb3BoaWxzIGR1cmluZyBD

T1BEIGV4YWNlcmJhdGlvbnM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+VGhvcmF4PC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+VGhvcmF4PC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzQ4LTM1MTwvcGFnZXM+PHZvbHVtZT41ODwvdm9sdW1l

PjxudW1iZXI+NDwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQt

ZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MDwva2V5d29yZD48a2V5d29yZD4xMTwva2V5d29y

ZD48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29y

ZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5D

SFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUg

cHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2xpbmljYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVY

QUNFUkJBVElPTjwva2V5d29yZD48a2V5d29yZD5FWEFDRVJCQVRJT05TPC9rZXl3b3JkPjxrZXl3

b3JkPklNTVVOT1JFQUNUSVZJVFk8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdv

cmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5

d29yZD5MT0NBTElTQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48

a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtl

eXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NT0RFUkFURTwva2V5d29yZD48a2V5d29y

ZD5OQVRVUkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRyb3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1dHJvcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+TlVDTEVBUjwva2V5d29yZD48a2V5d29yZD5P

QlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+

U0lHTkFMPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TVEFCTEU8

L2tleXdvcmQ+PGtleXdvcmQ+c3RhaW5pbmc8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5

d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAz

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+NC8yMDAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGxhYmVsPkNBUkFNT1JJMjAwMzwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+

ADDIN EN.CITE.DATA [42] and by p38 MAP kinase, which is also activated in these cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5kYTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMDA2NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNDNdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwMDY1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5ODAiPjEwMDY1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5SZW5kYSxULjwvYXV0aG9yPjxhdXRob3I+QmFyYWxkbyxTLjwvYXV0aG9yPjxhdXRob3I+UGVs

YWlhLEcuPC9hdXRob3I+PGF1dGhvcj5CYXp6YW4sRS48L2F1dGhvcj48YXV0aG9yPlR1cmF0byxH

LjwvYXV0aG9yPjxhdXRob3I+UGFwaSxBLjwvYXV0aG9yPjxhdXRob3I+TWFlc3RyZWxsaSxQLjwv

YXV0aG9yPjxhdXRob3I+TWFzZWxsaSxSLjwvYXV0aG9yPjxhdXRob3I+VmF0cmVsbGEsQS48L2F1

dGhvcj48YXV0aG9yPkZhYmJyaSxMLk0uPC9hdXRob3I+PGF1dGhvcj5adWluLFIuPC9hdXRob3I+

PGF1dGhvcj5NYXJzaWNvLFMuQS48L2F1dGhvcj48YXV0aG9yPlNhZXR0YSxNLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JbmNyZWFzZWQgYWN0aXZhdGlv

biBvZiBwMzggTUFQSyBpbiBDT1BEPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBSZXNwaXIg

Si48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIg

UmVzcGlyIEouPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjItNjk8L3BhZ2VzPjx2

b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBp

biBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRJT048L2tl

eXdvcmQ+PGtleXdvcmQ+QUxWRU9MQVI8L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9w

aGFnZTwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29yZD5hcG9wdG9z

aXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29y

ZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FWFBJUkFUT1JZPC9rZXl3b3JkPjxr

ZXl3b3JkPkVYUFJFU1NFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5d29yZD48a2V5d29yZD5mdW5jdGlv

bjwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPktJTkFTRTwva2V5d29yZD48a2V5d29yZD5LSU5BU0VT

PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+

PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29y

ZD48a2V5d29yZD5NQVBLPC9rZXl3b3JkPjxrZXl3b3JkPm1pdG9nZW4tYWN0aXZhdGVkIHByb3Rl

aW4ga2luYXNlczwva2V5d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JT

VFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T1hJREFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk94

aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+cDM4PC9rZXl3b3JkPjxrZXl3b3JkPnBh

dGhvZ2VuZXNpczwva2V5d29yZD48a2V5d29yZD5QQVRIV0FZPC9rZXl3b3JkPjxrZXl3b3JkPlBB

VElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9naWNhbDwva2V5d29yZD48a2V5d29y

ZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4ga2luYXNlPC9rZXl3b3JkPjxrZXl3

b3JkPlByb3RlaW4gS2luYXNlczwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+

PGtleXdvcmQ+U0VDT05EPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48a2V5d29y

ZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnN0

cmVzczwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9r

ZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29y

ZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD5WSVRBTDwva2V5d29yZD48

a2V5d29yZD5WaXRhbCBDYXBhY2l0eTwva2V5d29yZD48a2V5d29yZD5WT0xVTUU8L2tleXdvcmQ+

PGtleXdvcmQ+V0FMTDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MS8yMDA4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVs

PlJFTkRBMjAwODwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5kYTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT4xMDA2NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNDNdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEwMDY1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5ODAiPjEwMDY1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5SZW5kYSxULjwvYXV0aG9yPjxhdXRob3I+QmFyYWxkbyxTLjwvYXV0aG9yPjxhdXRob3I+UGVs

YWlhLEcuPC9hdXRob3I+PGF1dGhvcj5CYXp6YW4sRS48L2F1dGhvcj48YXV0aG9yPlR1cmF0byxH

LjwvYXV0aG9yPjxhdXRob3I+UGFwaSxBLjwvYXV0aG9yPjxhdXRob3I+TWFlc3RyZWxsaSxQLjwv

YXV0aG9yPjxhdXRob3I+TWFzZWxsaSxSLjwvYXV0aG9yPjxhdXRob3I+VmF0cmVsbGEsQS48L2F1

dGhvcj48YXV0aG9yPkZhYmJyaSxMLk0uPC9hdXRob3I+PGF1dGhvcj5adWluLFIuPC9hdXRob3I+

PGF1dGhvcj5NYXJzaWNvLFMuQS48L2F1dGhvcj48YXV0aG9yPlNhZXR0YSxNLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5JbmNyZWFzZWQgYWN0aXZhdGlv

biBvZiBwMzggTUFQSyBpbiBDT1BEPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBSZXNwaXIg

Si48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIg

UmVzcGlyIEouPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjItNjk8L3BhZ2VzPjx2

b2x1bWU+MzE8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBp

biBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRJT048L2tl

eXdvcmQ+PGtleXdvcmQ+QUxWRU9MQVI8L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9w

aGFnZTwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29yZD5hcG9wdG9z

aXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29y

ZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FWFBJUkFUT1JZPC9rZXl3b3JkPjxr

ZXl3b3JkPkVYUFJFU1NFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5d29yZD48a2V5d29yZD5mdW5jdGlv

bjwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29y

ZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPktJTkFTRTwva2V5d29yZD48a2V5d29yZD5LSU5BU0VT

PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+

PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29y

ZD48a2V5d29yZD5NQVBLPC9rZXl3b3JkPjxrZXl3b3JkPm1pdG9nZW4tYWN0aXZhdGVkIHByb3Rl

aW4ga2luYXNlczwva2V5d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JT

VFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T1hJREFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk94

aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+cDM4PC9rZXl3b3JkPjxrZXl3b3JkPnBh

dGhvZ2VuZXNpczwva2V5d29yZD48a2V5d29yZD5QQVRIV0FZPC9rZXl3b3JkPjxrZXl3b3JkPlBB

VElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9naWNhbDwva2V5d29yZD48a2V5d29y

ZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4ga2luYXNlPC9rZXl3b3JkPjxrZXl3

b3JkPlByb3RlaW4gS2luYXNlczwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+

PGtleXdvcmQ+U0VDT05EPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48a2V5d29y

ZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnN0

cmVzczwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9r

ZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29y

ZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD5WSVRBTDwva2V5d29yZD48

a2V5d29yZD5WaXRhbCBDYXBhY2l0eTwva2V5d29yZD48a2V5d29yZD5WT0xVTUU8L2tleXdvcmQ+

PGtleXdvcmQ+V0FMTDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+MS8yMDA4PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVs

PlJFTkRBMjAwODwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

AG==

ADDIN EN.CITE.DATA [43]. Macrophages also release CXCL9, CXCL10 and CXCL11, which are chemotactic for CD8+ Tc1 and CD4+ Th1 cells, via interaction with the chemokine receptor CXCR3 expressed on these cells ADDIN EN.CITE <EndNote><Cite><Author>Grumelli</Author><Year>2004</Year><RecNum>9006</RecNum><DisplayText>[44]</DisplayText><record><rec-number>9006</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478962">9006</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grumelli,S.</author><author>Corry,D.B.</author><author>Song,L-X.</author><author>Song,L.</author><author>Green,L.</author><author>Huh,J.</author><author>Haccken,J.</author><author>Espada,R.</author><author>Bag,R.</author><author>Lewis,D.E.</author><author>Kheradmand,F.</author></authors></contributors><titles><title>An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema</title><secondary-title>PLoS Med</secondary-title></titles><periodical><full-title>PLoS Med</full-title></periodical><pages>75-83</pages><volume>1</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>IMMUNE</keyword><keyword>Lung</keyword><keyword>IN</keyword><keyword>CHRONIC</keyword><keyword>CHRONIC OBSTRUCTIVE</keyword><keyword>Chronic obstructive pulmonary disease</keyword><keyword>OBSTRUCTIVE</keyword><keyword>PULMONARY</keyword><keyword>DISEASE</keyword><keyword>EMPHYSEMA</keyword></keywords><dates><year>2004</year><pub-dates><date>2004</date></pub-dates></dates><label>GRUMELLI2004A</label><urls></urls></record></Cite></EndNote>[44]. Macrophages from COPD patients release more inflammatory proteins than macrophages from normal smokers and non-smokers, indicating increased activation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DdWxwaXR0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48

UmVjTnVtPjgwOTE8L1JlY051bT48RGlzcGxheVRleHQ+WzQwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj44MDkxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NDYiPjgwOTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRob3I+Um9nZXJzLEQuRi48L2F1dGhvcj48YXV0aG9y

PlNoYWgsUC48L2F1dGhvcj48YXV0aG9yPmRlIE1hdG9zLEMuPC9hdXRob3I+PGF1dGhvcj5SdXNz

ZWxsLFIuRS48L2F1dGhvcj48YXV0aG9yPkRvbm5lbGx5LEwuRS48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkltcGFpcmVkIGluaGliaXRpb24gYnkgZGV4YW1ldGhhc29uZSBvZiBjeXRva2luZSByZWxlYXNl

IGJ5IGFsdmVvbGFyIG1hY3JvcGhhZ2VzIGZyb20gcGF0aWVudHMgd2l0aCBjaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVz

cGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MjQtMzE8L3BhZ2VzPjx2b2x1bWU+MTY3PC92b2x1bWU+PG51bWJlcj4xPC9u

dW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD4xNTwva2V5d29yZD48a2V5d29yZD4yMjM5MDU1NDwva2V5d29yZD48a2V5

d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdlPC9rZXl3

b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hPQUxW

RU9MQVIgTEFWQUdFPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0hS

T05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3

b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdv

cmQ+Q0lHQVJFVFRFPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURSBTTU9LRTwva2V5d29yZD48

a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lEPC9rZXl3b3JkPjxr

ZXl3b3JkPkNvcnRpY29zdGVyb2lkczwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29y

ZD48a2V5d29yZD5kZXhhbWV0aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRklDQUNZPC9rZXl3b3JkPjxr

ZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5HTS1DU0Y8L2tleXdvcmQ+PGtleXdvcmQ+

R1JBTlVMT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+R3JhbnVsb2N5dGUgTWFjcm9waGFnZSBDb2xv

bnkgU3RpbXVsYXRpbmcgRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtl

eXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5D

UkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVDwva2V5d29yZD48a2V5d29yZD5J

TkhJQklUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3Jk

PkxBVkFHRTwva2V5d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1h

Y3JvcGhhZ2UgQ29sb255IFN0aW11bGF0aW5nIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5NYWNy

b3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRURJVU08L2tleXdvcmQ+PGtleXdvcmQ+Tjwva2V5

d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29y

ZD48a2V5d29yZD5SRVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFD

VDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3

b3JkPjxrZXl3b3JkPlNUSU1VTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+U1RJTVVMQVRJTkc8L2tl

eXdvcmQ+PGtleXdvcmQ+VFJBQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5UPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzEv

MjAwMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5DVUxQSVRUMjAwMzwvbGFiZWw+

PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DdWxwaXR0PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48

UmVjTnVtPjgwOTE8L1JlY051bT48RGlzcGxheVRleHQ+WzQwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj44MDkxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NDYiPjgwOTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRob3I+Um9nZXJzLEQuRi48L2F1dGhvcj48YXV0aG9y

PlNoYWgsUC48L2F1dGhvcj48YXV0aG9yPmRlIE1hdG9zLEMuPC9hdXRob3I+PGF1dGhvcj5SdXNz

ZWxsLFIuRS48L2F1dGhvcj48YXV0aG9yPkRvbm5lbGx5LEwuRS48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkltcGFpcmVkIGluaGliaXRpb24gYnkgZGV4YW1ldGhhc29uZSBvZiBjeXRva2luZSByZWxlYXNl

IGJ5IGFsdmVvbGFyIG1hY3JvcGhhZ2VzIGZyb20gcGF0aWVudHMgd2l0aCBjaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVz

cGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9k

aWNhbD48cGFnZXM+MjQtMzE8L3BhZ2VzPjx2b2x1bWU+MTY3PC92b2x1bWU+PG51bWJlcj4xPC9u

dW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3

b3Jkcz48a2V5d29yZD4xNTwva2V5d29yZD48a2V5d29yZD4yMjM5MDU1NDwva2V5d29yZD48a2V5

d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdlPC9rZXl3

b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hPQUxW

RU9MQVIgTEFWQUdFPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0hS

T05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3

b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdv

cmQ+Q0lHQVJFVFRFPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURSBTTU9LRTwva2V5d29yZD48

a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lEPC9rZXl3b3JkPjxr

ZXl3b3JkPkNvcnRpY29zdGVyb2lkczwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29y

ZD48a2V5d29yZD5kZXhhbWV0aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRklDQUNZPC9rZXl3b3JkPjxr

ZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5HTS1DU0Y8L2tleXdvcmQ+PGtleXdvcmQ+

R1JBTlVMT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+R3JhbnVsb2N5dGUgTWFjcm9waGFnZSBDb2xv

bnkgU3RpbXVsYXRpbmcgRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtl

eXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5D

UkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVDwva2V5d29yZD48a2V5d29yZD5J

TkhJQklUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3Jk

PkxBVkFHRTwva2V5d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1h

Y3JvcGhhZ2UgQ29sb255IFN0aW11bGF0aW5nIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5NYWNy

b3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRURJVU08L2tleXdvcmQ+PGtleXdvcmQ+Tjwva2V5

d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29y

ZD48a2V5d29yZD5SRVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFD

VDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3

b3JkPjxrZXl3b3JkPlNUSU1VTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+U1RJTVVMQVRJTkc8L2tl

eXdvcmQ+PGtleXdvcmQ+VFJBQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5UPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzEv

MjAwMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5DVUxQSVRUMjAwMzwvbGFiZWw+

PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [40]Both alveolar macrophages and monocyte-derived macrophages from COPD patients also show reduced phagocytic uptake of bacteria and this may predispose to chronic colonization of the lower airways by bacteria such as Haemophilus influenzae or Streptococcus pneumoniae PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXlsb3I8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MTA5MTA8L1JlY051bT48RGlzcGxheVRleHQ+WzQ1XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMDkxMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTkzIj4xMDkxMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+VGF5bG9yLEEuRS48L2F1dGhvcj48YXV0aG9yPkZpbm5leS1IYXl3YXJkLFQuSy48L2F1dGhv

cj48YXV0aG9yPlF1aW50LEouSy48L2F1dGhvcj48YXV0aG9yPlRob21hcyxDLk0uPC9hdXRob3I+

PGF1dGhvcj5UdWRob3BlLFMuSi48L2F1dGhvcj48YXV0aG9yPldlZHppY2hhLEouQS48L2F1dGhv

cj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5Eb25uZWxseSxMLkUuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkRlZmVjdGl2ZSBtYWNy

b3BoYWdlIHBoYWdvY3l0b3NpcyBvZiBiYWN0ZXJpYSBpbiBDT1BEPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkV1ciBSZXNwaXIgSi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5FdXIgUmVzcGlyIEouPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MTAzOS0xMDQ3PC9wYWdlcz48dm9sdW1lPjM1PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5O

b3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BSVJGTE9XPC9r

ZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFMVkVPTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkFsdmVvbGFyIG1hY3JvcGhhZ2U8

L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+QXppdGhyb215Y2lu

PC9rZXl3b3JkPjxrZXl3b3JkPkJhY3RlcmlhPC9rZXl3b3JkPjxrZXl3b3JkPmJ1ZGVzb25pZGU8

L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48

a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FWEFDRVJCQVRJT048L2tleXdvcmQ+

PGtleXdvcmQ+RVhBQ0VSQkFUSU9OUzwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPkZMT1c8L2tleXdvcmQ+PGtleXdvcmQ+RmxvdyBDeXRvbWV0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+Rm9ybW90ZXJvbDwva2V5d29yZD48a2V5d29yZD5IT1NQSVRBTElaQVRJT048

L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3Jk

PjxrZXl3b3JkPkluZmVjdGlvbjwva2V5d29yZD48a2V5d29yZD5MZWFkPC9rZXl3b3JkPjxrZXl3

b3JkPkxPV0VSPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+

TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+bWFubm9zZSByZWNlcHRvcjwva2V5d29yZD48

a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElPTjwva2V5d29yZD48a2V5d29y

ZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29y

ZD5QaGFnb2N5dG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3

b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9yIGV4cHJlc3Npb248L2tleXdv

cmQ+PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRU1PVkFMPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48a2V5

d29yZD5zdHJlcHRvY29jY3VzIHBuZXVtb25pYWU8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwv

a2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVVJGQUNFPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEw

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlRBWUxPUjIwMTA8L2xhYmVsPjx1cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXlsb3I8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MTA5MTA8L1JlY051bT48RGlzcGxheVRleHQ+WzQ1XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMDkxMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTkzIj4xMDkxMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+VGF5bG9yLEEuRS48L2F1dGhvcj48YXV0aG9yPkZpbm5leS1IYXl3YXJkLFQuSy48L2F1dGhv

cj48YXV0aG9yPlF1aW50LEouSy48L2F1dGhvcj48YXV0aG9yPlRob21hcyxDLk0uPC9hdXRob3I+

PGF1dGhvcj5UdWRob3BlLFMuSi48L2F1dGhvcj48YXV0aG9yPldlZHppY2hhLEouQS48L2F1dGhv

cj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5Eb25uZWxseSxMLkUuPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkRlZmVjdGl2ZSBtYWNy

b3BoYWdlIHBoYWdvY3l0b3NpcyBvZiBiYWN0ZXJpYSBpbiBDT1BEPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPkV1ciBSZXNwaXIgSi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5FdXIgUmVzcGlyIEouPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MTAzOS0xMDQ3PC9wYWdlcz48dm9sdW1lPjM1PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5O

b3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BSVJGTE9XPC9r

ZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFMVkVPTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkFsdmVvbGFyIG1hY3JvcGhhZ2U8

L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+QXppdGhyb215Y2lu

PC9rZXl3b3JkPjxrZXl3b3JkPkJhY3RlcmlhPC9rZXl3b3JkPjxrZXl3b3JkPmJ1ZGVzb25pZGU8

L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48

a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tl

eXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5

d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FWEFDRVJCQVRJT048L2tleXdvcmQ+

PGtleXdvcmQ+RVhBQ0VSQkFUSU9OUzwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPkZMT1c8L2tleXdvcmQ+PGtleXdvcmQ+RmxvdyBDeXRvbWV0cnk8L2tleXdv

cmQ+PGtleXdvcmQ+Rm9ybW90ZXJvbDwva2V5d29yZD48a2V5d29yZD5IT1NQSVRBTElaQVRJT048

L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3Jk

PjxrZXl3b3JkPkluZmVjdGlvbjwva2V5d29yZD48a2V5d29yZD5MZWFkPC9rZXl3b3JkPjxrZXl3

b3JkPkxPV0VSPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+

TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+bWFubm9zZSByZWNlcHRvcjwva2V5d29yZD48

a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElPTjwva2V5d29yZD48a2V5d29y

ZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29y

ZD5QaGFnb2N5dG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3

b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9yIGV4cHJlc3Npb248L2tleXdv

cmQ+PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRU1PVkFMPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48a2V5

d29yZD5zdHJlcHRvY29jY3VzIHBuZXVtb25pYWU8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwv

a2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVVJGQUNFPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDEw

PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlRBWUxPUjIwMTA8L2xhYmVsPjx1cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [45] COPD macrophages also show reduced uptake (clearance) of apoptotic cells (efferocytosis) and this may contribute to the failure to resolve inflammation in COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2RnZTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl

Y051bT44MzczPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls0Nl08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+ODM3MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTUxIj44MzczPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5I

b2RnZSxTLjwvYXV0aG9yPjxhdXRob3I+SG9kZ2UsRy48L2F1dGhvcj48YXV0aG9yPlNjaWNjaGl0

YW5vLFIuPC9hdXRob3I+PGF1dGhvcj5SZXlub2xkcyxQLk4uPC9hdXRob3I+PGF1dGhvcj5Ib2xt

ZXMsTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx2

ZW9sYXIgbWFjcm9waGFnZXMgZnJvbSBzdWJqZWN0cyB3aXRoIGNocm9uaWMgb2JzdHJ1Y3RpdmUg

cHVsbW9uYXJ5IGRpc2Vhc2UgYXJlIGRlZmljaWVudCBpbiB0aGVpciBhYmlsaXR5IHRvIHBoYWdv

Y3l0b3NlIGFwb3B0b3RpYyBhaXJ3YXkgZXBpdGhlbGlhbCBjZWxsczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5JbW11bm9sLkNlbGwgQmlvbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5JbW11bm9sLkNlbGwgQmlvbC48L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4yODktMjk2PC9wYWdlcz48dm9sdW1lPjgxPC92b2x1bWU+PG51bWJlcj40

PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD4yMjczNDA5OTwva2V5d29yZD48a2V5d29yZD5BQ0NVTVVMQVRJT048

L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFMVkVPTEFSPC9rZXl3

b3JkPjxrZXl3b3JkPkFsdmVvbGFyIG1hY3JvcGhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+QU5USTwv

a2V5d29yZD48a2V5d29yZD5hcG9wdG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdv

cmQ+PGtleXdvcmQ+QkFTSUM8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFSPC9rZXl3

b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUiBMQVZBR0U8L2tleXdvcmQ+PGtleXdvcmQ+Q0VM

TDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25p

YyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVU

VEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRFIFNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPkNP

TU1VTklUWTwva2V5d29yZD48a2V5d29yZD5DT01QTEVYRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q09O

VFJPTDwva2V5d29yZD48a2V5d29yZD5DVUxUVVJFRDwva2V5d29yZD48a2V5d29yZD5EQU1BR0U8

L2tleXdvcmQ+PGtleXdvcmQ+REVGRUNUUzwva2V5d29yZD48a2V5d29yZD5ERUZJQ0lFTkNZPC9r

ZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RVBJVEhFTElBTDwva2V5

d29yZD48a2V5d29yZD5lcGl0aGVsaWFsIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkVYVFJBQ0VM

TFVMQVI8L2tleXdvcmQ+PGtleXdvcmQ+ZXh0cmFjZWxsdWxhciBtYXRyaXg8L2tleXdvcmQ+PGtl

eXdvcmQ+RkxPVzwva2V5d29yZD48a2V5d29yZD5GbG93IEN5dG9tZXRyeTwva2V5d29yZD48a2V5

d29yZD5nbG9iYWw8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVB

U0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklOR0VTVEVEPC9rZXl3b3JkPjxrZXl3b3JkPkxBVkFHRTwv

a2V5d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1hY3JvcGhhZ2Vz

PC9rZXl3b3JkPjxrZXl3b3JkPk1BVFJJWDwva2V5d29yZD48a2V5d29yZD5NT1JCSURJVFk8L2tl

eXdvcmQ+PGtleXdvcmQ+TU9SVEFMSVRZPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxr

ZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwva2V5d29y

ZD48a2V5d29yZD5QaGFnb2N5dG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3

b3JkPjxrZXl3b3JkPlJFRFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+U01PS0U8L2tleXdvcmQ+PGtl

eXdvcmQ+U1BFQ0lGSUM8L2tleXdvcmQ+PGtleXdvcmQ+c3RhaW5pbmc8L2tleXdvcmQ+PGtleXdv

cmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJK

RUNUUzwva2V5d29yZD48a2V5d29yZD5UQVJHRVQ8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5U

PC9rZXl3b3JkPjxrZXl3b3JkPlVOREVSU1RBTkRJTkc8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAwMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjAwMzwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5IT0RHRTIwMDM8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2RnZTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl

Y051bT44MzczPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls0Nl08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+ODM3MzwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTUxIj44MzczPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5I

b2RnZSxTLjwvYXV0aG9yPjxhdXRob3I+SG9kZ2UsRy48L2F1dGhvcj48YXV0aG9yPlNjaWNjaGl0

YW5vLFIuPC9hdXRob3I+PGF1dGhvcj5SZXlub2xkcyxQLk4uPC9hdXRob3I+PGF1dGhvcj5Ib2xt

ZXMsTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx2

ZW9sYXIgbWFjcm9waGFnZXMgZnJvbSBzdWJqZWN0cyB3aXRoIGNocm9uaWMgb2JzdHJ1Y3RpdmUg

cHVsbW9uYXJ5IGRpc2Vhc2UgYXJlIGRlZmljaWVudCBpbiB0aGVpciBhYmlsaXR5IHRvIHBoYWdv

Y3l0b3NlIGFwb3B0b3RpYyBhaXJ3YXkgZXBpdGhlbGlhbCBjZWxsczwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5JbW11bm9sLkNlbGwgQmlvbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5JbW11bm9sLkNlbGwgQmlvbC48L2Z1bGwtdGl0bGU+PC9wZXJp

b2RpY2FsPjxwYWdlcz4yODktMjk2PC9wYWdlcz48dm9sdW1lPjgxPC92b2x1bWU+PG51bWJlcj40

PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD4yMjczNDA5OTwva2V5d29yZD48a2V5d29yZD5BQ0NVTVVMQVRJT048

L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFMVkVPTEFSPC9rZXl3

b3JkPjxrZXl3b3JkPkFsdmVvbGFyIG1hY3JvcGhhZ2U8L2tleXdvcmQ+PGtleXdvcmQ+QU5USTwv

a2V5d29yZD48a2V5d29yZD5hcG9wdG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdv

cmQ+PGtleXdvcmQ+QkFTSUM8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFSPC9rZXl3

b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUiBMQVZBR0U8L2tleXdvcmQ+PGtleXdvcmQ+Q0VM

TDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25p

YyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVU

VEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRFIFNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPkNP

TU1VTklUWTwva2V5d29yZD48a2V5d29yZD5DT01QTEVYRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q09O

VFJPTDwva2V5d29yZD48a2V5d29yZD5DVUxUVVJFRDwva2V5d29yZD48a2V5d29yZD5EQU1BR0U8

L2tleXdvcmQ+PGtleXdvcmQ+REVGRUNUUzwva2V5d29yZD48a2V5d29yZD5ERUZJQ0lFTkNZPC9r

ZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RVBJVEhFTElBTDwva2V5

d29yZD48a2V5d29yZD5lcGl0aGVsaWFsIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkVYVFJBQ0VM

TFVMQVI8L2tleXdvcmQ+PGtleXdvcmQ+ZXh0cmFjZWxsdWxhciBtYXRyaXg8L2tleXdvcmQ+PGtl

eXdvcmQ+RkxPVzwva2V5d29yZD48a2V5d29yZD5GbG93IEN5dG9tZXRyeTwva2V5d29yZD48a2V5

d29yZD5nbG9iYWw8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVB

U0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklOR0VTVEVEPC9rZXl3b3JkPjxrZXl3b3JkPkxBVkFHRTwv

a2V5d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1hY3JvcGhhZ2Vz

PC9rZXl3b3JkPjxrZXl3b3JkPk1BVFJJWDwva2V5d29yZD48a2V5d29yZD5NT1JCSURJVFk8L2tl

eXdvcmQ+PGtleXdvcmQ+TU9SVEFMSVRZPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxr

ZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwva2V5d29y

ZD48a2V5d29yZD5QaGFnb2N5dG9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3

b3JkPjxrZXl3b3JkPlJFRFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+U01PS0U8L2tleXdvcmQ+PGtl

eXdvcmQ+U1BFQ0lGSUM8L2tleXdvcmQ+PGtleXdvcmQ+c3RhaW5pbmc8L2tleXdvcmQ+PGtleXdv

cmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJK

RUNUUzwva2V5d29yZD48a2V5d29yZD5UQVJHRVQ8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5U

PC9rZXl3b3JkPjxrZXl3b3JkPlVOREVSU1RBTkRJTkc8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAwMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjAwMzwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5IT0RHRTIwMDM8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [46]. Bacterial colonization of lower airways, found in around half of COPD patients, may predispose to increased acute exacerbations ADDIN EN.CITE <EndNote><Cite><Author>Singh</Author><Year>2014</Year><RecNum>12078</RecNum><DisplayText>[47]</DisplayText><record><rec-number>12078</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1412586608">12078</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Singh, R.</author><author>Mackay, A. J.</author><author>Patel, A.</author><author>Garcha, D. S.</author><author>Kowlessar, B. S.</author><author>Brill, S. E.</author><author>Donnelly, L. E.</author><author>Barnes, P. J.</author><author>Donaldson, G. C.</author><author>Wedzicha, J. A.</author></authors></contributors><titles><title>Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive pulmonary disease</title><secondary-title>Respir Res</secondary-title><alt-title>Respiratory research</alt-title></titles><periodical><full-title>Respir Res</full-title></periodical><pages>114</pages><volume>15</volume><number>1</number><edition>2014/09/15</edition><dates><year>2014</year><pub-dates><date>Sep 14</date></pub-dates></dates><isbn>1465-9921</isbn><accession-num>25218165</accession-num><urls></urls><custom2>Pmc4173051</custom2><electronic-resource-num>10.1186/s12931-014-0114-1</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[47]. Reduced macrophage phagocytosis of bacteria has also been described in patients with severe asthma ADDIN EN.CITE <EndNote><Cite><Author>Liang</Author><Year>2014</Year><RecNum>11970</RecNum><DisplayText>[48]</DisplayText><record><rec-number>11970</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1405068892">11970</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liang, Z.</author><author>Zhang, Q.</author><author>Thomas, C. M.</author><author>Chana, K. K.</author><author>Gibeon, D.</author><author>Barnes, P. J.</author><author>Chung, K. F.</author><author>Bhavsar, P. K.</author><author>Donnelly, L. E.</author></authors></contributors><auth-address>Airway Disease, National Heart and Lung Institute, Imperial College London, &amp; Biomedical Research Unit, Royal Brompton &amp; Harefield NHS Trust, London SW3, UK. p.bhavsar@imperial.ac.uk.</auth-address><titles><title>Impaired macrophage phagocytosis of bacteria in severe asthma</title><secondary-title>Respir Res</secondary-title><alt-title>Respiratory research</alt-title></titles><periodical><full-title>Respir Res</full-title></periodical><pages>72</pages><volume>15</volume><number>1</number><edition>2014/06/29</edition><dates><year>2014</year></dates><isbn>1465-9921</isbn><accession-num>24972601</accession-num><urls></urls><custom2>Pmc4086996</custom2><electronic-resource-num>10.1186/1465-9921-15-72</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[48].Dendritic cellsDendritic cells are specialized macrophage-like cells in the airway epithelium, which are the major antigen-presenting cells in the airways and an important link between innate and adaptive immunity in the lungs ADDIN EN.CITE <EndNote><Cite><Author>Upham</Author><Year>2016</Year><RecNum>12930</RecNum><DisplayText>[49]</DisplayText><record><rec-number>12930</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482421366">12930</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Upham, J. W.</author><author>Xi, Y.</author></authors></contributors><auth-address>School of Medicine, The University of Queensland, Translational Research Institute (TRI), Woolloongabba, Brisbane, Australia; Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, Australia. Electronic address: j.upham@uq.edu.au.&#xD;School of Medicine, The University of Queensland, Translational Research Institute (TRI), Woolloongabba, Brisbane, Australia; Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, Australia.</auth-address><titles><title>Dendritic cells in human lung disease: recent advances</title><secondary-title>Chest</secondary-title><alt-title>Chest</alt-title></titles><periodical><full-title>Chest</full-title></periodical><alt-periodical><full-title>Chest</full-title></alt-periodical><edition>2016/10/13</edition><dates><year>2016</year><pub-dates><date>Oct 08</date></pub-dates></dates><isbn>0012-3692</isbn><accession-num>27729261</accession-num><urls></urls><electronic-resource-num>10.1016/j.chest.2016.09.030</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[49]. Dendritic cells take up allergens, process them to peptides, and migrate to local lymph nodes where they present the allergenic peptides to uncommitted T-lymphocytes to program the production of allergen-specific T-cells. Immature dendritic cells in the respiratory tract promote helper T-cell (Th2) cell differentiation ADDIN EN.CITE <EndNote><Cite><Author>Upham</Author><Year>2016</Year><RecNum>12930</RecNum><DisplayText>[49]</DisplayText><record><rec-number>12930</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482421366">12930</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Upham, J. W.</author><author>Xi, Y.</author></authors></contributors><auth-address>School of Medicine, The University of Queensland, Translational Research Institute (TRI), Woolloongabba, Brisbane, Australia; Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, Australia. Electronic address: j.upham@uq.edu.au.&#xD;School of Medicine, The University of Queensland, Translational Research Institute (TRI), Woolloongabba, Brisbane, Australia; Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, Australia.</auth-address><titles><title>Dendritic cells in human lung disease: recent advances</title><secondary-title>Chest</secondary-title><alt-title>Chest</alt-title></titles><periodical><full-title>Chest</full-title></periodical><alt-periodical><full-title>Chest</full-title></alt-periodical><edition>2016/10/13</edition><dates><year>2016</year><pub-dates><date>Oct 08</date></pub-dates></dates><isbn>0012-3692</isbn><accession-num>27729261</accession-num><urls></urls><electronic-resource-num>10.1016/j.chest.2016.09.030</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[49]. The cytokine thymic stromal lymphopoietin (TSLP) released from epithelial cells in asthmatic patients programmes dendritic cells to release chemokines that attract Th2 cells into the airways ADDIN EN.CITE <EndNote><Cite><Author>Hammad</Author><Year>2015</Year><RecNum>12361</RecNum><DisplayText>[50]</DisplayText><record><rec-number>12361</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1438165232">12361</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hammad, H.</author><author>Lambrecht, B. N.</author></authors></contributors><auth-address>VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium; Laboratory of Immunoregulation and Mucosal Immunology, Department of Respiratory Medicine, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: hamida.hammad@irc.vib-ugent.be.&#xD;VIB Inflammation Research Center, Technologiepark 927, 9052 Ghent, Belgium; Laboratory of Immunoregulation and Mucosal Immunology, Department of Respiratory Medicine, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium; Department of Pulmonary Medicine, ErasmusMC, Dr Molewaterplein 50, 3015 GE Rotterdam, the Netherlands. Electronic address: bart.lambrecht@irc.vib-ugent.be.</auth-address><titles><title>Barrier epithelial cells and the control of type 2 immunity</title><secondary-title>Immunity</secondary-title><alt-title>Immunity</alt-title></titles><periodical><full-title>Immunity</full-title></periodical><alt-periodical><full-title>Immunity</full-title></alt-periodical><pages>29-40</pages><volume>43</volume><number>1</number><edition>2015/07/23</edition><dates><year>2015</year><pub-dates><date>Jul 21</date></pub-dates></dates><isbn>1074-7613</isbn><accession-num>26200011</accession-num><urls></urls><electronic-resource-num>10.1016/j.immuni.2015.07.007</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[50]. Dendritic cells are activated and increased in number in the lungs of COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gUG90dGVsYmVyZ2U8L0F1dGhvcj48WWVhcj4yMDEw

PC9ZZWFyPjxSZWNOdW0+MTE2MjU8L1JlY051bT48RGlzcGxheVRleHQ+WzUxXTwvRGlzcGxheVRl

eHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMTYyNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIg

dGltZXN0YW1wPSIxMzc4NDc5MDA0Ij4xMTYyNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+VmFuIFBvdHRlbGJlcmdlLEcuUi48L2F1dGhvcj48YXV0aG9yPkJyYWNrZSxL

LlIuPC9hdXRob3I+PGF1dGhvcj5EZW1lZHRzLEkuSy48L2F1dGhvcj48YXV0aG9yPkRlIFJpamNr

LEsuPC9hdXRob3I+PGF1dGhvcj5SZWluYXJ0eixTLk0uPC9hdXRob3I+PGF1dGhvcj52YW4gRHJ1

bmVuLEMuTS48L2F1dGhvcj48YXV0aG9yPlZlcmxlZGVuLEcuTS48L2F1dGhvcj48YXV0aG9yPlZl

cm1hc3NlbixGLkUuPC9hdXRob3I+PGF1dGhvcj5Kb29zLEcuRi48L2F1dGhvcj48YXV0aG9yPkJy

dXNzZWxsZSxHLkcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlNlbGVjdGl2ZSBhY2N1bXVsYXRpb24gb2YgbGFuZ2VyaGFucy10eXBlIGRlbmRyaXRpYyBj

ZWxscyBpbiBzbWFsbCBhaXJ3YXlzIG9mIHBhdGllbnRzIHdpdGggQ09QRDwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5SZXNwaXIuUmVzLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPlJlc3Bpci5SZXMuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MzU8L3BhZ2VzPjx2b2x1bWU+MTE6MzUuPC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3Qg

aW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ0NVTVVMQVRJT048

L2tleXdvcmQ+PGtleXdvcmQ+QWN0aXZpbnM8L2tleXdvcmQ+PGtleXdvcmQ+YWR2ZXJzZSBlZmZl

Y3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3

b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QUxURVJFRDwva2V5d29yZD48

a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29yZD5BbnRpZ2VucyxDRDwva2V5d29yZD48

a2V5d29yZD5BbnRpZ2VucyxDRDE8L2tleXdvcmQ+PGtleXdvcmQ+YW50aWdlbnMsc3VyZmFjZTwv

a2V5d29yZD48a2V5d29yZD5CZWxnaXVtPC9rZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9rZXl3b3Jk

PjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBBZGhlc2lvbiBNb2xlY3VsZXM8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBEaWZmZXJlbnRpYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hhcmFjdGVyaXphdGlvbjwva2V5d29yZD48a2V5d29y

ZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRFQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5ERU5E

UklUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVuZHJpdGljIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5USUFUSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdv

cmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdv

cmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUlM8L2tleXdvcmQ+PGtleXdvcmQ+RmVt

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPmZ1

dHVyZTwva2V5d29yZD48a2V5d29yZD5HRU5FVElDUzwva2V5d29yZD48a2V5d29yZD5IT1NQSVRB

TDwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdv

cmQ+PGtleXdvcmQ+SU1NVU5FPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0hJU1RPQ0hFTUlDQUw8

L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+

SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JbnRlcmxl

dWtpbi0xNTwva2V5d29yZD48a2V5d29yZD5JbnRyYWNlbGx1bGFyIFNpZ25hbGluZyBQZXB0aWRl

cyBhbmQgUHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+bGFuZ2VyaGFucyBjZWxsczwva2V5d29y

ZD48a2V5d29yZD5MZWN0aW5zLEMtVHlwZTwva2V5d29yZD48a2V5d29yZD5saW5lYXIgbW9kZWxz

PC9rZXl3b3JkPjxrZXl3b3JkPkxPV0VSPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+

PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5N

YW5ub3NlLUJpbmRpbmcgTGVjdGluczwva2V5d29yZD48a2V5d29yZD5NRURJQ0lORTwva2V5d29y

ZD48a2V5d29yZD5tZW1icmFuZSBwcm90ZWluczwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tl

eXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5

d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5wYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+

PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBSRUNVUlNPUjwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vh

c2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29yZD48a2V5d29yZD5SYW5rIExpZ2FuZDwva2V5

d29yZD48a2V5d29yZD5SZWNlcHRvcnMsQ2VsbCBTdXJmYWNlPC9rZXl3b3JkPjxrZXl3b3JkPlJF

TEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUElS

QVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9O

U0VTPC9rZXl3b3JkPjxrZXl3b3JkPnJldmVyc2UgdHJhbnNjcmlwdGFzZSBwb2x5bWVyYXNlIGNo

YWluIHJlYWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJOQTwva2V5d29yZD48a2V5d29yZD5STkEs

TWVzc2VuZ2VyPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0VMRUNU

SVZFPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3JkPlNJTkdMRTwv

a2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3Jk

PjxrZXl3b3JkPnNtb2tpbmcgY2Vzc2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnN0YWluaW5nPC9r

ZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+

PGtleXdvcmQ+U3VzcGVuc2lvbnM8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VFPC9rZXl3b3JkPjxr

ZXl3b3JkPlRXTzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+My8yMi8yMDEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVs

PlZBTlBPVFRFTEJFUkdFMjAxMDwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WYW4gUG90dGVsYmVyZ2U8L0F1dGhvcj48WWVhcj4yMDEw

PC9ZZWFyPjxSZWNOdW0+MTE2MjU8L1JlY051bT48RGlzcGxheVRleHQ+WzUxXTwvRGlzcGxheVRl

eHQ+PHJlY29yZD48cmVjLW51bWJlcj4xMTYyNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxr

ZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIg

dGltZXN0YW1wPSIxMzc4NDc5MDA0Ij4xMTYyNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlw

ZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRo

b3JzPjxhdXRob3I+VmFuIFBvdHRlbGJlcmdlLEcuUi48L2F1dGhvcj48YXV0aG9yPkJyYWNrZSxL

LlIuPC9hdXRob3I+PGF1dGhvcj5EZW1lZHRzLEkuSy48L2F1dGhvcj48YXV0aG9yPkRlIFJpamNr

LEsuPC9hdXRob3I+PGF1dGhvcj5SZWluYXJ0eixTLk0uPC9hdXRob3I+PGF1dGhvcj52YW4gRHJ1

bmVuLEMuTS48L2F1dGhvcj48YXV0aG9yPlZlcmxlZGVuLEcuTS48L2F1dGhvcj48YXV0aG9yPlZl

cm1hc3NlbixGLkUuPC9hdXRob3I+PGF1dGhvcj5Kb29zLEcuRi48L2F1dGhvcj48YXV0aG9yPkJy

dXNzZWxsZSxHLkcuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlNlbGVjdGl2ZSBhY2N1bXVsYXRpb24gb2YgbGFuZ2VyaGFucy10eXBlIGRlbmRyaXRpYyBj

ZWxscyBpbiBzbWFsbCBhaXJ3YXlzIG9mIHBhdGllbnRzIHdpdGggQ09QRDwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5SZXNwaXIuUmVzLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPlJlc3Bpci5SZXMuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MzU8L3BhZ2VzPjx2b2x1bWU+MTE6MzUuPC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3Qg

aW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ0NVTVVMQVRJT048

L2tleXdvcmQ+PGtleXdvcmQ+QWN0aXZpbnM8L2tleXdvcmQ+PGtleXdvcmQ+YWR2ZXJzZSBlZmZl

Y3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3

b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QUxURVJFRDwva2V5d29yZD48

a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29yZD5BbnRpZ2VucyxDRDwva2V5d29yZD48

a2V5d29yZD5BbnRpZ2VucyxDRDE8L2tleXdvcmQ+PGtleXdvcmQ+YW50aWdlbnMsc3VyZmFjZTwv

a2V5d29yZD48a2V5d29yZD5CZWxnaXVtPC9rZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9rZXl3b3Jk

PjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBBZGhlc2lvbiBNb2xlY3VsZXM8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBEaWZmZXJlbnRpYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hhcmFjdGVyaXphdGlvbjwva2V5d29yZD48a2V5d29y

ZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRFQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5ERU5E

UklUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVuZHJpdGljIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3Jk

PkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5USUFUSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdv

cmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdv

cmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUlM8L2tleXdvcmQ+PGtleXdvcmQ+RmVt

YWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPmZ1

dHVyZTwva2V5d29yZD48a2V5d29yZD5HRU5FVElDUzwva2V5d29yZD48a2V5d29yZD5IT1NQSVRB

TDwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdv

cmQ+PGtleXdvcmQ+SU1NVU5FPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0hJU1RPQ0hFTUlDQUw8

L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+

SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JbnRlcmxl

dWtpbi0xNTwva2V5d29yZD48a2V5d29yZD5JbnRyYWNlbGx1bGFyIFNpZ25hbGluZyBQZXB0aWRl

cyBhbmQgUHJvdGVpbnM8L2tleXdvcmQ+PGtleXdvcmQ+bGFuZ2VyaGFucyBjZWxsczwva2V5d29y

ZD48a2V5d29yZD5MZWN0aW5zLEMtVHlwZTwva2V5d29yZD48a2V5d29yZD5saW5lYXIgbW9kZWxz

PC9rZXl3b3JkPjxrZXl3b3JkPkxPV0VSPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+

PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5N

YW5ub3NlLUJpbmRpbmcgTGVjdGluczwva2V5d29yZD48a2V5d29yZD5NRURJQ0lORTwva2V5d29y

ZD48a2V5d29yZD5tZW1icmFuZSBwcm90ZWluczwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tl

eXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5

d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5wYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+

PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBSRUNVUlNPUjwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vh

c2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29yZD48a2V5d29yZD5SYW5rIExpZ2FuZDwva2V5

d29yZD48a2V5d29yZD5SZWNlcHRvcnMsQ2VsbCBTdXJmYWNlPC9rZXl3b3JkPjxrZXl3b3JkPlJF

TEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUElS

QVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9O

U0VTPC9rZXl3b3JkPjxrZXl3b3JkPnJldmVyc2UgdHJhbnNjcmlwdGFzZSBwb2x5bWVyYXNlIGNo

YWluIHJlYWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJOQTwva2V5d29yZD48a2V5d29yZD5STkEs

TWVzc2VuZ2VyPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0VMRUNU

SVZFPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3JkPlNJTkdMRTwv

a2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3Jk

PjxrZXl3b3JkPnNtb2tpbmcgY2Vzc2F0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnN0YWluaW5nPC9r

ZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+

PGtleXdvcmQ+U3VzcGVuc2lvbnM8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VFPC9rZXl3b3JkPjxr

ZXl3b3JkPlRXTzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEwPC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+My8yMi8yMDEwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVs

PlZBTlBPVFRFTEJFUkdFMjAxMDwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [51], especially in severe disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmVlbWFuPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

UmVjTnVtPjExODI5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls1Ml08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE4Mjk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwNyI+MTE4Mjk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkZyZWVtYW4sQy5NLjwvYXV0aG9yPjxhdXRob3I+TWFydGluZXosRi5KLjwvYXV0aG9yPjxh

dXRob3I+SGFuLE0uSy48L2F1dGhvcj48YXV0aG9yPkFtZXMsVC5NLjwvYXV0aG9yPjxhdXRob3I+

Q2hlbnN1ZSxTLlcuPC9hdXRob3I+PGF1dGhvcj5Ub2R0LEouQy48L2F1dGhvcj48YXV0aG9yPkFy

ZW5iZXJnLEQuQS48L2F1dGhvcj48YXV0aG9yPk1lbGRydW0sQy5BLjwvYXV0aG9yPjxhdXRob3I+

R2V0dHksQy48L2F1dGhvcj48YXV0aG9yPk1jQ2xvc2tleSxMLjwvYXV0aG9yPjxhdXRob3I+Q3Vy

dGlzLEouTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

THVuZyBkZW5kcml0aWMgY2VsbCBleHByZXNzaW9uIG9mIG1hdHVyYXRpb24gbW9sZWN1bGVzIGlu

Y3JlYXNlcyB3aXRoIHdvcnNlbmluZyBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNl

YXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtLkogUmVzcGlyLkNyaXQgQ2FyZSBNZWQuPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0uSiBSZXNw

aXIuQ3JpdCBDYXJlIE1lZC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTc5LTEx

ODg8L3BhZ2VzPjx2b2x1bWU+MTgwPC92b2x1bWU+PG51bWJlcj4xMjwvbnVtYmVyPjxyZXByaW50

LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5BQ1VURTwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlnZW5zLENE

PC9rZXl3b3JkPjxrZXl3b3JkPmFudGlnZW5zLGRpZmZlcmVudGlhdGlvbix0LWx5bXBob2N5dGU8

L2tleXdvcmQ+PGtleXdvcmQ+Y2Q0LXBvc2l0aXZlIHQtbHltcGhvY3l0ZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DZWxsIEN1bHR1cmUgVGVjaG5pcXVlczwva2V5

d29yZD48a2V5d29yZD5DZWxsIERpZmZlcmVudGlhdGlvbjwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JT

VFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkg

ZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BE

PC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPU1RJTVVM

QVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+Q3JpdGljYWwgQ2FyZTwva2V5d29yZD48a2V5d29yZD5D

cm9zcyBTZWN0aW9uYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5jcm9zcy1zZWN0aW9uYWwg

c3R1ZGllczwva2V5d29yZD48a2V5d29yZD5ERU5EUklUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVu

ZHJpdGljIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+

ZGlzZWFzZSBwcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3Jk

PkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+

SElHSDwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48

a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtl

eXdvcmQ+SU5URVJBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJBQ1RJT05TPC9rZXl3b3Jk

PjxrZXl3b3JkPkxlY3RpbnMsQy1UeXBlPC9rZXl3b3JkPjxrZXl3b3JkPkxFVUtPQ1lURTwva2V5

d29yZD48a2V5d29yZD5sZXVrb2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+

PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5NRUFTVVJFPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1FQVNVUkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs

ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVDVUxFPC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVD

VUxFUzwva2V5d29yZD48a2V5d29yZD5NVUxUSVBMRTwva2V5d29yZD48a2V5d29yZD5OPC9rZXl3

b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwv

a2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tl

eXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFyeSBEaXNl

YXNlLENocm9uaWMgT2JzdHJ1Y3RpdmU8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9r

ZXl3b3JkPjxrZXl3b3JkPlJFTEVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+

PGtleXdvcmQ+U0VWRVJJVFk8L2tleXdvcmQ+PGtleXdvcmQ+c2V2ZXJpdHkgb2YgaWxsbmVzcyBp

bmRleDwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8

L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNPC9rZXl3b3Jk

PjxrZXl3b3JkPlQ8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMPC9rZXl3b3JkPjxrZXl3b3JkPlQg

Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+VC1DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPlRSSUFMPC9r

ZXl3b3JkPjxrZXl3b3JkPlRXTzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMTUvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxsYWJlbD5GUkVFTUFOMjAwOTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0

ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmVlbWFuPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

UmVjTnVtPjExODI5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls1Ml08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE4Mjk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwNyI+MTE4Mjk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkZyZWVtYW4sQy5NLjwvYXV0aG9yPjxhdXRob3I+TWFydGluZXosRi5KLjwvYXV0aG9yPjxh

dXRob3I+SGFuLE0uSy48L2F1dGhvcj48YXV0aG9yPkFtZXMsVC5NLjwvYXV0aG9yPjxhdXRob3I+

Q2hlbnN1ZSxTLlcuPC9hdXRob3I+PGF1dGhvcj5Ub2R0LEouQy48L2F1dGhvcj48YXV0aG9yPkFy

ZW5iZXJnLEQuQS48L2F1dGhvcj48YXV0aG9yPk1lbGRydW0sQy5BLjwvYXV0aG9yPjxhdXRob3I+

R2V0dHksQy48L2F1dGhvcj48YXV0aG9yPk1jQ2xvc2tleSxMLjwvYXV0aG9yPjxhdXRob3I+Q3Vy

dGlzLEouTC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

THVuZyBkZW5kcml0aWMgY2VsbCBleHByZXNzaW9uIG9mIG1hdHVyYXRpb24gbW9sZWN1bGVzIGlu

Y3JlYXNlcyB3aXRoIHdvcnNlbmluZyBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNl

YXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtLkogUmVzcGlyLkNyaXQgQ2FyZSBNZWQuPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0uSiBSZXNw

aXIuQ3JpdCBDYXJlIE1lZC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTc5LTEx

ODg8L3BhZ2VzPjx2b2x1bWU+MTgwPC92b2x1bWU+PG51bWJlcj4xMjwvbnVtYmVyPjxyZXByaW50

LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5BQ1VURTwva2V5d29yZD48a2V5d29yZD5BZ2Vk

PC9rZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkFudGlnZW5zLENE

PC9rZXl3b3JkPjxrZXl3b3JkPmFudGlnZW5zLGRpZmZlcmVudGlhdGlvbix0LWx5bXBob2N5dGU8

L2tleXdvcmQ+PGtleXdvcmQ+Y2Q0LXBvc2l0aXZlIHQtbHltcGhvY3l0ZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DZWxsIEN1bHR1cmUgVGVjaG5pcXVlczwva2V5

d29yZD48a2V5d29yZD5DZWxsIERpZmZlcmVudGlhdGlvbjwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JT

VFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkg

ZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BE

PC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPU1RJTVVM

QVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+Q3JpdGljYWwgQ2FyZTwva2V5d29yZD48a2V5d29yZD5D

cm9zcyBTZWN0aW9uYWwgU3R1ZGllczwva2V5d29yZD48a2V5d29yZD5jcm9zcy1zZWN0aW9uYWwg

c3R1ZGllczwva2V5d29yZD48a2V5d29yZD5ERU5EUklUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVu

ZHJpdGljIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+

ZGlzZWFzZSBwcm9ncmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3Jk

PkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+

SElHSDwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48

a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtl

eXdvcmQ+SU5URVJBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJBQ1RJT05TPC9rZXl3b3Jk

PjxrZXl3b3JkPkxlY3RpbnMsQy1UeXBlPC9rZXl3b3JkPjxrZXl3b3JkPkxFVUtPQ1lURTwva2V5

d29yZD48a2V5d29yZD5sZXVrb2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+

PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5NRUFTVVJFPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1FQVNVUkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRs

ZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVDVUxFPC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVD

VUxFUzwva2V5d29yZD48a2V5d29yZD5NVUxUSVBMRTwva2V5d29yZD48a2V5d29yZD5OPC9rZXl3

b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwv

a2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tl

eXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFyeSBEaXNl

YXNlLENocm9uaWMgT2JzdHJ1Y3RpdmU8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9r

ZXl3b3JkPjxrZXl3b3JkPlJFTEVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+

PGtleXdvcmQ+U0VWRVJJVFk8L2tleXdvcmQ+PGtleXdvcmQ+c2V2ZXJpdHkgb2YgaWxsbmVzcyBp

bmRleDwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8

L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNPC9rZXl3b3Jk

PjxrZXl3b3JkPlQ8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMPC9rZXl3b3JkPjxrZXl3b3JkPlQg

Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+VC1DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPlRSSUFMPC9r

ZXl3b3JkPjxrZXl3b3JkPlRXTzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMTUvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxsYWJlbD5GUkVFTUFOMjAwOTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0

ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [52]. EosinophilsEosinophilic inflammation is a characteristic feature of asthmatic airways PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

PjxSZWNOdW0+MTE3MTU8L1JlY051bT48RGlzcGxheVRleHQ+WzUzXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMTcxNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc5MDA1Ij4xMTcxNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+Um9zZW5iZXJnLEguRi48L2F1dGhvcj48YXV0aG9yPkR5ZXIsSy5ELjwvYXV0aG9yPjxh

dXRob3I+Rm9zdGVyLFAuUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+RW9zaW5vcGhpbHM6IGNoYW5naW5nIHBlcnNwZWN0aXZlcyBpbiBoZWFsdGggYW5k

IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IFJldiBJbW11bm9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdCBSZXYgSW1tdW5v

bC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz45LTIyPC9wYWdlcz48dm9sdW1lPjEz

PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwv

cmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVklUSUVTPC9rZXl3b3JkPjxr

ZXl3b3JkPkFDVElWSVRZPC9rZXl3b3JkPjxrZXl3b3JkPkFMTEVSR0lDPC9rZXl3b3JkPjxrZXl3

b3JkPkFsbGVyZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QUxURVJFRDwva2V5d29yZD48a2V5d29yZD5B

bmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5DRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPmNlbGwgZGVncmFudWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwv

a2V5d29yZD48a2V5d29yZD5EZWdyYW51bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRFVkVMT1BN

RU5UPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8

L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+ZW9zaW5vcGhpbDwv

a2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsaWE8L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhp

bHM8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248

L2tleXdvcmQ+PGtleXdvcmQ+RlVOQ1RJT05TPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkVSQVRFRDwv

a2V5d29yZD48a2V5d29yZD5IRUFMVEg8L2tleXdvcmQ+PGtleXdvcmQ+SG9tZW9zdGFzaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVyZW9zaW5vcGhpbGlj

IHN5bmRyb21lPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+

SU1QUk9WRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SW5mZWN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPmxldWtvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+bWFyeWxhbmQ8

L2tleXdvcmQ+PGtleXdvcmQ+TUlDRTwva2V5d29yZD48a2V5d29yZD5tb2RlbHMsaW1tdW5vbG9n

aWNhbDwva2V5d29yZD48a2V5d29yZD5NT0xFQ1VMQVI8L2tleXdvcmQ+PGtleXdvcmQ+TkFUSU9O

QUw8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3JkPnBhcmFzaXRpYyBkaXNl

YXNlczwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SFdBWTwva2V5d29yZD48a2V5d29yZD5QQVRIV0FZUzwva2V5d29yZD48a2V5d29yZD5wZXJzcGVj

dGl2ZXM8L2tleXdvcmQ+PGtleXdvcmQ+UFJJTUFSWTwva2V5d29yZD48a2V5d29yZD5SRUNFTlQ8

L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3JzLGltbXVub2xvZ2ljPC9rZXl3b3JkPjxrZXl3b3Jk

PlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwv

a2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TWU5EUk9NRTwva2V5d29y

ZD48a2V5d29yZD5VTFRSQVNUUlVDVFVSRTwva2V5d29yZD48a2V5d29yZD5VTkRFUlNUQU5ESU5H

PC9rZXl3b3JkPjxrZXl3b3JkPlVTQTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MS8yMDEzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGxhYmVsPlJPU0VOQkVSRzIwMTM8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3NlbmJlcmc8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

PjxSZWNOdW0+MTE3MTU8L1JlY051bT48RGlzcGxheVRleHQ+WzUzXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMTcxNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc5MDA1Ij4xMTcxNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+Um9zZW5iZXJnLEguRi48L2F1dGhvcj48YXV0aG9yPkR5ZXIsSy5ELjwvYXV0aG9yPjxh

dXRob3I+Rm9zdGVyLFAuUy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+RW9zaW5vcGhpbHM6IGNoYW5naW5nIHBlcnNwZWN0aXZlcyBpbiBoZWFsdGggYW5k

IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IFJldiBJbW11bm9sLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdCBSZXYgSW1tdW5v

bC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz45LTIyPC9wYWdlcz48dm9sdW1lPjEz

PC92b2x1bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwv

cmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVklUSUVTPC9rZXl3b3JkPjxr

ZXl3b3JkPkFDVElWSVRZPC9rZXl3b3JkPjxrZXl3b3JkPkFMTEVSR0lDPC9rZXl3b3JkPjxrZXl3

b3JkPkFsbGVyZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QUxURVJFRDwva2V5d29yZD48a2V5d29yZD5B

bmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5DRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPmNlbGwgZGVncmFudWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwv

a2V5d29yZD48a2V5d29yZD5EZWdyYW51bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkRFVkVMT1BN

RU5UPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8

L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+ZW9zaW5vcGhpbDwv

a2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsaWE8L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhp

bHM8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248

L2tleXdvcmQ+PGtleXdvcmQ+RlVOQ1RJT05TPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkVSQVRFRDwv

a2V5d29yZD48a2V5d29yZD5IRUFMVEg8L2tleXdvcmQ+PGtleXdvcmQ+SG9tZW9zdGFzaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPkh5cGVyZW9zaW5vcGhpbGlj

IHN5bmRyb21lPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+

SU1QUk9WRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SW5mZWN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPmxldWtvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+bWFyeWxhbmQ8

L2tleXdvcmQ+PGtleXdvcmQ+TUlDRTwva2V5d29yZD48a2V5d29yZD5tb2RlbHMsaW1tdW5vbG9n

aWNhbDwva2V5d29yZD48a2V5d29yZD5NT0xFQ1VMQVI8L2tleXdvcmQ+PGtleXdvcmQ+TkFUSU9O

QUw8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3JkPnBhcmFzaXRpYyBkaXNl

YXNlczwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SFdBWTwva2V5d29yZD48a2V5d29yZD5QQVRIV0FZUzwva2V5d29yZD48a2V5d29yZD5wZXJzcGVj

dGl2ZXM8L2tleXdvcmQ+PGtleXdvcmQ+UFJJTUFSWTwva2V5d29yZD48a2V5d29yZD5SRUNFTlQ8

L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3JzLGltbXVub2xvZ2ljPC9rZXl3b3JkPjxrZXl3b3Jk

PlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwv

a2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TWU5EUk9NRTwva2V5d29y

ZD48a2V5d29yZD5VTFRSQVNUUlVDVFVSRTwva2V5d29yZD48a2V5d29yZD5VTkRFUlNUQU5ESU5H

PC9rZXl3b3JkPjxrZXl3b3JkPlVTQTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDEzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MS8yMDEzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0

ZXM+PGxhYmVsPlJPU0VOQkVSRzIwMTM8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [53]. Eosinophil recruitment involves their adhesion to vascular endothelial cells in the bronchial circulation via adhesion molecules, migration into the submucosa under the direction of chemokines, such as CCL11 (eotaxin) and CCL5 (RANTES) secreted from airway epithelial cells and their subsequent activation and prolonged survival in the airways (Fig. 4). IL-5 plays a critical role in the generation of eosinophils in the bone marrow and their survival in the airways. IL-5 is secreted by Th2 cells but also by innate type-2 lymphoid cells (ILC2), which are regulated by epithelia alarmins rather than dendritic cells and may be important in non-atopic (intrinsic) asthma ADDIN EN.CITE <EndNote><Cite><Author>Scanlon</Author><Year>2012</Year><RecNum>11709</RecNum><DisplayText>[54]</DisplayText><record><rec-number>11709</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378479005">11709</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scanlon,S.T.</author><author>McKenzie,A.N.</author></authors></contributors><titles><title>Type 2 innate lymphoid cells: new players in asthma and allergy</title><secondary-title>Curr.Opin.Immunol.</secondary-title></titles><periodical><full-title>Curr.Opin.Immunol.</full-title></periodical><pages>707-712</pages><volume>24</volume><number>6</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>2</keyword><keyword>ALLERGEN-INDUCED</keyword><keyword>Allergy</keyword><keyword>Asthma</keyword><keyword>CELL</keyword><keyword>CELLS</keyword><keyword>CYTOKINE</keyword><keyword>DISEASE</keyword><keyword>IL-5</keyword><keyword>IMMUNE</keyword><keyword>IN</keyword><keyword>inflammatory</keyword><keyword>Lung</keyword><keyword>MEDIATOR</keyword><keyword>mediators</keyword><keyword>NEW</keyword><keyword>RESPONSE</keyword><keyword>RESPONSES</keyword><keyword>Review</keyword><keyword>ROLE</keyword><keyword>T</keyword><keyword>Th17</keyword><keyword>Th17 Cells</keyword><keyword>Th2</keyword><keyword>TWO</keyword><keyword>TYPE</keyword></keywords><dates><year>2012</year><pub-dates><date>12/2012</date></pub-dates></dates><label>SCANLON2012</label><urls></urls></record></Cite></EndNote>[54]. Blocking antibodies to IL-5 and its receptor cause a profound and prolonged reduction in circulating and sputum eosinophils, but is not associated with reduced AHR or asthma symptoms ADDIN EN.CITE <EndNote><Cite><Author>Leckie</Author><Year>2000</Year><RecNum>6714</RecNum><DisplayText>[55]</DisplayText><record><rec-number>6714</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478924">6714</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leckie,M.J.</author><author>ten Brincke,A.</author><author>Khan,J.</author><author>Diamant,Z.</author><author>O&apos;Connor,B.J.</author><author>Walls,C.M.</author><author>Mathur,M.</author><author>Cowley,H.</author><author>Chung,K.F.</author><author>Djukanovic,R.J.</author><author>Hansel,T.T.</author><author>Holgate,S.T.</author><author>Sterk,P.J.</author><author>Barnes,P.J.</author></authors></contributors><titles><title>Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>2144-2148</pages><volume>356</volume><reprint-edition>In File</reprint-edition><keywords><keyword>MONOCLONAL</keyword><keyword>ANTIBODY</keyword><keyword>SINGLE</keyword><keyword>DOSE</keyword><keyword>safety</keyword><keyword>ACTIVITY</keyword><keyword>IN</keyword><keyword>PATIENTS</keyword><keyword>Asthma</keyword><keyword>EFFECTS</keyword><keyword>EFFECT</keyword><keyword>INTERLEUKIN-5</keyword><keyword>Interleukin 5</keyword><keyword>BLOCKING</keyword><keyword>ANTIBODIES</keyword><keyword>Eosinophils</keyword><keyword>eosinophil</keyword><keyword>AIRWAY</keyword><keyword>hyperresponsiveness</keyword><keyword>LATE</keyword><keyword>asthmatic</keyword><keyword>RESPONSE</keyword></keywords><dates><year>2000</year><pub-dates><date>2000</date></pub-dates></dates><label>LECKIE1999</label><urls></urls></record></Cite></EndNote>[55]. However, in selected patients with steroid-resistant airway eosinophils, there is a marked reduction in exacerbations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcnRlZ2E8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MTIyNTU8L1JlY051bT48RGlzcGxheVRleHQ+WzU2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMjI1NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxNDI4MjI0OTIwIj4xMjI1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+T3J0ZWdhLCBILiBHLjwvYXV0aG9yPjxhdXRob3I+TGl1LCBNLiBDLjwvYXV0aG9yPjxhdXRo

b3I+UGF2b3JkLCBJLiBELjwvYXV0aG9yPjxhdXRob3I+QnJ1c3NlbGxlLCBHLiBHLjwvYXV0aG9y

PjxhdXRob3I+Rml0ekdlcmFsZCwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkNoZXR0YSwgQS48L2F1

dGhvcj48YXV0aG9yPkh1bWJlcnQsIE0uPC9hdXRob3I+PGF1dGhvcj5LYXR6LCBMLiBFLjwvYXV0

aG9yPjxhdXRob3I+S2VlbmUsIE8uIE4uPC9hdXRob3I+PGF1dGhvcj5ZYW5jZXksIFMuIFcuPC9h

dXRob3I+PGF1dGhvcj5DaGFuZXosIFAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RnJvbSB0aGUgUmVzcGlyYXRvcnkgVGhlcmFwZXV0aWMgQXJlYSBVbml0

LCBHbGF4b1NtaXRoS2xpbmUsIFJlc2VhcmNoIFRyaWFuZ2xlIFBhcmssIE5DIChILkcuTy4sIEwu

RS5LLiwgUy5XLlkuKTsgSm9obnMgSG9wa2lucyBBc3RobWEgYW5kIEFsbGVyZ3kgQ2VudGVyLCBC

YWx0aW1vcmUgKE0uQy5MLik7IFJlc3BpcmF0b3J5IE1lZGljaW5lIFVuaXQsIE51ZmZpZWxkIERl

cGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgT3hmb3JkLCBPeGZvcmQgKEkuRC5Q

LiksIGFuZCBDbGluaWNhbCBTdGF0aXN0aWNzLCBHbGF4b1NtaXRoS2xpbmUsIFN0b2NrbGV5IFBh

cmssIE1pZGRsZXNleCAoTy5OLksuKSAtIGJvdGggaW4gdGhlIFVuaXRlZCBLaW5nZG9tOyB0aGUg

RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgR2hlbnQsIEJlbGdpdW0gKEcuRy5CLik7IHRoZSBMdW5nIENlbnRyZSwgSW5zdGl0dXRl

IGZvciBIZWFydCBhbmQgTHVuZyBIZWFsdGgsIFZhbmNvdXZlciwgQkMsIENhbmFkYSAoSi5NLkYu

KTsgdGhlIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgYW5kIEV4cGVyaW1lbnRhbCBNZWRpY2luZSwg

VW5pdmVyc2l0eSBvZiBQYXJtYSwgUGFybWEsIEl0YWx5IChBLkMuKTsgYW5kIEFzc2lzdGFuY2Ug

UHVibGlxdWUtSG9waXRhdXggZGUgUGFyaXMsIERlcGFydGVtZW50IEhvc3BpdGFsby1Vbml2ZXJz

aXRhaXJlIFRob3JheCBJbm5vdmF0aW9uLCBTZXJ2aWNlIGRlIFBuZXVtb2xvZ2llLCBIb3BpdGFs

IEJpY2V0cmUsIFVuaXZlcnNpdGUgUGFyaXMtU3VkLCBhbmQgSU5TRVJNIFVuaXRlIE1peHRlIGRl

IFJlY2hlcmNoZSA5OTksIExlIEtyZW1saW4tQmljZXRyZSAoTS5ILiksIGFuZCBVbml0ZXMgTWl4

dGVzIGRlIFJlY2hlcmNoZSBJTlNFUk0gVW5pdGUgMTA2NyBDZW50cmUgTmF0aW9uYWxlIGRlIGxh

IFJlY2hlcmNoZSBTY2llbnRpZmlxdWUgNzczMywgQWl4LU1hcnNlaWxsZSBVbml2ZXJzaXRlLCBE

ZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IERpc2Vhc2VzIGFuZCBDbGluaWNhbCBJbnZlc3RpZ2F0

aW9uIENlbnRlciwgQXNzaXN0YW5jZSBQdWJsaXF1ZS1Ib3BpdGF1eCBkZSBNYXJzZWlsbGUsIEhv

cGl0YWwgTm9yZCwgTWFyc2VpbGxlIChQLkMuKSAtIGJvdGggaW4gRnJhbmNlLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPk1lcG9saXp1bWFiIHRyZWF0bWVudCBpbiBwYXRpZW50cyB3aXRo

IHNldmVyZSBlb3Npbm9waGlsaWMgYXN0aG1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5n

bCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJu

YWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTk4LTIwNzwv

cGFnZXM+PHZvbHVtZT4zNzE8L3ZvbHVtZT48bnVtYmVyPjEzPC9udW1iZXI+PGVkaXRpb24+MjAx

NC8wOS8xMDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWRtaW5pc3RyYXRpb24sIE9yYWw8

L2tleXdvcmQ+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5

d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9r

ZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50cy8qYWRtaW5pc3RyYXRpb24gJmFt

cDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBN

b25vY2xvbmFsLCBIdW1hbml6ZWQvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZlcnNl

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hLypkcnVnIHRoZXJhcHkvaW1tdW5vbG9n

eS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdv

cmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHksIENv

bWJpbmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipFb3Npbm9waGlsaWE8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5

d29yZD48a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBJ

bnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBTdWJjdXRhbmVvdXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y

ZD48a2V5d29yZD5RdWFsaXR5IG9mIExpZmU8L2tleXdvcmQ+PGtleXdvcmQ+UXVlc3Rpb25uYWly

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+U2Vjb25kYXJ5IFByZXZlbnRpb248L2tleXdvcmQ+PGtleXdv

cmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMjgtNDc5MzwvaXNibj48YWNjZXNzaW9uLW51bT4yNTE5OTA1OTwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTQwMzI5

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5ObG08

L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcnRlZ2E8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MTIyNTU8L1JlY051bT48RGlzcGxheVRleHQ+WzU2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMjI1NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxNDI4MjI0OTIwIj4xMjI1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+T3J0ZWdhLCBILiBHLjwvYXV0aG9yPjxhdXRob3I+TGl1LCBNLiBDLjwvYXV0aG9yPjxhdXRo

b3I+UGF2b3JkLCBJLiBELjwvYXV0aG9yPjxhdXRob3I+QnJ1c3NlbGxlLCBHLiBHLjwvYXV0aG9y

PjxhdXRob3I+Rml0ekdlcmFsZCwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkNoZXR0YSwgQS48L2F1

dGhvcj48YXV0aG9yPkh1bWJlcnQsIE0uPC9hdXRob3I+PGF1dGhvcj5LYXR6LCBMLiBFLjwvYXV0

aG9yPjxhdXRob3I+S2VlbmUsIE8uIE4uPC9hdXRob3I+PGF1dGhvcj5ZYW5jZXksIFMuIFcuPC9h

dXRob3I+PGF1dGhvcj5DaGFuZXosIFAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RnJvbSB0aGUgUmVzcGlyYXRvcnkgVGhlcmFwZXV0aWMgQXJlYSBVbml0

LCBHbGF4b1NtaXRoS2xpbmUsIFJlc2VhcmNoIFRyaWFuZ2xlIFBhcmssIE5DIChILkcuTy4sIEwu

RS5LLiwgUy5XLlkuKTsgSm9obnMgSG9wa2lucyBBc3RobWEgYW5kIEFsbGVyZ3kgQ2VudGVyLCBC

YWx0aW1vcmUgKE0uQy5MLik7IFJlc3BpcmF0b3J5IE1lZGljaW5lIFVuaXQsIE51ZmZpZWxkIERl

cGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgT3hmb3JkLCBPeGZvcmQgKEkuRC5Q

LiksIGFuZCBDbGluaWNhbCBTdGF0aXN0aWNzLCBHbGF4b1NtaXRoS2xpbmUsIFN0b2NrbGV5IFBh

cmssIE1pZGRsZXNleCAoTy5OLksuKSAtIGJvdGggaW4gdGhlIFVuaXRlZCBLaW5nZG9tOyB0aGUg

RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgR2hlbnQsIEJlbGdpdW0gKEcuRy5CLik7IHRoZSBMdW5nIENlbnRyZSwgSW5zdGl0dXRl

IGZvciBIZWFydCBhbmQgTHVuZyBIZWFsdGgsIFZhbmNvdXZlciwgQkMsIENhbmFkYSAoSi5NLkYu

KTsgdGhlIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgYW5kIEV4cGVyaW1lbnRhbCBNZWRpY2luZSwg

VW5pdmVyc2l0eSBvZiBQYXJtYSwgUGFybWEsIEl0YWx5IChBLkMuKTsgYW5kIEFzc2lzdGFuY2Ug

UHVibGlxdWUtSG9waXRhdXggZGUgUGFyaXMsIERlcGFydGVtZW50IEhvc3BpdGFsby1Vbml2ZXJz

aXRhaXJlIFRob3JheCBJbm5vdmF0aW9uLCBTZXJ2aWNlIGRlIFBuZXVtb2xvZ2llLCBIb3BpdGFs

IEJpY2V0cmUsIFVuaXZlcnNpdGUgUGFyaXMtU3VkLCBhbmQgSU5TRVJNIFVuaXRlIE1peHRlIGRl

IFJlY2hlcmNoZSA5OTksIExlIEtyZW1saW4tQmljZXRyZSAoTS5ILiksIGFuZCBVbml0ZXMgTWl4

dGVzIGRlIFJlY2hlcmNoZSBJTlNFUk0gVW5pdGUgMTA2NyBDZW50cmUgTmF0aW9uYWxlIGRlIGxh

IFJlY2hlcmNoZSBTY2llbnRpZmlxdWUgNzczMywgQWl4LU1hcnNlaWxsZSBVbml2ZXJzaXRlLCBE

ZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IERpc2Vhc2VzIGFuZCBDbGluaWNhbCBJbnZlc3RpZ2F0

aW9uIENlbnRlciwgQXNzaXN0YW5jZSBQdWJsaXF1ZS1Ib3BpdGF1eCBkZSBNYXJzZWlsbGUsIEhv

cGl0YWwgTm9yZCwgTWFyc2VpbGxlIChQLkMuKSAtIGJvdGggaW4gRnJhbmNlLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPk1lcG9saXp1bWFiIHRyZWF0bWVudCBpbiBwYXRpZW50cyB3aXRo

IHNldmVyZSBlb3Npbm9waGlsaWMgYXN0aG1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5n

bCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJu

YWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTk4LTIwNzwv

cGFnZXM+PHZvbHVtZT4zNzE8L3ZvbHVtZT48bnVtYmVyPjEzPC9udW1iZXI+PGVkaXRpb24+MjAx

NC8wOS8xMDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWRtaW5pc3RyYXRpb24sIE9yYWw8

L2tleXdvcmQ+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5

d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9r

ZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50cy8qYWRtaW5pc3RyYXRpb24gJmFt

cDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBN

b25vY2xvbmFsLCBIdW1hbml6ZWQvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZlcnNl

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hLypkcnVnIHRoZXJhcHkvaW1tdW5vbG9n

eS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdv

cmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHksIENv

bWJpbmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipFb3Npbm9waGlsaWE8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5

d29yZD48a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBJ

bnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBTdWJjdXRhbmVvdXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y

ZD48a2V5d29yZD5RdWFsaXR5IG9mIExpZmU8L2tleXdvcmQ+PGtleXdvcmQ+UXVlc3Rpb25uYWly

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+U2Vjb25kYXJ5IFByZXZlbnRpb248L2tleXdvcmQ+PGtleXdv

cmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMjgtNDc5MzwvaXNibj48YWNjZXNzaW9uLW51bT4yNTE5OTA1OTwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTQwMzI5

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5ObG08

L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [56]. Eosinophils may be important in release of growth factors, such as TGF-β, involved in airway remodelling and in exacerbations but probably do not contribute to AHR, which is not reduced by anti-IL-5 therapies.While eosinophils are the predominant leukocyte in asthma, their role in COPD is less certain. Increased numbers of eosinophils have been described in the airways and BAL of patients with stable COPD, whereas others have not found them. The presence of eosinophils in patients with COPD predicts a more favourable therapeutic response to bronchodilators and corticosteroids may indicate coexisting asthma or asthma-COPD overlap PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3N0bWE8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTI0NDY8L1JlY051bT48RGlzcGxheVRleHQ+WzEtM108L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI0NDY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTQ0NzE2NzM3MSI+MTI0NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBvc3RtYSwgRC4gUy48L2F1dGhvcj48YXV0aG9yPlJhYmUsIEsuIEYuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBBc3RobWEtQ09QRCBPdmVy

bGFwIFN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25k

YXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8

L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjQxLTk8L3BhZ2VzPjx2b2x1bWU+Mzcz

PC92b2x1bWU+PG51bWJlcj4xMzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDkvMjQ8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuZXJnaWMgYmV0YS1BZ29uaXN0cy90aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5IE9ic3RydWN0aW9uL2RydWcgdGhlcmFweS9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Bc3RobWEvKmNvbXBsaWNhdGlvbnMvZGlhZ25vc2lzL2Ry

dWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpYWwgSHlwZXJyZWFjdGl2aXR5L2Rp

YWdub3Npcy9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsczwva2V5d29yZD48

a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

TXVzY2FyaW5pYyBBbnRhZ29uaXN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1Y3RpdmUvKmNvbXBsaWNhdGlvbnMvZGlh

Z25vc2lzL2RydWcgdGhlcmFweTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDAyOC00NzkzPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2Mzk4MDcyPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNcmEx

NDExODYzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJhdGVtYW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+MTI3ODQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNzg0PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZl

dnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NjEwNzM3NzAiPjEyNzg0PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5CYXRlbWFuLCBFLiBELjwvYXV0aG9y

PjxhdXRob3I+UmVkZGVsLCBILiBLLjwvYXV0aG9yPjxhdXRob3I+dmFuIFp5bC1TbWl0LCBSLiBO

LjwvYXV0aG9yPjxhdXRob3I+QWd1c3RpLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIFB1bG1vbm9sb2d5LCBEZXBhcnRtZW50IG9m

IE1lZGljaW5lLCBGYWN1bHR5IG9mIEhlYWx0aCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBDYXBl

IFRvd24sIENhcGUgVG93biwgU291dGggQWZyaWNhLiBFbGVjdHJvbmljIGFkZHJlc3M6IGVyaWMu

YmF0ZW1hbkB1Y3QuYWMuemEuJiN4RDtXb29sY29jayBJbnN0aXR1dGUgb2YgTWVkaWNhbCBSZXNl

YXJjaCwgVW5pdmVyc2l0eSBvZiBTeWRuZXksIFN5ZG5leSwgQXVzdHJhbGlhLiYjeEQ7RGl2aXNp

b24gb2YgUHVsbW9ub2xvZ3ksIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIEZhY3VsdHkgb2YgSGVh

bHRoIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhcGUgVG93biwgQ2FwZSBUb3duLCBTb3V0aCBB

ZnJpY2EuJiN4RDtUaG9yYXggSW5zdGl0dXRlLCBIb3NwaXRhbCBDbGluaWMsIElESUJBUFMsIENJ

QkVSRVMsIFVuaXZlcnNpdHkgb2YgQmFyY2Vsb25hLCBTcGFpbi48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5UaGUgYXN0aG1hLUNPUEQgb3ZlcmxhcCBzeW5kcm9tZTogdG93YXJkcyBhIHJl

dmlzZWQgdGF4b25vbXkgb2YgY2hyb25pYyBhaXJ3YXlzIGRpc2Vhc2VzPzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

VGhlIExhbmNldC4gUmVzcGlyYXRvcnkgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48YWJici0x

PlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxh

bHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48

YWJici0xPlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVy

aW9kaWNhbD48cGFnZXM+NzE5LTI4PC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjk8

L251bWJlcj48ZWRpdGlvbj4yMDE1LzA4LzEwPC9lZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MjIxMy0yNjAwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MjU1MTA4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMjIxMy0yNjAwKDE1

KTAwMjU0LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlk

ZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QmFybmVzPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjEyNjIwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMjYyMDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVm

ZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxNDU1MDIwNTU0Ij4xMjYyMDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFybmVzLCBQLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5hdGlvbmFsIEhlYXJ0IGFu

ZCBMdW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgRW5nbGFu

ZC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBwLmouYmFybmVzQGltcGVyaWFsLmFjLnVrLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFzdGhtYS1DT1BEIE92ZXJsYXA8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+Q2hlc3Q8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkNoZXN0PC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3Q8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRsZT48

L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz43LTg8L3BhZ2VzPjx2b2x1bWU+MTQ5PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MjAxNi8wMS8xMzwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjAwMTItMzY5MjwvaXNibj48YWNjZXNzaW9uLW51bT4yNjc1NzI4MTwvYWNjZXNzaW9u

LW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5jaGVz

dC4yMDE1LjA4LjAxNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1w

cm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5n

dWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb3N0bWE8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTI0NDY8L1JlY051bT48RGlzcGxheVRleHQ+WzEtM108L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTI0NDY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTQ0NzE2NzM3MSI+MTI0NDY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBvc3RtYSwgRC4gUy48L2F1dGhvcj48YXV0aG9yPlJhYmUsIEsuIEYuPC9hdXRob3I+PC9h

dXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBBc3RobWEtQ09QRCBPdmVy

bGFwIFN5bmRyb21lPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vjb25k

YXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJuYWwgb2YgbWVkaWNpbmU8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OIEVuZ2wgSiBNZWQ8

L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjQxLTk8L3BhZ2VzPjx2b2x1bWU+Mzcz

PC92b2x1bWU+PG51bWJlcj4xMzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDkvMjQ8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFkcmVuZXJnaWMgYmV0YS1BZ29uaXN0cy90aGVyYXBldXRpYyB1

c2U8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5IE9ic3RydWN0aW9uL2RydWcgdGhlcmFweS9ldGlv

bG9neTwva2V5d29yZD48a2V5d29yZD5Bc3RobWEvKmNvbXBsaWNhdGlvbnMvZGlhZ25vc2lzL2Ry

dWcgdGhlcmFweTwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpYWwgSHlwZXJyZWFjdGl2aXR5L2Rp

YWdub3Npcy9ldGlvbG9neTwva2V5d29yZD48a2V5d29yZD5Fb3Npbm9waGlsczwva2V5d29yZD48

a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

TXVzY2FyaW5pYyBBbnRhZ29uaXN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1Y3RpdmUvKmNvbXBsaWNhdGlvbnMvZGlh

Z25vc2lzL2RydWcgdGhlcmFweTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE1

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwIDI0PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDAyOC00NzkzPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2Mzk4MDcyPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA1Ni9ORUpNcmEx

NDExODYzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJhdGVtYW48L0F1dGhvcj48WWVhcj4yMDE1PC9Z

ZWFyPjxSZWNOdW0+MTI3ODQ8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEyNzg0PC9yZWMt

bnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZl

dnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NjEwNzM3NzAiPjEyNzg0PC9rZXk+

PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10

eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5CYXRlbWFuLCBFLiBELjwvYXV0aG9y

PjxhdXRob3I+UmVkZGVsLCBILiBLLjwvYXV0aG9yPjxhdXRob3I+dmFuIFp5bC1TbWl0LCBSLiBO

LjwvYXV0aG9yPjxhdXRob3I+QWd1c3RpLCBBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1

dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9uIG9mIFB1bG1vbm9sb2d5LCBEZXBhcnRtZW50IG9m

IE1lZGljaW5lLCBGYWN1bHR5IG9mIEhlYWx0aCBTY2llbmNlcywgVW5pdmVyc2l0eSBvZiBDYXBl

IFRvd24sIENhcGUgVG93biwgU291dGggQWZyaWNhLiBFbGVjdHJvbmljIGFkZHJlc3M6IGVyaWMu

YmF0ZW1hbkB1Y3QuYWMuemEuJiN4RDtXb29sY29jayBJbnN0aXR1dGUgb2YgTWVkaWNhbCBSZXNl

YXJjaCwgVW5pdmVyc2l0eSBvZiBTeWRuZXksIFN5ZG5leSwgQXVzdHJhbGlhLiYjeEQ7RGl2aXNp

b24gb2YgUHVsbW9ub2xvZ3ksIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIEZhY3VsdHkgb2YgSGVh

bHRoIFNjaWVuY2VzLCBVbml2ZXJzaXR5IG9mIENhcGUgVG93biwgQ2FwZSBUb3duLCBTb3V0aCBB

ZnJpY2EuJiN4RDtUaG9yYXggSW5zdGl0dXRlLCBIb3NwaXRhbCBDbGluaWMsIElESUJBUFMsIENJ

QkVSRVMsIFVuaXZlcnNpdHkgb2YgQmFyY2Vsb25hLCBTcGFpbi48L2F1dGgtYWRkcmVzcz48dGl0

bGVzPjx0aXRsZT5UaGUgYXN0aG1hLUNPUEQgb3ZlcmxhcCBzeW5kcm9tZTogdG93YXJkcyBhIHJl

dmlzZWQgdGF4b25vbXkgb2YgY2hyb25pYyBhaXJ3YXlzIGRpc2Vhc2VzPzwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+

VGhlIExhbmNldC4gUmVzcGlyYXRvcnkgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48YWJici0x

PlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9wZXJpb2RpY2FsPjxh

bHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5MYW5jZXQgUmVzcGlyIE1lZDwvZnVsbC10aXRsZT48

YWJici0xPlRoZSBsYW5jZXQuIFJlc3BpcmF0b3J5IG1lZGljaW5lPC9hYmJyLTE+PC9hbHQtcGVy

aW9kaWNhbD48cGFnZXM+NzE5LTI4PC9wYWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjk8

L251bWJlcj48ZWRpdGlvbj4yMDE1LzA4LzEwPC9lZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE1PC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+U2VwPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MjIxMy0yNjAwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MjU1MTA4PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAxNi9zMjIxMy0yNjAwKDE1

KTAwMjU0LTQ8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlk

ZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+QmFybmVzPC9BdXRob3I+PFllYXI+MjAxNjwv

WWVhcj48UmVjTnVtPjEyNjIwPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMjYyMDwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVm

ZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxNDU1MDIwNTU0Ij4xMjYyMDwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+QmFybmVzLCBQLiBKLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPk5hdGlvbmFsIEhlYXJ0IGFu

ZCBMdW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSBMb25kb24sIExvbmRvbiwgRW5nbGFu

ZC4gRWxlY3Ryb25pYyBhZGRyZXNzOiBwLmouYmFybmVzQGltcGVyaWFsLmFjLnVrLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkFzdGhtYS1DT1BEIE92ZXJsYXA8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+Q2hlc3Q8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkNoZXN0PC9hbHQtdGl0

bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3Q8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRsZT48

L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz43LTg8L3BhZ2VzPjx2b2x1bWU+MTQ5PC92b2x1bWU+PG51

bWJlcj4xPC9udW1iZXI+PGVkaXRpb24+MjAxNi8wMS8xMzwvZWRpdGlvbj48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkphbjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVz

Pjxpc2JuPjAwMTItMzY5MjwvaXNibj48YWNjZXNzaW9uLW51bT4yNjc1NzI4MTwvYWNjZXNzaW9u

LW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5jaGVz

dC4yMDE1LjA4LjAxNzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1w

cm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5n

dWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [1-3]. The mechanisms for increased eosinophils in COPD patients is likely to involve ILC2, which may be regulated by epithelial mediators such as IL-33, released as a result of epithelial cell injury PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeWVyczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

Y051bT4xMjI2NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNTddPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEyMjY2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjE0Mjg0Mjc0OTAiPjEyMjY2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CeWVycywgRC4gRS48L2F1dGhvcj48YXV0aG9yPkFsZXhhbmRlci1CcmV0dCwgSi48L2F1dGhv

cj48YXV0aG9yPlBhdGVsLCBBLiBDLjwvYXV0aG9yPjxhdXRob3I+QWdhcG92LCBFLjwvYXV0aG9y

PjxhdXRob3I+RGFuZy1WdSwgRy48L2F1dGhvcj48YXV0aG9yPkppbiwgWC48L2F1dGhvcj48YXV0

aG9yPld1LCBLLjwvYXV0aG9yPjxhdXRob3I+WW91LCBZLjwvYXV0aG9yPjxhdXRob3I+QWxldnks

IFkuPC9hdXRob3I+PGF1dGhvcj5HaXJhcmQsIEouIFAuPC9hdXRob3I+PGF1dGhvcj5TdGFwcGVu

YmVjaywgVC4gUy48L2F1dGhvcj48YXV0aG9yPlBhdHRlcnNvbiwgRy4gQS48L2F1dGhvcj48YXV0

aG9yPlBpZXJjZSwgUi4gQS48L2F1dGhvcj48YXV0aG9yPkJyb2R5LCBTLiBMLjwvYXV0aG9yPjxh

dXRob3I+SG9sdHptYW4sIE0uIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgV2FzaGluZ3RvbiBVbml2ZXJzaXR5

IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1pc3NvdXJpIDYzMTEwLCBVU0EuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TG9uZy10ZXJtIElMLTMzLXByb2R1Y2luZyBlcGl0

aGVsaWFsIHByb2dlbml0b3IgY2VsbHMgaW4gY2hyb25pYyBvYnN0cnVjdGl2ZSBsdW5nIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBDbGluIEludmVzdDwvc2Vjb25kYXJ5LXRpdGxl

PjxhbHQtdGl0bGU+VGhlIEpvdXJuYWwgb2YgY2xpbmljYWwgaW52ZXN0aWdhdGlvbjwvYWx0LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQ2xpbiBJbnZlc3Q8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zOTY3LTgyPC9wYWdlcz48dm9sdW1lPjEyMzwvdm9s

dW1lPjxudW1iZXI+OTwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDgvMTY8L2VkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FzZS1Db250cm9sIFN0dWRp

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkVw

aXRoZWxpYWwgQ2VsbHMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkltbXVuaXR5LCBJbm5hdGU8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVr

aW5zL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmcvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tv

dXQ8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1Y3Rp

dmUvaW1tdW5vbG9neS9tZXRhYm9saXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVj

ZXB0b3JzLCBJbnRlcmxldWtpbi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJlc3BpcmF0

b3J5IE11Y29zYS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U3BoZXJvaWRzLCBDZWxsdWxh

ci9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN0ZW0gQ2VsbHMvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+VHJhbnNjcmlwdG9tZTwva2V5d29yZD48a2V5d29yZD5VcC1SZWd1bGF0

aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5TZXA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIxLTk3Mzg8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjM5NDUyMzU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxj

dXN0b20yPlBtYzM3NTQyMzk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEx

NzIvamNpNjU1NzA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+TmxtPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3Vh

Z2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeWVyczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

Y051bT4xMjI2NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNTddPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEyMjY2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjE0Mjg0Mjc0OTAiPjEyMjY2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CeWVycywgRC4gRS48L2F1dGhvcj48YXV0aG9yPkFsZXhhbmRlci1CcmV0dCwgSi48L2F1dGhv

cj48YXV0aG9yPlBhdGVsLCBBLiBDLjwvYXV0aG9yPjxhdXRob3I+QWdhcG92LCBFLjwvYXV0aG9y

PjxhdXRob3I+RGFuZy1WdSwgRy48L2F1dGhvcj48YXV0aG9yPkppbiwgWC48L2F1dGhvcj48YXV0

aG9yPld1LCBLLjwvYXV0aG9yPjxhdXRob3I+WW91LCBZLjwvYXV0aG9yPjxhdXRob3I+QWxldnks

IFkuPC9hdXRob3I+PGF1dGhvcj5HaXJhcmQsIEouIFAuPC9hdXRob3I+PGF1dGhvcj5TdGFwcGVu

YmVjaywgVC4gUy48L2F1dGhvcj48YXV0aG9yPlBhdHRlcnNvbiwgRy4gQS48L2F1dGhvcj48YXV0

aG9yPlBpZXJjZSwgUi4gQS48L2F1dGhvcj48YXV0aG9yPkJyb2R5LCBTLiBMLjwvYXV0aG9yPjxh

dXRob3I+SG9sdHptYW4sIE0uIEouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxh

dXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgV2FzaGluZ3RvbiBVbml2ZXJzaXR5

IFNjaG9vbCBvZiBNZWRpY2luZSwgU2FpbnQgTG91aXMsIE1pc3NvdXJpIDYzMTEwLCBVU0EuPC9h

dXRoLWFkZHJlc3M+PHRpdGxlcz48dGl0bGU+TG9uZy10ZXJtIElMLTMzLXByb2R1Y2luZyBlcGl0

aGVsaWFsIHByb2dlbml0b3IgY2VsbHMgaW4gY2hyb25pYyBvYnN0cnVjdGl2ZSBsdW5nIGRpc2Vh

c2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBDbGluIEludmVzdDwvc2Vjb25kYXJ5LXRpdGxl

PjxhbHQtdGl0bGU+VGhlIEpvdXJuYWwgb2YgY2xpbmljYWwgaW52ZXN0aWdhdGlvbjwvYWx0LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQ2xpbiBJbnZlc3Q8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4zOTY3LTgyPC9wYWdlcz48dm9sdW1lPjEyMzwvdm9s

dW1lPjxudW1iZXI+OTwvbnVtYmVyPjxlZGl0aW9uPjIwMTMvMDgvMTY8L2VkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FzZS1Db250cm9sIFN0dWRp

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbHMsIEN1bHR1cmVkPC9rZXl3b3JkPjxrZXl3b3JkPkVw

aXRoZWxpYWwgQ2VsbHMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5zPC9rZXl3

b3JkPjxrZXl3b3JkPkltbXVuaXR5LCBJbm5hdGU8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVr

aW5zL2dlbmV0aWNzLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmcvcGF0aG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48

a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tv

dXQ8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsIENocm9uaWMgT2JzdHJ1Y3Rp

dmUvaW1tdW5vbG9neS9tZXRhYm9saXNtLypwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmVj

ZXB0b3JzLCBJbnRlcmxldWtpbi9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlJlc3BpcmF0

b3J5IE11Y29zYS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+U3BoZXJvaWRzLCBDZWxsdWxh

ci9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlN0ZW0gQ2VsbHMvKm1ldGFib2xpc208L2tl

eXdvcmQ+PGtleXdvcmQ+VHJhbnNjcmlwdG9tZTwva2V5d29yZD48a2V5d29yZD5VcC1SZWd1bGF0

aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRl

cz48ZGF0ZT5TZXA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDIxLTk3Mzg8L2lz

Ym4+PGFjY2Vzc2lvbi1udW0+MjM5NDUyMzU8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91cmxzPjxj

dXN0b20yPlBtYzM3NTQyMzk8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEx

NzIvamNpNjU1NzA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJv

dmlkZXI+TmxtPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3Vh

Z2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [57]. Eosinophils in the airways may indicate a better response to corticosteroid therapy and therefore may define a therapeutic phenotype of COPD patient. Sputum concentrations of IL-5 are correlated with sputum eosinophils and both are reduced by oral corticosteroids PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWZhZGhlbDwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xMjM5MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNThdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyMzkwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0NDA0ODkwMTkiPjEyMzkwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5CYWZhZGhlbCwgTS48L2F1dGhvcj48YXV0aG9yPlNhaGEsIFMuPC9hdXRob3I+PGF1dGhv

cj5TaXZhLCBSLjwvYXV0aG9yPjxhdXRob3I+TWNDb3JtaWNrLCBNLjwvYXV0aG9yPjxhdXRob3I+

TW9udGVpcm8sIFcuPC9hdXRob3I+PGF1dGhvcj5SdWdtYW4sIFAuPC9hdXRob3I+PGF1dGhvcj5E

b2Rzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5QYXZvcmQsIEkuIEQuPC9hdXRob3I+PGF1dGhvcj5O

ZXdib2xkLCBQLjwvYXV0aG9yPjxhdXRob3I+QnJpZ2h0bGluZywgQy4gRS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgZm9yIEx1bmcgSGVh

bHRoLCBMZWljZXN0ZXIsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNwdXR1bSBJ

TC01IGNvbmNlbnRyYXRpb24gaXMgYXNzb2NpYXRlZCB3aXRoIGEgc3B1dHVtIGVvc2lub3BoaWxp

YSBhbmQgYXR0ZW51YXRlZCBieSBjb3J0aWNvc3Rlcm9pZCB0aGVyYXB5IGluIENPUEQ8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+UmVzcGlyYXRpb248L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxl

PlJlc3BpcmF0aW9uOyBpbnRlcm5hdGlvbmFsIHJldmlldyBvZiB0aG9yYWNpYyBkaXNlYXNlczwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlJlc3BpcmF0aW9uPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjU2LTYyPC9wYWdlcz48dm9sdW1lPjc4PC92

b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGVkaXRpb24+MjAwOS8wNS8zMDwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWRyZW5hbCBDb3J0ZXggSG9ybW9uZXMvdGhlcmFwZXV0aWMgdXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8

L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzL2FuYWx5c2lzPC9rZXl3b3JkPjxr

ZXl3b3JkPkNoZW1va2luZXMvKmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkVvc2lub3BoaWxp

YS9jb21wbGljYXRpb25zLypkaWFnbm9zaXMvZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3Jk

PkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJs

ZXVraW4tNS8qYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QdWxtb25hcnkgRGlzZWFzZSwgQ2hyb25p

YyBPYnN0cnVjdGl2ZS8qY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+UmVwcm9kdWNpYmlsaXR5IG9mIFJlc3VsdHM8L2tleXdvcmQ+PGtleXdvcmQ+U3B1dHVtLypj

aGVtaXN0cnk8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48L2Rh

dGVzPjxpc2JuPjAwMjUtNzkzMTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTQ3ODQ3NDwvYWNjZXNz

aW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTI+UG1jMjc1NDk0NDwvY3VzdG9tMj48Y3VzdG9t

Nj5Va21zMjc1MjM8L2N1c3RvbTY+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNTkvMDAw

MjIxOTAyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWZhZGhlbDwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xMjM5MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNThdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyMzkwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0NDA0ODkwMTkiPjEyMzkwPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5CYWZhZGhlbCwgTS48L2F1dGhvcj48YXV0aG9yPlNhaGEsIFMuPC9hdXRob3I+PGF1dGhv

cj5TaXZhLCBSLjwvYXV0aG9yPjxhdXRob3I+TWNDb3JtaWNrLCBNLjwvYXV0aG9yPjxhdXRob3I+

TW9udGVpcm8sIFcuPC9hdXRob3I+PGF1dGhvcj5SdWdtYW4sIFAuPC9hdXRob3I+PGF1dGhvcj5E

b2Rzb24sIFAuPC9hdXRob3I+PGF1dGhvcj5QYXZvcmQsIEkuIEQuPC9hdXRob3I+PGF1dGhvcj5O

ZXdib2xkLCBQLjwvYXV0aG9yPjxhdXRob3I+QnJpZ2h0bGluZywgQy4gRS48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5JbnN0aXR1dGUgZm9yIEx1bmcgSGVh

bHRoLCBMZWljZXN0ZXIsIFVLLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlNwdXR1bSBJ

TC01IGNvbmNlbnRyYXRpb24gaXMgYXNzb2NpYXRlZCB3aXRoIGEgc3B1dHVtIGVvc2lub3BoaWxp

YSBhbmQgYXR0ZW51YXRlZCBieSBjb3J0aWNvc3Rlcm9pZCB0aGVyYXB5IGluIENPUEQ8L3RpdGxl

PjxzZWNvbmRhcnktdGl0bGU+UmVzcGlyYXRpb248L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxl

PlJlc3BpcmF0aW9uOyBpbnRlcm5hdGlvbmFsIHJldmlldyBvZiB0aG9yYWNpYyBkaXNlYXNlczwv

YWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlJlc3BpcmF0aW9uPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjU2LTYyPC9wYWdlcz48dm9sdW1lPjc4PC92

b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PGVkaXRpb24+MjAwOS8wNS8zMDwvZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+QWRyZW5hbCBDb3J0ZXggSG9ybW9uZXMvdGhlcmFwZXV0aWMgdXNlPC9r

ZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCwgODAgYW5kIG92ZXI8

L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzL2FuYWx5c2lzPC9rZXl3b3JkPjxr

ZXl3b3JkPkNoZW1va2luZXMvKmFuYWx5c2lzPC9rZXl3b3JkPjxrZXl3b3JkPkVvc2lub3BoaWxp

YS9jb21wbGljYXRpb25zLypkaWFnbm9zaXMvZHJ1ZyB0aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3Jk

PkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJs

ZXVraW4tNS8qYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29y

ZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QdWxtb25hcnkgRGlzZWFzZSwgQ2hyb25p

YyBPYnN0cnVjdGl2ZS8qY29tcGxpY2F0aW9ucy9kcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdv

cmQ+UmVwcm9kdWNpYmlsaXR5IG9mIFJlc3VsdHM8L2tleXdvcmQ+PGtleXdvcmQ+U3B1dHVtLypj

aGVtaXN0cnk8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48L2Rh

dGVzPjxpc2JuPjAwMjUtNzkzMTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTQ3ODQ3NDwvYWNjZXNz

aW9uLW51bT48dXJscz48L3VybHM+PGN1c3RvbTI+UG1jMjc1NDk0NDwvY3VzdG9tMj48Y3VzdG9t

Nj5Va21zMjc1MjM8L2N1c3RvbTY+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjExNTkvMDAw

MjIxOTAyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVy

Pk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [58]. NeutrophilsIncreased numbers of activated neutrophils are found in sputum and airways of some patients with severe asthma, smoking asthmatics and during exacerbations, although there is a proportion of patients even with mild or moderate asthma who have a predominance of neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Trejo Bittar</Author><Year>2015</Year><RecNum>12444</RecNum><DisplayText>[59]</DisplayText><record><rec-number>12444</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1446806041">12444</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Trejo Bittar, H. E.</author><author>Yousem, S. A.</author><author>Wenzel, S. E.</author></authors></contributors><auth-address>Department of Pathology.</auth-address><titles><title>Pathobiology of severe asthma</title><secondary-title>Annu Rev Pathol</secondary-title><alt-title>Annual review of pathology</alt-title></titles><periodical><full-title>Annu Rev Pathol</full-title><abbr-1>Annual review of pathology</abbr-1></periodical><alt-periodical><full-title>Annu Rev Pathol</full-title><abbr-1>Annual review of pathology</abbr-1></alt-periodical><pages>511-45</pages><volume>10</volume><edition>2014/11/26</edition><keywords><keyword>Animals</keyword><keyword>Asthma/*pathology</keyword><keyword>Humans</keyword><keyword>Phenotype</keyword><keyword>airway</keyword><keyword>epithelium</keyword><keyword>histology</keyword><keyword>inflammation</keyword><keyword>interleukins</keyword><keyword>pathology</keyword></keywords><dates><year>2015</year></dates><isbn>1553-4006</isbn><accession-num>25423350</accession-num><urls></urls><electronic-resource-num>10.1146/annurev-pathol-012414-040343</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[59]. The mechanisms of neutrophilic inflammation in asthma are uncertain and could be related to the use of high doses of corticosteroids which prolongs neutrophil survival in the airways or due to bacterial infection ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2015</Year><RecNum>12409</RecNum><DisplayText>[60]</DisplayText><record><rec-number>12409</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1441888570">12409</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, P. J.</author></authors></contributors><auth-address>National Heart and Lung Institute, Imperial College, London, United Kingdom. Electronic address: p.j.barnes@imperial.ac.uk.</auth-address><titles><title>Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes</title><secondary-title>J Allergy Clin Immunol</secondary-title><alt-title>The Journal of allergy and clinical immunology</alt-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>531-45</pages><volume>136</volume><number>3</number><edition>2015/09/08</edition><keywords><keyword>Corticosteroids</keyword><keyword>IgE</keyword><keyword>bronchial thermoplasty</keyword><keyword>bronchodilator</keyword><keyword>chemokine</keyword><keyword>corticosteroid resistance</keyword><keyword>cytokine</keyword><keyword>kinase</keyword><keyword>macrolide</keyword><keyword>p38 mitogen-activated protein kinase</keyword></keywords><dates><year>2015</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0091-6749</isbn><accession-num>26343937</accession-num><urls></urls><electronic-resource-num>10.1016/j.jaci.2015.05.052</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[60]. The neutrophilic inflammation in severe asthma may be orchestrated by Th17 cells and increased expression of IL-17A and IL-17F is described in airways of patients with severe asthma (Fig. 5) ADDIN EN.CITE <EndNote><Cite><Author>Al-Ramli</Author><Year>2009</Year><RecNum>12280</RecNum><DisplayText>[61]</DisplayText><record><rec-number>12280</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1429546246">12280</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Al-Ramli, W.</author><author>Prefontaine, D.</author><author>Chouiali, F.</author><author>Martin, J. G.</author><author>Olivenstein, R.</author><author>Lemiere, C.</author><author>Hamid, Q.</author></authors></contributors><titles><title>T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma</title><secondary-title>J Allergy Clin Immunol</secondary-title><alt-title>The Journal of allergy and clinical immunology</alt-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>1185-7</pages><volume>123</volume><number>5</number><edition>2009/04/14</edition><keywords><keyword>Asthma/*immunology/pathology</keyword><keyword>Bronchoscopy</keyword><keyword>Epithelium/immunology/metabolism/pathology</keyword><keyword>Humans</keyword><keyword>Interleukin-17/*immunology</keyword><keyword>Lung/immunology/metabolism/pathology</keyword><keyword>T-Lymphocytes, Helper-Inducer/*immunology</keyword></keywords><dates><year>2009</year><pub-dates><date>May</date></pub-dates></dates><isbn>0091-6749</isbn><accession-num>19361847</accession-num><urls></urls><electronic-resource-num>10.1016/j.jaci.2009.02.024</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[61]. The roles of neutrophils in asthma is also unclear and anti-neutrophilic therapies have so far been ineffective clinically.The inflammation in COPD is characteristically described as neutrophilic, with increased numbers of activated neutrophils in sputum and BAL fluid, which correlates with disease severity. Few neutrophils are seen airway wall and lung parenchyma, due their rapid transit into the lumen. Smoking has a direct stimulatory effect on granulocyte production, release from the bone marrow and survival in the respiratory tract, possibly mediated by the hematopoietic growth factors granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF released from airway epithelial cells and lung macrophages. An anti-GM-CSF antibody blocks lung neutrophilic inflammation after cigarette smoke exposure in mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WbGFob3M8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MTE1MTI8L1JlY051bT48RGlzcGxheVRleHQ+WzYyXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTUxMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDAyIj4xMTUxMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+VmxhaG9zLFIuPC9hdXRob3I+PGF1dGhvcj5Cb3ppbm92c2tpLFMuPC9hdXRob3I+PGF1dGhv

cj5DaGFuLFMuUC48L2F1dGhvcj48YXV0aG9yPkl2YW5vdixTLjwvYXV0aG9yPjxhdXRob3I+TGlu

ZGVuLEEuPC9hdXRob3I+PGF1dGhvcj5IYW1pbHRvbixKLkEuPC9hdXRob3I+PGF1dGhvcj5BbmRl

cnNvbixHLlAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

Pk5ldXRyYWxpemluZyBncmFudWxvY3l0ZS9tYWNyb3BoYWdlIGNvbG9ueS1zdGltdWxhdGluZyBm

YWN0b3IgaW5oaWJpdHMgY2lnYXJldHRlIHNtb2tlLWluZHVjZWQgbHVuZyBpbmZsYW1tYXRpb248

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0uSi5SZXNwaXIuQ3JpdCBDYXJlIE1lZC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbS5KLlJlc3Bpci5D

cml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM0LTQwPC9wYWdl

cz48dm9sdW1lPjE4Mjwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+

Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MDwva2V5d29y

ZD48a2V5d29yZD4xPC9rZXl3b3JkPjxrZXl3b3JkPjI8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZB

VElPTjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUT1I8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJ

VElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BZmZlY3Q8

L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdv

cmQ+PGtleXdvcmQ+QUxWRU9MQVI8L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9waGFn

ZTwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPmFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8L2tleXdvcmQ+PGtl

eXdvcmQ+QU5USUJPRElFUzwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLE5ldXRyYWxpemlu

Zzwva2V5d29yZD48a2V5d29yZD5BTlRJQk9EWTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hy

b25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdB

UkVUVEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRFIFNNT0tFPC9rZXl3b3JkPjxrZXl3b3Jk

PkNPTE9OWS1TVElNVUxBVElORzwva2V5d29yZD48a2V5d29yZD5DT0xPTlktU1RJTVVMQVRJTkcg

RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwv

a2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3

b3JkPjxrZXl3b3JkPkVYUE9TVVJFPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdv

cmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxr

ZXl3b3JkPmdlbGF0aW5hc2U8L2tleXdvcmQ+PGtleXdvcmQ+R0VORVJBVEVEPC9rZXl3b3JkPjxr

ZXl3b3JkPkdFTk9NSUM8L2tleXdvcmQ+PGtleXdvcmQ+R00tQ1NGPC9rZXl3b3JkPjxrZXl3b3Jk

PkdyYW51bG9jeXRlIE1hY3JvcGhhZ2UgQ29sb255IFN0aW11bGF0aW5nIEZhY3Rvcjwva2V5d29y

ZD48a2V5d29yZD5HUkFOVUxPQ1lURS1NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPmdyYW51

bG9jeXRlLW1hY3JvcGhhZ2UgY29sb255LXN0aW11bGF0aW5nIGZhY3Rvcjwva2V5d29yZD48a2V5

d29yZD5HUkFOVUxPQ1lURS9NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVuaXR5PC9r

ZXl3b3JkPjxrZXl3b3JkPkltbXVuaXR5LElubmF0ZTwva2V5d29yZD48a2V5d29yZD5JTU1VTk9M

T0dZPC9rZXl3b3JkPjxrZXl3b3JkPklNUExJQ0FUSU9OUzwva2V5d29yZD48a2V5d29yZD5JTjwv

a2V5d29yZD48a2V5d29yZD5JTiBWSVZPPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8

L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVDwva2V5d29yZD48a2V5d29yZD5JTkhJQklUUzwva2V5

d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxVTkdTPC9rZXl3b3JkPjxrZXl3

b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5NQVRS

SVg8L2tleXdvcmQ+PGtleXdvcmQ+bWF0cml4IG1ldGFsbG9wcm90ZWluYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FQVNVUkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElBVE9SPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSxJbmJyZWQgQkFMQiBDPC9rZXl3b3JkPjxrZXl3

b3JkPk1NUDk8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwva2V5d29yZD48a2V5d29yZD5uZXV0cm9w

aGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9r

ZXl3b3JkPjxrZXl3b3JkPk5VQ0xFQVI8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tl

eXdvcmQ+PGtleXdvcmQ+cG5ldW1vbmlhPC9rZXl3b3JkPjxrZXl3b3JkPnByZXZlbnRpb24gJmFt

cDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPlBV

TE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURVM8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

RUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydDwva2V5d29yZD48a2V5d29y

ZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LRS1JTkRVQ0VEPC9rZXl3b3JkPjxrZXl3b3Jk

PlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVE

WTwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD50aGVyYXBl

dXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5UPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzEvMjAxMDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5WTEFIT1MyMDEwPC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WbGFob3M8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxS

ZWNOdW0+MTE1MTI8L1JlY051bT48RGlzcGxheVRleHQ+WzYyXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTUxMjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDAyIj4xMTUxMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+VmxhaG9zLFIuPC9hdXRob3I+PGF1dGhvcj5Cb3ppbm92c2tpLFMuPC9hdXRob3I+PGF1dGhv

cj5DaGFuLFMuUC48L2F1dGhvcj48YXV0aG9yPkl2YW5vdixTLjwvYXV0aG9yPjxhdXRob3I+TGlu

ZGVuLEEuPC9hdXRob3I+PGF1dGhvcj5IYW1pbHRvbixKLkEuPC9hdXRob3I+PGF1dGhvcj5BbmRl

cnNvbixHLlAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

Pk5ldXRyYWxpemluZyBncmFudWxvY3l0ZS9tYWNyb3BoYWdlIGNvbG9ueS1zdGltdWxhdGluZyBm

YWN0b3IgaW5oaWJpdHMgY2lnYXJldHRlIHNtb2tlLWluZHVjZWQgbHVuZyBpbmZsYW1tYXRpb248

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0uSi5SZXNwaXIuQ3JpdCBDYXJlIE1lZC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbS5KLlJlc3Bpci5D

cml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM0LTQwPC9wYWdl

cz48dm9sdW1lPjE4Mjwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+

Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MDwva2V5d29y

ZD48a2V5d29yZD4xPC9rZXl3b3JkPjxrZXl3b3JkPjI8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZB

VElPTjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUT1I8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJ

VElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BZmZlY3Q8

L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdv

cmQ+PGtleXdvcmQ+QUxWRU9MQVI8L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9waGFn

ZTwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29yZD5BbmltYWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPmFudGFnb25pc3RzICZhbXA7IGluaGliaXRvcnM8L2tleXdvcmQ+PGtl

eXdvcmQ+QU5USUJPRElFUzwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLE5ldXRyYWxpemlu

Zzwva2V5d29yZD48a2V5d29yZD5BTlRJQk9EWTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hy

b25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdB

UkVUVEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRFIFNNT0tFPC9rZXl3b3JkPjxrZXl3b3Jk

PkNPTE9OWS1TVElNVUxBVElORzwva2V5d29yZD48a2V5d29yZD5DT0xPTlktU1RJTVVMQVRJTkcg

RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwv

a2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3

b3JkPjxrZXl3b3JkPkVYUE9TVVJFPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdv

cmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxr

ZXl3b3JkPmdlbGF0aW5hc2U8L2tleXdvcmQ+PGtleXdvcmQ+R0VORVJBVEVEPC9rZXl3b3JkPjxr

ZXl3b3JkPkdFTk9NSUM8L2tleXdvcmQ+PGtleXdvcmQ+R00tQ1NGPC9rZXl3b3JkPjxrZXl3b3Jk

PkdyYW51bG9jeXRlIE1hY3JvcGhhZ2UgQ29sb255IFN0aW11bGF0aW5nIEZhY3Rvcjwva2V5d29y

ZD48a2V5d29yZD5HUkFOVUxPQ1lURS1NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPmdyYW51

bG9jeXRlLW1hY3JvcGhhZ2UgY29sb255LXN0aW11bGF0aW5nIGZhY3Rvcjwva2V5d29yZD48a2V5

d29yZD5HUkFOVUxPQ1lURS9NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPmltbXVuaXR5PC9r

ZXl3b3JkPjxrZXl3b3JkPkltbXVuaXR5LElubmF0ZTwva2V5d29yZD48a2V5d29yZD5JTU1VTk9M

T0dZPC9rZXl3b3JkPjxrZXl3b3JkPklNUExJQ0FUSU9OUzwva2V5d29yZD48a2V5d29yZD5JTjwv

a2V5d29yZD48a2V5d29yZD5JTiBWSVZPPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8

L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVDwva2V5d29yZD48a2V5d29yZD5JTkhJQklUUzwva2V5

d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxVTkdTPC9rZXl3b3JkPjxrZXl3

b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5NQVRS

SVg8L2tleXdvcmQ+PGtleXdvcmQ+bWF0cml4IG1ldGFsbG9wcm90ZWluYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FQVNVUkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElBVE9SPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TWljZSxJbmJyZWQgQkFMQiBDPC9rZXl3b3JkPjxrZXl3

b3JkPk1NUDk8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwva2V5d29yZD48a2V5d29yZD5uZXV0cm9w

aGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9r

ZXl3b3JkPjxrZXl3b3JkPk5VQ0xFQVI8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tl

eXdvcmQ+PGtleXdvcmQ+cG5ldW1vbmlhPC9rZXl3b3JkPjxrZXl3b3JkPnByZXZlbnRpb24gJmFt

cDsgY29udHJvbDwva2V5d29yZD48a2V5d29yZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPlBV

TE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURVM8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

RUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydDwva2V5d29yZD48a2V5d29y

ZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LRS1JTkRVQ0VEPC9rZXl3b3JkPjxrZXl3b3Jk

PlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVE

WTwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD50aGVyYXBl

dXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRo

ZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+VFJFQVRNRU5UPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMTA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT43LzEvMjAxMDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5WTEFIT1MyMDEwPC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [62]. Neutrophil recruitment to the airways and parenchyma involves initial adhesion to endothelial cells via E-selectin, which is up-regulated on endothelial cells in the airways of COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaSBTdGVmYW5vPC9BdXRob3I+PFllYXI+MTk5NDwvWWVh

cj48UmVjTnVtPjU2MzY8L1JlY051bT48RGlzcGxheVRleHQ+WzYzXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj41NjM2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5MDgiPjU2MzY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkRpIFN0ZWZhbm8sQS48L2F1dGhvcj48YXV0aG9yPk1hZXN0cmVsbGksUC48L2F1dGhvcj48

YXV0aG9yPlJvZ2dlcmksQS48L2F1dGhvcj48YXV0aG9yPlR1cmF0byxHLjwvYXV0aG9yPjxhdXRo

b3I+Q2FsYWJybyxTLjwvYXV0aG9yPjxhdXRob3I+UG90ZW5hLEEuPC9hdXRob3I+PGF1dGhvcj5N

YXBwLEMuRS48L2F1dGhvcj48YXV0aG9yPkNpYWNjaWEsQS48L2F1dGhvcj48YXV0aG9yPkNvdmFj

ZXYsTC48L2F1dGhvcj48YXV0aG9yPkZhYmJyaSxMLk0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlVwcmVndWxhdGlvbiBvZiBhZGhlc2lvbiBtb2xlY3Vs

ZXMgaW4gdGhlIGJyb25jaGlhbCBtdWNvc2Egb2Ygc3ViamVjdHMgd2l0aCBjaHJvbmljIG9ic3Ry

dWN0aXZlIGJyb25jaGl0aXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0uSi5SZXNwaXIuQ3Jp

dC5DYXJlIE1lZC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5BbS5KLlJlc3Bpci5Dcml0LkNhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjgwMy04MTA8L3BhZ2VzPjx2b2x1bWU+MTQ5PC92b2x1bWU+PG51bWJlcj4zIFB0IDE8

L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFESEVTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVDVUxFUzwva2V5

d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+TVVDT1NBPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hJVElTPC9rZXl3b3Jk

PjxrZXl3b3JkPk9DQ1VQQVRJT05BTDwva2V5d29yZD48a2V5d29yZD5NRURJQ0lORTwva2V5d29y

ZD48a2V5d29yZD5VTklURUQgU1RBVEVTPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwva2V5

d29yZD48a2V5d29yZD5CSU9QU0lFUzwva2V5d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+

PGtleXdvcmQ+RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5WRVNTRUxTPC9rZXl3b3JkPjxr

ZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJMRVVLSU4tMTwva2V5d29y

ZD48a2V5d29yZD5CRVRBPC9rZXl3b3JkPjxrZXl3b3JkPklMLTE8L2tleXdvcmQ+PGtleXdvcmQ+

VFVNT1I8L2tleXdvcmQ+PGtleXdvcmQ+TkVDUk9TSVM8L2tleXdvcmQ+PGtleXdvcmQ+bmV1dHJv

cGhpbDwva2V5d29yZD48a2V5d29yZD5lb3Npbm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPkVvc2lu

b3BoaWwgY2F0aW9uaWMgcHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5DQVRJT05JQzwva2V5d29y

ZD48a2V5d29yZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3

b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5OVU1CRVJTPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5B

aXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+

PGtleXdvcmQ+RVBJVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lcGl0aGVsaWFsIGNlbGxzPC9r

ZXl3b3JkPjxrZXl3b3JkPklOVk9MVkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNp

czwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5

d29yZD48a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5CSU9Q

U1k8L2tleXdvcmQ+PGtleXdvcmQ+QnJvbmNoaXRpcyBkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+QnJvbmNoaXRpcyBwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RW5kb3RoZWxp

dW0sVmFzY3VsYXI8L2tleXdvcmQ+PGtleXdvcmQ+Rm9yY2VkIEV4cGlyYXRvcnkgVm9sdW1lPC9r

ZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5MdW5nIERpc2Vhc2VzLE9ic3RydWN0aXZl

IGRpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5MdW5nIERpc2Vhc2VzLE9ic3RydWN0aXZlIHBo

eXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlPC9rZXl3b3JkPjxrZXl3

b3JkPk11Y291cyBNZW1icmFuZTwva2V5d29yZD48a2V5d29yZD5TbW9raW5nIHBoeXNpb3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5WaXRhbCBDYXBhY2l0eTwva2V5d29yZD48a2V5d29yZD5B

bnRpZ2VucyxDRCBhbmFseXNpczwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpdGlzIHBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5DZWxsIEFkaGVzaW9uIE1vbGVjdWxlcyBhbmFseXNpczwva2V5

d29yZD48a2V5d29yZD5DeXRva2luZXMgYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+THVuZyBE

aXNlYXNlcyxPYnN0cnVjdGl2ZSBwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWVtYnJhbmUg

R2x5Y29wcm90ZWlucyBhbmFseXNpczwva2V5d29yZD48a2V5d29yZD5TbW9raW5nIHBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5VcCBSZWd1bGF0aW9uIFBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+Q29tcGFyYXRpdmUgU3R1ZHk8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPmh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+

U3VwcG9ydCxOb24gVS5TLkdvdiZhcG9zO3Q8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWdlbnMsQ0Q8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBBZGhlc2lvbiBNb2xlY3VsZXM8L2tleXdvcmQ+PGtleXdv

cmQ+RSBTZWxlY3Rpbjwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBHbHljb3Byb3RlaW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkludGVyY2VsbHVsYXIgQWRoZXNpb24gTW9sZWN1bGUgMTwva2V5d29y

ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTk5

NDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5ESVNURUZBTk8xOTk0PC9sYWJlbD48

dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaSBTdGVmYW5vPC9BdXRob3I+PFllYXI+MTk5NDwvWWVh

cj48UmVjTnVtPjU2MzY8L1JlY051bT48RGlzcGxheVRleHQ+WzYzXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj41NjM2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5MDgiPjU2MzY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkRpIFN0ZWZhbm8sQS48L2F1dGhvcj48YXV0aG9yPk1hZXN0cmVsbGksUC48L2F1dGhvcj48

YXV0aG9yPlJvZ2dlcmksQS48L2F1dGhvcj48YXV0aG9yPlR1cmF0byxHLjwvYXV0aG9yPjxhdXRo

b3I+Q2FsYWJybyxTLjwvYXV0aG9yPjxhdXRob3I+UG90ZW5hLEEuPC9hdXRob3I+PGF1dGhvcj5N

YXBwLEMuRS48L2F1dGhvcj48YXV0aG9yPkNpYWNjaWEsQS48L2F1dGhvcj48YXV0aG9yPkNvdmFj

ZXYsTC48L2F1dGhvcj48YXV0aG9yPkZhYmJyaSxMLk0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlVwcmVndWxhdGlvbiBvZiBhZGhlc2lvbiBtb2xlY3Vs

ZXMgaW4gdGhlIGJyb25jaGlhbCBtdWNvc2Egb2Ygc3ViamVjdHMgd2l0aCBjaHJvbmljIG9ic3Ry

dWN0aXZlIGJyb25jaGl0aXM8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0uSi5SZXNwaXIuQ3Jp

dC5DYXJlIE1lZC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5BbS5KLlJlc3Bpci5Dcml0LkNhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjgwMy04MTA8L3BhZ2VzPjx2b2x1bWU+MTQ5PC92b2x1bWU+PG51bWJlcj4zIFB0IDE8

L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtl

eXdvcmRzPjxrZXl3b3JkPkFESEVTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVDVUxFUzwva2V5

d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+TVVDT1NBPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hJVElTPC9rZXl3b3Jk

PjxrZXl3b3JkPk9DQ1VQQVRJT05BTDwva2V5d29yZD48a2V5d29yZD5NRURJQ0lORTwva2V5d29y

ZD48a2V5d29yZD5VTklURUQgU1RBVEVTPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwva2V5

d29yZD48a2V5d29yZD5CSU9QU0lFUzwva2V5d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+

PGtleXdvcmQ+RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5WRVNTRUxTPC9rZXl3b3JkPjxr

ZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJMRVVLSU4tMTwva2V5d29y

ZD48a2V5d29yZD5CRVRBPC9rZXl3b3JkPjxrZXl3b3JkPklMLTE8L2tleXdvcmQ+PGtleXdvcmQ+

VFVNT1I8L2tleXdvcmQ+PGtleXdvcmQ+TkVDUk9TSVM8L2tleXdvcmQ+PGtleXdvcmQ+bmV1dHJv

cGhpbDwva2V5d29yZD48a2V5d29yZD5lb3Npbm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPkVvc2lu

b3BoaWwgY2F0aW9uaWMgcHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5DQVRJT05JQzwva2V5d29y

ZD48a2V5d29yZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3

b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5OVU1CRVJTPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5B

aXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+

PGtleXdvcmQ+RVBJVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lcGl0aGVsaWFsIGNlbGxzPC9r

ZXl3b3JkPjxrZXl3b3JkPklOVk9MVkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNp

czwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3

b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5

d29yZD48a2V5d29yZD5BbmFseXNpcyBvZiBWYXJpYW5jZTwva2V5d29yZD48a2V5d29yZD5CSU9Q

U1k8L2tleXdvcmQ+PGtleXdvcmQ+QnJvbmNoaXRpcyBkaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdv

cmQ+QnJvbmNoaXRpcyBwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RW5kb3RoZWxp

dW0sVmFzY3VsYXI8L2tleXdvcmQ+PGtleXdvcmQ+Rm9yY2VkIEV4cGlyYXRvcnkgVm9sdW1lPC9r

ZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5JbW11bm9o

aXN0b2NoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5MdW5nIERpc2Vhc2VzLE9ic3RydWN0aXZl

IGRpYWdub3Npczwva2V5d29yZD48a2V5d29yZD5MdW5nIERpc2Vhc2VzLE9ic3RydWN0aXZlIHBo

eXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlPC9rZXl3b3JkPjxrZXl3

b3JkPk11Y291cyBNZW1icmFuZTwva2V5d29yZD48a2V5d29yZD5TbW9raW5nIHBoeXNpb3BhdGhv

bG9neTwva2V5d29yZD48a2V5d29yZD5WaXRhbCBDYXBhY2l0eTwva2V5d29yZD48a2V5d29yZD5B

bnRpZ2VucyxDRCBhbmFseXNpczwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpdGlzIHBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5DZWxsIEFkaGVzaW9uIE1vbGVjdWxlcyBhbmFseXNpczwva2V5

d29yZD48a2V5d29yZD5DeXRva2luZXMgYW5hbHlzaXM8L2tleXdvcmQ+PGtleXdvcmQ+THVuZyBE

aXNlYXNlcyxPYnN0cnVjdGl2ZSBwYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+TWVtYnJhbmUg

R2x5Y29wcm90ZWlucyBhbmFseXNpczwva2V5d29yZD48a2V5d29yZD5TbW9raW5nIHBhdGhvbG9n

eTwva2V5d29yZD48a2V5d29yZD5VcCBSZWd1bGF0aW9uIFBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtl

eXdvcmQ+Q29tcGFyYXRpdmUgU3R1ZHk8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3Jk

PjxrZXl3b3JkPmh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+

U3VwcG9ydCxOb24gVS5TLkdvdiZhcG9zO3Q8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWdlbnMsQ0Q8

L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBBZGhlc2lvbiBNb2xlY3VsZXM8L2tleXdvcmQ+PGtleXdv

cmQ+RSBTZWxlY3Rpbjwva2V5d29yZD48a2V5d29yZD5NZW1icmFuZSBHbHljb3Byb3RlaW5zPC9r

ZXl3b3JkPjxrZXl3b3JkPkludGVyY2VsbHVsYXIgQWRoZXNpb24gTW9sZWN1bGUgMTwva2V5d29y

ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTk5

NDwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5ESVNURUZBTk8xOTk0PC9sYWJlbD48

dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [63]. Adherent neutrophils migrate into the respiratory tract under the direction of various neutrophil chemotactic factors, including LTB4, CXCL1, CXCL5 (ENA-78) and CXCL8, which are increased in COPD airways. These chemotactic mediators may be derived from epithelial cells macrophages and T-cells, but neutrophils may be a major source of CXCL8. Neutrophils recruited to the airways of COPD patients are activated with increased secretion of granule proteins, such as myeloperoxidase (MPO) and human neutrophil lipocalin ADDIN EN.CITE <EndNote><Cite><Author>Keatings</Author><Year>1997</Year><RecNum>5083</RecNum><DisplayText>[64]</DisplayText><record><rec-number>5083</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478901">5083</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Keatings,V.M.</author><author>Barnes,P.J.</author></authors></contributors><titles><title>Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma and normal subjects</title><secondary-title>Am J Respir Crit Care Med</secondary-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>449-453</pages><volume>155</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>GRANULOCYTE</keyword><keyword>ACTIVATION</keyword><keyword>IN</keyword><keyword>INDUCED</keyword><keyword>SPUTUM</keyword><keyword>COMPARISON</keyword><keyword>CHRONIC</keyword><keyword>CHRONIC OBSTRUCTIVE</keyword><keyword>OBSTRUCTIVE</keyword><keyword>PULMONARY</keyword><keyword>DISEASE</keyword><keyword>Asthma</keyword><keyword>normal</keyword><keyword>SUBJECTS</keyword></keywords><dates><year>1997</year><pub-dates><date>1997</date></pub-dates></dates><label>KEATINGS1997</label><urls></urls></record></Cite></EndNote>[64]. Neutrophils secrete serine proteases, including neutrophil elastase (NE), cathepsin G and proteinase-3, as well as MMP-8 and MMP-9, which may contribute to alveolar destruction. Airway neutrophilia is linked to mucus hypersecretion as neutrophil elastase, cathepsin G and proteinase-3 are potent stimulants of mucus secretion from submucosal glands and goblet cells ADDIN EN.CITE <EndNote><Cite><Author>Fahy</Author><Year>2010</Year><RecNum>11222</RecNum><DisplayText>[65]</DisplayText><record><rec-number>11222</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478998">11222</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fahy,J.V.</author><author>Dickey,B.F.</author></authors></contributors><titles><title>Airway mucus function and dysfunction</title><secondary-title>N.Engl.J Med.</secondary-title></titles><periodical><full-title>N.Engl.J Med.</full-title></periodical><pages>2233-2247</pages><volume>363</volume><number>23</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>AIRWAY</keyword><keyword>anatomy &amp; histology</keyword><keyword>Asthma</keyword><keyword>CARDIOVASCULAR</keyword><keyword>CYSTIC FIBROSIS</keyword><keyword>DYSFUNCTION</keyword><keyword>function</keyword><keyword>HUMANS</keyword><keyword>lung diseases</keyword><keyword>MEDICINE</keyword><keyword>Mucociliary Clearance</keyword><keyword>MUCUS</keyword><keyword>physiology</keyword><keyword>physiopathology</keyword><keyword>Pulmonary Disease,Chronic Obstructive</keyword><keyword>RESEARCH</keyword><keyword>Respiratory Physiological Processes</keyword><keyword>respiratory system</keyword><keyword>SECRETION</keyword></keywords><dates><year>2010</year><pub-dates><date>12/2/2010</date></pub-dates></dates><label>FAHY2010</label><urls></urls></record></Cite></EndNote>[65]. Neutrophil numbers in the airways are increased in acute exacerbations, accounting for the increased purulence of sputum. Neutrophils from COPD patients show aberrant chemotactic responses, with increased migration but reduced accuracy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXBleTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT4xMTU3NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNjZdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjExNTc1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0NzkwMDMiPjExNTc1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5TYXBleSxFLjwvYXV0aG9yPjxhdXRob3I+U3RvY2tsZXksSi5BLjwvYXV0aG9yPjxhdXRob3I+

R3JlZW53b29kLEguPC9hdXRob3I+PGF1dGhvcj5BaG1hZCxBLjwvYXV0aG9yPjxhdXRob3I+QmF5

bGV5LEQuPC9hdXRob3I+PGF1dGhvcj5Mb3JkLEouTS48L2F1dGhvcj48YXV0aG9yPkluc2FsbCxS

LkguPC9hdXRob3I+PGF1dGhvcj5TdG9ja2xleSxSLkEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJlaGF2aW9yYWwgYW5kIHN0cnVjdHVyYWwgZGlmZmVy

ZW5jZXMgaW4gbWlncmF0aW5nIHBlcmlwaGVyYWwgbmV1dHJvcGhpbHMgZnJvbSBwYXRpZW50cyB3

aXRoIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QW0uSi5SZXNwaXIuQ3JpdCBDYXJlIE1lZC48L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbS5KLlJlc3Bpci5Dcml0IENhcmUgTWVkLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjExNzYtMTE4NjwvcGFnZXM+PHZvbHVtZT4x

ODM8L3ZvbHVtZT48bnVtYmVyPjk8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDQ1VNVUxBVElPTjwva2V5d29y

ZD48a2V5d29yZD5BRFVMVDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFMUEhBPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWxvZ3MgJmFtcDsgZGVyaXZhdGl2ZXM8L2tleXdv

cmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5DaGVt

b2tpbmUgQ1hDTDE8L2tleXdvcmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hlbW90YXhpczwva2V5d29yZD48a2V5d29yZD5DaHJvbW9uZXM8L2tleXdvcmQ+PGtleXdv

cmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+Y2lyY3VsYXRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Y2xpbmljYWw8L2tleXdvcmQ+

PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3Jk

PkRBTUFHRTwva2V5d29yZD48a2V5d29yZD5ERUZJQ0lFTkNZPC9rZXl3b3JkPjxrZXl3b3JkPkRJ

RkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5USUFMPC9rZXl3b3JkPjxrZXl3b3Jk

PkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVD

VFM8L2tleXdvcmQ+PGtleXdvcmQ+RVhQRVJJTUVOVEFMPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJF

U1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZMT1c8L2tl

eXdvcmQ+PGtleXdvcmQ+RmxvdyBDeXRvbWV0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SEVBTFRIWTwv

a2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SUwtODwva2V5d29yZD48

a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3Jk

PklOIFZJVFJPPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3Jk

PklOVEVSTEVVS0lOLTg8L2tleXdvcmQ+PGtleXdvcmQ+SVNPTEFURUQ8L2tleXdvcmQ+PGtleXdv

cmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5MVU5HUzwva2V5d29yZD48a2V5d29yZD5NQUxFPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FQVNVUkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJU008L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3

b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdv

cmQ+PGtleXdvcmQ+TUlHUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPm1vcnBob2xpbmVzPC9rZXl3

b3JkPjxrZXl3b3JkPm4tZm9ybXlsbWV0aGlvbmluZSBsZXVjeWwtcGhlbnlsYWxhbmluZTwva2V5

d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXRyb3BoaWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5

d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5

d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBIT1NQSE9JTk9TSVRJREU8L2tleXdv

cmQ+PGtleXdvcmQ+UE9QVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29y

ZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRUxBVEVEPC9rZXl3b3JkPjxrZXl3

b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3JkPnNldmVyaXR5IG9mIGlsbG5lc3MgaW5kZXg8

L2tleXdvcmQ+PGtleXdvcmQ+U0lHTkFMPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tJTkc8L2tleXdv

cmQ+PGtleXdvcmQ+U1BVVFVNPC9rZXl3b3JkPjxrZXl3b3JkPlNUUlVDVFVSQUw8L2tleXdvcmQ+

PGtleXdvcmQ+U1RSVUNUVVJBTExZPC9rZXl3b3JkPjxrZXl3b3JkPlN0cnVjdHVyZTwva2V5d29y

ZD48a2V5d29yZD5TVUJKRUNUUzwva2V5d29yZD48a2V5d29yZD5TVVJGQUNFPC9rZXl3b3JkPjxr

ZXl3b3JkPlRJU1NVRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+NS8xLzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFi

ZWw+U0FQRVkyMDExPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXBleTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

Y051bT4xMTU3NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNjZdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjExNTc1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0NzkwMDMiPjExNTc1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5TYXBleSxFLjwvYXV0aG9yPjxhdXRob3I+U3RvY2tsZXksSi5BLjwvYXV0aG9yPjxhdXRob3I+

R3JlZW53b29kLEguPC9hdXRob3I+PGF1dGhvcj5BaG1hZCxBLjwvYXV0aG9yPjxhdXRob3I+QmF5

bGV5LEQuPC9hdXRob3I+PGF1dGhvcj5Mb3JkLEouTS48L2F1dGhvcj48YXV0aG9yPkluc2FsbCxS

LkguPC9hdXRob3I+PGF1dGhvcj5TdG9ja2xleSxSLkEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29u

dHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkJlaGF2aW9yYWwgYW5kIHN0cnVjdHVyYWwgZGlmZmVy

ZW5jZXMgaW4gbWlncmF0aW5nIHBlcmlwaGVyYWwgbmV1dHJvcGhpbHMgZnJvbSBwYXRpZW50cyB3

aXRoIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+QW0uSi5SZXNwaXIuQ3JpdCBDYXJlIE1lZC48L3NlY29uZGFyeS10aXRsZT48L3Rp

dGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbS5KLlJlc3Bpci5Dcml0IENhcmUgTWVkLjwv

ZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjExNzYtMTE4NjwvcGFnZXM+PHZvbHVtZT4x

ODM8L3ZvbHVtZT48bnVtYmVyPjk8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDQ1VNVUxBVElPTjwva2V5d29y

ZD48a2V5d29yZD5BRFVMVDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3Jk

PkFMUEhBPC9rZXl3b3JkPjxrZXl3b3JkPmFuYWxvZ3MgJmFtcDsgZGVyaXZhdGl2ZXM8L2tleXdv

cmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5DaGVt

b2tpbmUgQ1hDTDE8L2tleXdvcmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdv

cmQ+Q2hlbW90YXhpczwva2V5d29yZD48a2V5d29yZD5DaHJvbW9uZXM8L2tleXdvcmQ+PGtleXdv

cmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+

PGtleXdvcmQ+Y2lyY3VsYXRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Y2xpbmljYWw8L2tleXdvcmQ+

PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3Jk

PkRBTUFHRTwva2V5d29yZD48a2V5d29yZD5ERUZJQ0lFTkNZPC9rZXl3b3JkPjxrZXl3b3JkPkRJ

RkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5USUFMPC9rZXl3b3JkPjxrZXl3b3Jk

PkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVD

VFM8L2tleXdvcmQ+PGtleXdvcmQ+RVhQRVJJTUVOVEFMPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJF

U1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZMT1c8L2tl

eXdvcmQ+PGtleXdvcmQ+RmxvdyBDeXRvbWV0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SEVBTFRIWTwv

a2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SUwtODwva2V5d29yZD48

a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3Jk

PklOIFZJVFJPPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3Jk

PklOVEVSTEVVS0lOLTg8L2tleXdvcmQ+PGtleXdvcmQ+SVNPTEFURUQ8L2tleXdvcmQ+PGtleXdv

cmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5MVU5HUzwva2V5d29yZD48a2V5d29yZD5NQUxFPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FQVNVUkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJU008L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3

b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdv

cmQ+PGtleXdvcmQ+TUlHUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPm1vcnBob2xpbmVzPC9rZXl3

b3JkPjxrZXl3b3JkPm4tZm9ybXlsbWV0aGlvbmluZSBsZXVjeWwtcGhlbnlsYWxhbmluZTwva2V5

d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXRyb3BoaWxzPC9r

ZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5

d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5

d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBIT1NQSE9JTk9TSVRJREU8L2tleXdv

cmQ+PGtleXdvcmQ+UE9QVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29y

ZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRUxBVEVEPC9rZXl3b3JkPjxrZXl3

b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3JkPnNldmVyaXR5IG9mIGlsbG5lc3MgaW5kZXg8

L2tleXdvcmQ+PGtleXdvcmQ+U0lHTkFMPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tJTkc8L2tleXdv

cmQ+PGtleXdvcmQ+U1BVVFVNPC9rZXl3b3JkPjxrZXl3b3JkPlNUUlVDVFVSQUw8L2tleXdvcmQ+

PGtleXdvcmQ+U1RSVUNUVVJBTExZPC9rZXl3b3JkPjxrZXl3b3JkPlN0cnVjdHVyZTwva2V5d29y

ZD48a2V5d29yZD5TVUJKRUNUUzwva2V5d29yZD48a2V5d29yZD5TVVJGQUNFPC9rZXl3b3JkPjxr

ZXl3b3JkPlRJU1NVRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+NS8xLzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFi

ZWw+U0FQRVkyMDExPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT4A

ADDIN EN.CITE.DATA [66].LymphocytesT-lymphocytes play a very important role in coordinating the inflammatory response in asthma through the release of specific patterns of cytokines (called T2-cytokines), resulting in the recruitment and survival of eosinophils and in the maintenance of a mast cell population in the airways ADDIN EN.CITE <EndNote><Cite><Author>Lambrecht</Author><Year>2015</Year><RecNum>12627</RecNum><DisplayText>[67]</DisplayText><record><rec-number>12627</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1456228608">12627</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lambrecht, B. N.</author><author>Hammad, H.</author></authors></contributors><auth-address>1] VIB Inflammation Research Center, Ghent University, Ghent, Belgium. [2] Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium. [3] Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.&#xD;1] VIB Inflammation Research Center, Ghent University, Ghent, Belgium. [2] Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium.</auth-address><titles><title>The immunology of asthma</title><secondary-title>Nat Immunol</secondary-title><alt-title>Nature immunology</alt-title></titles><periodical><full-title>Nat Immunol</full-title><abbr-1>Nature immunology</abbr-1></periodical><alt-periodical><full-title>Nat Immunol</full-title><abbr-1>Nature immunology</abbr-1></alt-periodical><pages>45-56</pages><volume>16</volume><number>1</number><edition>2014/12/19</edition><keywords><keyword>Animals</keyword><keyword>Asthma/drug therapy/*immunology</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Disease Models, Animal</keyword><keyword>Eosinophils/cytology/immunology</keyword><keyword>Humans</keyword><keyword>Th17 Cells/cytology/immunology</keyword><keyword>Th2 Cells/immunology</keyword></keywords><dates><year>2015</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1529-2908</isbn><accession-num>25521684</accession-num><urls></urls><electronic-resource-num>10.1038/ni.3049</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[67]. The na?ve immune system and the immune system of asthmatics are skewed to express the Th2 phenotype, whereas in normal airways Th1 cells predominate. Th2 cells, release of IL-5, which drives eosinophilic inflammation and IL-4 and IL-13, which promote IgE formation. Regulatory T-cells (Treg) suppress Th2 cells and may be reduced in asthma. ILC2 cells also release T2 cytokines and have been identified in the airways of asthmatic patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT4xMjM5OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNjhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEyMzk5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjE0NDExMDM3MTQiPjEyMzk5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5TbWl0aCwgUy4gRy48L2F1dGhvcj48YXV0aG9yPkNoZW4sIFIuPC9hdXRob3I+PGF1dGhvcj5L

amFyc2dhYXJkLCBNLjwvYXV0aG9yPjxhdXRob3I+SHVhbmcsIEMuPC9hdXRob3I+PGF1dGhvcj5P

bGl2ZXJpYSwgSi4gUC48L2F1dGhvcj48YXV0aG9yPk8mYXBvcztCeXJuZSwgUC4gTS48L2F1dGhv

cj48YXV0aG9yPkdhdXZyZWF1LCBHLiBNLjwvYXV0aG9yPjxhdXRob3I+Qm91bGV0LCBMLiBQLjwv

YXV0aG9yPjxhdXRob3I+TGVtaWVyZSwgQy48L2F1dGhvcj48YXV0aG9yPk1hcnRpbiwgSi48L2F1

dGhvcj48YXV0aG9yPk5haXIsIFAuPC9hdXRob3I+PGF1dGhvcj5TZWhtaSwgUi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBSZXNwaXJv

bG9neSwgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgTWNNYXN0ZXIgVW5pdmVyc2l0eSwgSGFtaWx0

b24sIE9udGFyaW8sIENhbmFkYS4mI3hEO0RpdmlzaW9uIG9mIFJlc3Bpcm9sb2d5LCBEZXBhcnRt

ZW50IG9mIE1lZGljaW5lLCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwgT250YXJpbywg

Q2FuYWRhOyBHdWFuZ3pob3UgSW5zdGl0dXRlIG9mIFJlc3BpcmF0b3J5IERpc2Vhc2VzLCBHdWFu

Z3pob3UgTWVkaWNhbCBVbml2ZXJzaXR5LCBHdWFuZ3pob3UsIENoaW5hLiYjeEQ7SW5zdGl0dXQg

dW5pdmVyc2l0YWlyZSBkZSBjYXJkaW9sb2dpZSBldCBkZSBwbmV1bW9sb2dpZSBkZSBRdWViZWMs

IFF1ZWJlYyBDaXR5LCBRdWViZWMsIENhbmFkYS4mI3hEO0RpdmlzaW9uIG9mIFBuZXVtb2xvZ2ll

LCBVbml2ZXJzaXR5IG9mIE1vbnRyZWFsLCBNb250cmVhbCwgUXVlYmVjLCBDYW5hZGEuJiN4RDtN

ZWFraW5zLUNocmlzdGllIExhYm9yYXRvcmllcywgUmVzZWFyY2ggSW5zdGl0dXRlIG9mIHRoZSBN

Y0dpbGwgVW5pdmVyc2l0eSBIZWFsdGggQ2VudGVyLCBIYW1pbHRvbiwgT250YXJpbywgQ2FuYWRh

LiYjeEQ7RGl2aXNpb24gb2YgUmVzcGlyb2xvZ3ksIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIE1j

TWFzdGVyIFVuaXZlcnNpdHksIEhhbWlsdG9uLCBPbnRhcmlvLCBDYW5hZGEuIEVsZWN0cm9uaWMg

YWRkcmVzczogcGFyYW1lc0BtY21hc3Rlci5jYS4mI3hEO0RpdmlzaW9uIG9mIFJlc3Bpcm9sb2d5

LCBEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwg

T250YXJpbywgQ2FuYWRhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHNlaG1pckBtY21hc3Rlci5jYS48

L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbmNyZWFzZWQgbnVtYmVycyBvZiBhY3RpdmF0

ZWQgZ3JvdXAgMiBpbm5hdGUgbHltcGhvaWQgY2VsbHMgaW4gdGhlIGFpcndheXMgb2YgcGF0aWVu

dHMgd2l0aCBzZXZlcmUgYXN0aG1hIGFuZCBwZXJzaXN0ZW50IGFpcndheSBlb3Npbm9waGlsaWE8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbGxlcmd5IENsaW4gSW1tdW5vbDwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+VGhlIEpvdXJuYWwgb2YgYWxsZXJneSBhbmQgY2xpbmljYWwgaW1t

dW5vbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWxs

ZXJneSBDbGluIEltbXVub2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43NS04Njwv

cGFnZXM+PHZvbHVtZT4xMzc8L3ZvbHVtZT48ZWRpdGlvbj4yMDE1LzA3LzIyPC9lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD5Hcm91cCAyIGlubmF0ZSBseW1waG9pZCBjZWxsczwva2V5d29yZD48

a2V5d29yZD5lb3Npbm9waGlsaWMgYnJvbmNoaXRpczwva2V5d29yZD48a2V5d29yZD5zZXZlcmUg

YXN0aG1hPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5KdWwgMTc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDkxLTY3

NDk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjYxOTQ1NDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91

cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFjaS4yMDE1LjA1LjAzNzwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08L3Jl

bW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+RW5nPC9sYW5ndWFnZT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbWl0aDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

Y051bT4xMjM5OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNjhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjEyMzk5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjE0NDExMDM3MTQiPjEyMzk5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5TbWl0aCwgUy4gRy48L2F1dGhvcj48YXV0aG9yPkNoZW4sIFIuPC9hdXRob3I+PGF1dGhvcj5L

amFyc2dhYXJkLCBNLjwvYXV0aG9yPjxhdXRob3I+SHVhbmcsIEMuPC9hdXRob3I+PGF1dGhvcj5P

bGl2ZXJpYSwgSi4gUC48L2F1dGhvcj48YXV0aG9yPk8mYXBvcztCeXJuZSwgUC4gTS48L2F1dGhv

cj48YXV0aG9yPkdhdXZyZWF1LCBHLiBNLjwvYXV0aG9yPjxhdXRob3I+Qm91bGV0LCBMLiBQLjwv

YXV0aG9yPjxhdXRob3I+TGVtaWVyZSwgQy48L2F1dGhvcj48YXV0aG9yPk1hcnRpbiwgSi48L2F1

dGhvcj48YXV0aG9yPk5haXIsIFAuPC9hdXRob3I+PGF1dGhvcj5TZWhtaSwgUi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EaXZpc2lvbiBvZiBSZXNwaXJv

bG9neSwgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgTWNNYXN0ZXIgVW5pdmVyc2l0eSwgSGFtaWx0

b24sIE9udGFyaW8sIENhbmFkYS4mI3hEO0RpdmlzaW9uIG9mIFJlc3Bpcm9sb2d5LCBEZXBhcnRt

ZW50IG9mIE1lZGljaW5lLCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwgT250YXJpbywg

Q2FuYWRhOyBHdWFuZ3pob3UgSW5zdGl0dXRlIG9mIFJlc3BpcmF0b3J5IERpc2Vhc2VzLCBHdWFu

Z3pob3UgTWVkaWNhbCBVbml2ZXJzaXR5LCBHdWFuZ3pob3UsIENoaW5hLiYjeEQ7SW5zdGl0dXQg

dW5pdmVyc2l0YWlyZSBkZSBjYXJkaW9sb2dpZSBldCBkZSBwbmV1bW9sb2dpZSBkZSBRdWViZWMs

IFF1ZWJlYyBDaXR5LCBRdWViZWMsIENhbmFkYS4mI3hEO0RpdmlzaW9uIG9mIFBuZXVtb2xvZ2ll

LCBVbml2ZXJzaXR5IG9mIE1vbnRyZWFsLCBNb250cmVhbCwgUXVlYmVjLCBDYW5hZGEuJiN4RDtN

ZWFraW5zLUNocmlzdGllIExhYm9yYXRvcmllcywgUmVzZWFyY2ggSW5zdGl0dXRlIG9mIHRoZSBN

Y0dpbGwgVW5pdmVyc2l0eSBIZWFsdGggQ2VudGVyLCBIYW1pbHRvbiwgT250YXJpbywgQ2FuYWRh

LiYjeEQ7RGl2aXNpb24gb2YgUmVzcGlyb2xvZ3ksIERlcGFydG1lbnQgb2YgTWVkaWNpbmUsIE1j

TWFzdGVyIFVuaXZlcnNpdHksIEhhbWlsdG9uLCBPbnRhcmlvLCBDYW5hZGEuIEVsZWN0cm9uaWMg

YWRkcmVzczogcGFyYW1lc0BtY21hc3Rlci5jYS4mI3hEO0RpdmlzaW9uIG9mIFJlc3Bpcm9sb2d5

LCBEZXBhcnRtZW50IG9mIE1lZGljaW5lLCBNY01hc3RlciBVbml2ZXJzaXR5LCBIYW1pbHRvbiwg

T250YXJpbywgQ2FuYWRhLiBFbGVjdHJvbmljIGFkZHJlc3M6IHNlaG1pckBtY21hc3Rlci5jYS48

L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5JbmNyZWFzZWQgbnVtYmVycyBvZiBhY3RpdmF0

ZWQgZ3JvdXAgMiBpbm5hdGUgbHltcGhvaWQgY2VsbHMgaW4gdGhlIGFpcndheXMgb2YgcGF0aWVu

dHMgd2l0aCBzZXZlcmUgYXN0aG1hIGFuZCBwZXJzaXN0ZW50IGFpcndheSBlb3Npbm9waGlsaWE8

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbGxlcmd5IENsaW4gSW1tdW5vbDwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+VGhlIEpvdXJuYWwgb2YgYWxsZXJneSBhbmQgY2xpbmljYWwgaW1t

dW5vbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWxs

ZXJneSBDbGluIEltbXVub2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz43NS04Njwv

cGFnZXM+PHZvbHVtZT4xMzc8L3ZvbHVtZT48ZWRpdGlvbj4yMDE1LzA3LzIyPC9lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD5Hcm91cCAyIGlubmF0ZSBseW1waG9pZCBjZWxsczwva2V5d29yZD48

a2V5d29yZD5lb3Npbm9waGlsaWMgYnJvbmNoaXRpczwva2V5d29yZD48a2V5d29yZD5zZXZlcmUg

YXN0aG1hPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1k

YXRlcz48ZGF0ZT5KdWwgMTc8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4wMDkxLTY3

NDk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjYxOTQ1NDQ8L2FjY2Vzc2lvbi1udW0+PHVybHM+PC91

cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDE2L2ouamFjaS4yMDE1LjA1LjAzNzwv

ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08L3Jl

bW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+RW5nPC9sYW5ndWFnZT48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [68]. ILC2 are regulated by the epithelial cytokines IL-25, IL-33 and TSLP and may be important in intrinsic and severe asthma. As discussed above, Th17 cells are also increased in patients with severe asthma and may orchestrate neutrophilic inflammation by inducing the release of CXCL8 from airway epithelial cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbC1SYW1saTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xMjI4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNjEsIDY5XTwvRGlzcGxheVRleHQ+

PHJlY29yZD48cmVjLW51bWJlcj4xMjI4MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGlt

ZXN0YW1wPSIxNDI5NTQ2MjQ2Ij4xMjI4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+QWwtUmFtbGksIFcuPC9hdXRob3I+PGF1dGhvcj5QcmVmb250YWluZSwgRC48L2F1

dGhvcj48YXV0aG9yPkNob3VpYWxpLCBGLjwvYXV0aG9yPjxhdXRob3I+TWFydGluLCBKLiBHLjwv

YXV0aG9yPjxhdXRob3I+T2xpdmVuc3RlaW4sIFIuPC9hdXRob3I+PGF1dGhvcj5MZW1pZXJlLCBD

LjwvYXV0aG9yPjxhdXRob3I+SGFtaWQsIFEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPlQoSCkxNy1hc3NvY2lhdGVkIGN5dG9raW5lcyAoSUwtMTdBIGFu

ZCBJTC0xN0YpIGluIHNldmVyZSBhc3RobWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbGxl

cmd5IENsaW4gSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIEpvdXJuYWwg

b2YgYWxsZXJneSBhbmQgY2xpbmljYWwgaW1tdW5vbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWxsZXJneSBDbGluIEltbXVub2w8L2Z1bGwtdGl0bGU+

PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTg1LTc8L3BhZ2VzPjx2b2x1bWU+MTIzPC92b2x1bWU+PG51

bWJlcj41PC9udW1iZXI+PGVkaXRpb24+MjAwOS8wNC8xNDwvZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+QXN0aG1hLyppbW11bm9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Ccm9u

Y2hvc2NvcHk8L2tleXdvcmQ+PGtleXdvcmQ+RXBpdGhlbGl1bS9pbW11bm9sb2d5L21ldGFib2xp

c20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5J

bnRlcmxldWtpbi0xNy8qaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5MdW5nL2ltbXVub2xv

Z3kvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VC1MeW1waG9jeXRlcywg

SGVscGVyLUluZHVjZXIvKmltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjAwOTEtNjc0OTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTM2MTg0NzwvYWNjZXNz

aW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5q

YWNpLjIwMDkuMDIuMDI0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNl

LXByb3ZpZGVyPk5sbTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xh

bmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhbHdhbmk8L0F1dGhvcj48WWVh

cj4yMDEzPC9ZZWFyPjxSZWNOdW0+MTI0Mzk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEy

NDM5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnow

cmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NDY3MzgwODciPjEy

NDM5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5IYWx3YW5pLCBSLjwv

YXV0aG9yPjxhdXRob3I+QWwtTXVoc2VuLCBTLjwvYXV0aG9yPjxhdXRob3I+SGFtaWQsIFEuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UHJpbmNlIE5haWYg

Q2VudGVyIGZvciBJbW11bm9sb2d5IFJlc2VhcmNoLCBDb2xsZWdlIG9mIE1lZGljaW5lLCBLaW5n

IFNhdWQgVW5pdmVyc2l0eSwgUml5YWRoLCBTYXVkaSBBcmFiaWEuPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+VCBoZWxwZXIgMTcgY2VsbHMgaW4gYWlyd2F5IGRpc2Vhc2VzOiBmcm9tIGxh

Ym9yYXRvcnkgYmVuY2ggdG8gYmVkc2lkZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DaGVzdDwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q2hlc3Q8L2FsdC10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PGFsdC1w

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNoZXN0PC9mdWxsLXRpdGxlPjwvYWx0LXBlcmlvZGljYWw+

PHBhZ2VzPjQ5NC01MDE8L3BhZ2VzPjx2b2x1bWU+MTQzPC92b2x1bWU+PG51bWJlcj4yPC9udW1i

ZXI+PGVkaXRpb24+MjAxMy8wMi8wNjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QXN0aG1h

L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SW50ZXJsZXVraW4tMTcvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5MdW5nIERpc2Vh

c2VzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2Us

IENocm9uaWMgT2JzdHJ1Y3RpdmUvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRo

MTcgQ2VsbHMvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KlRyYW5zbGF0aW9uYWwgTWVk

aWNhbCBSZXNlYXJjaDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+RmViIDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4w

MDEyLTM2OTI8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMzODEzMTQ8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMzc4L2NoZXN0LjEyLTA1OTg8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9y

ZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbC1SYW1saTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xMjI4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNjEsIDY5XTwvRGlzcGxheVRleHQ+

PHJlY29yZD48cmVjLW51bWJlcj4xMjI4MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGlt

ZXN0YW1wPSIxNDI5NTQ2MjQ2Ij4xMjI4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+QWwtUmFtbGksIFcuPC9hdXRob3I+PGF1dGhvcj5QcmVmb250YWluZSwgRC48L2F1

dGhvcj48YXV0aG9yPkNob3VpYWxpLCBGLjwvYXV0aG9yPjxhdXRob3I+TWFydGluLCBKLiBHLjwv

YXV0aG9yPjxhdXRob3I+T2xpdmVuc3RlaW4sIFIuPC9hdXRob3I+PGF1dGhvcj5MZW1pZXJlLCBD

LjwvYXV0aG9yPjxhdXRob3I+SGFtaWQsIFEuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPlQoSCkxNy1hc3NvY2lhdGVkIGN5dG9raW5lcyAoSUwtMTdBIGFu

ZCBJTC0xN0YpIGluIHNldmVyZSBhc3RobWE8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBBbGxl

cmd5IENsaW4gSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIEpvdXJuYWwg

b2YgYWxsZXJneSBhbmQgY2xpbmljYWwgaW1tdW5vbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWxsZXJneSBDbGluIEltbXVub2w8L2Z1bGwtdGl0bGU+

PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTg1LTc8L3BhZ2VzPjx2b2x1bWU+MTIzPC92b2x1bWU+PG51

bWJlcj41PC9udW1iZXI+PGVkaXRpb24+MjAwOS8wNC8xNDwvZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+QXN0aG1hLyppbW11bm9sb2d5L3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Ccm9u

Y2hvc2NvcHk8L2tleXdvcmQ+PGtleXdvcmQ+RXBpdGhlbGl1bS9pbW11bm9sb2d5L21ldGFib2xp

c20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5J

bnRlcmxldWtpbi0xNy8qaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5MdW5nL2ltbXVub2xv

Z3kvbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+VC1MeW1waG9jeXRlcywg

SGVscGVyLUluZHVjZXIvKmltbXVub2xvZ3k8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPk1heTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxpc2JuPjAwOTEtNjc0OTwvaXNibj48YWNjZXNzaW9uLW51bT4xOTM2MTg0NzwvYWNjZXNz

aW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5q

YWNpLjIwMDkuMDIuMDI0PC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNl

LXByb3ZpZGVyPk5sbTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xh

bmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkhhbHdhbmk8L0F1dGhvcj48WWVh

cj4yMDEzPC9ZZWFyPjxSZWNOdW0+MTI0Mzk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEy

NDM5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnow

cmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NDY3MzgwODciPjEy

NDM5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5IYWx3YW5pLCBSLjwv

YXV0aG9yPjxhdXRob3I+QWwtTXVoc2VuLCBTLjwvYXV0aG9yPjxhdXRob3I+SGFtaWQsIFEuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UHJpbmNlIE5haWYg

Q2VudGVyIGZvciBJbW11bm9sb2d5IFJlc2VhcmNoLCBDb2xsZWdlIG9mIE1lZGljaW5lLCBLaW5n

IFNhdWQgVW5pdmVyc2l0eSwgUml5YWRoLCBTYXVkaSBBcmFiaWEuPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+VCBoZWxwZXIgMTcgY2VsbHMgaW4gYWlyd2F5IGRpc2Vhc2VzOiBmcm9tIGxh

Ym9yYXRvcnkgYmVuY2ggdG8gYmVkc2lkZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DaGVzdDwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+Q2hlc3Q8L2FsdC10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PGFsdC1w

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNoZXN0PC9mdWxsLXRpdGxlPjwvYWx0LXBlcmlvZGljYWw+

PHBhZ2VzPjQ5NC01MDE8L3BhZ2VzPjx2b2x1bWU+MTQzPC92b2x1bWU+PG51bWJlcj4yPC9udW1i

ZXI+PGVkaXRpb24+MjAxMy8wMi8wNjwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QXN0aG1h

L3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+SW50ZXJsZXVraW4tMTcvcGh5c2lvbG9neTwva2V5d29yZD48a2V5d29yZD5MdW5nIERpc2Vh

c2VzLypwaHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2Us

IENocm9uaWMgT2JzdHJ1Y3RpdmUvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRo

MTcgQ2VsbHMvKnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+KlRyYW5zbGF0aW9uYWwgTWVk

aWNhbCBSZXNlYXJjaDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95ZWFy

PjxwdWItZGF0ZXM+PGRhdGU+RmViIDE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4w

MDEyLTM2OTI8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjMzODEzMTQ8L2FjY2Vzc2lvbi1udW0+PHVy

bHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMzc4L2NoZXN0LjEyLTA1OTg8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9y

ZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [61, 69]. A distinct population of CD4+ cells that produce IL-9 (Th9) are increased in asthma and play a role in maintaining mast cells in the airways ADDIN EN.CITE <EndNote><Cite><Author>Koch</Author><Year>2016</Year><RecNum>12932</RecNum><DisplayText>[70]</DisplayText><record><rec-number>12932</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482487741">12932</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Koch, S.</author><author>Sopel, N.</author><author>Finotto, S.</author></authors></contributors><auth-address>Department of Molecular Pneumology, Friedrich-Alexander-Universitat (FAU) Erlangen-Nurnberg, Universitatsklinikum Erlangen, 91052, Erlangen, Germany.&#xD;Department of Molecular Pneumology, Friedrich-Alexander-Universitat (FAU) Erlangen-Nurnberg, Universitatsklinikum Erlangen, 91052, Erlangen, Germany. susetta.finotto@uk-erlangen.de.</auth-address><titles><title>Th9 and other IL-9-producing cells in allergic asthma</title><secondary-title>Semin Immunopathol</secondary-title><alt-title>Seminars in immunopathology</alt-title></titles><periodical><full-title>Semin Immunopathol</full-title><abbr-1>Seminars in immunopathology</abbr-1></periodical><alt-periodical><full-title>Semin Immunopathol</full-title><abbr-1>Seminars in immunopathology</abbr-1></alt-periodical><edition>2016/11/20</edition><keywords><keyword>Allergic asthma</keyword><keyword>Il-9</keyword><keyword>Il-9r</keyword><keyword>Ilc2</keyword><keyword>Mast cells</keyword><keyword>Th9</keyword></keywords><dates><year>2016</year><pub-dates><date>Nov 17</date></pub-dates></dates><isbn>1863-2297</isbn><accession-num>27858144</accession-num><urls></urls><electronic-resource-num>10.1007/s00281-016-0601-1</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[70]. B-lymphocytes produce IgE in allergic asthma under the direction of IL-4 and IL-13 but B-cells producing IgE locally in the airways have also been identified even in non-atopic asthmatics PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWtoYXI8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS

ZWNOdW0+MTAwMjA8L1JlY051bT48RGlzcGxheVRleHQ+WzcxXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMDAyMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTc5Ij4xMDAyMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+VGFraGFyLFAuPC9hdXRob3I+PGF1dGhvcj5Db3JyaWdhbixDLkouPC9hdXRob3I+PGF1dGhv

cj5TbXVydGh3YWl0ZSxMLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0Nvbm5vcixCLkouPC9hdXRo

b3I+PGF1dGhvcj5EdXJoYW0sUy5SLjwvYXV0aG9yPjxhdXRob3I+TGVlLFQuSC48L2F1dGhvcj48

YXV0aG9yPkdvdWxkLEguSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+Q2xhc3Mgc3dpdGNoIHJlY29tYmluYXRpb24gdG8gSWdFIGluIHRoZSBicm9uY2hp

YWwgbXVjb3NhIG9mIGF0b3BpYyBhbmQgbm9uYXRvcGljIHBhdGllbnRzIHdpdGggYXN0aG1hPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVub2wuPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbGxlcmd5IENsaW4uSW1t

dW5vbC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMTMtMjE4PC9wYWdlcz48dm9s

dW1lPjExOTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGlu

IEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QURVTFQ8L2tleXdvcmQ+

PGtleXdvcmQ+QUxMRVJHSUM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3

b3JkPkFUT1BJQzwva2V5d29yZD48a2V5d29yZD5CLUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Qmlv

cGh5c2ljczwva2V5d29yZD48a2V5d29yZD5CSU9QU0lFUzwva2V5d29yZD48a2V5d29yZD5CSU9Q

U1k8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNISTwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8

L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48

a2V5d29yZD5DSEFJTjwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29y

ZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkN5dGlkaW5lIERlYW1pbmFzZTwva2V5d29yZD48

a2V5d29yZD5FTkNPRElORzwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HRU5FPC9rZXl3b3JkPjxrZXl3b3JkPkdF

TkVUSUNTPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29yZD5oeXBlcnNl

bnNpdGl2aXR5LGltbWVkaWF0ZTwva2V5d29yZD48a2V5d29yZD5JZ0U8L2tleXdvcmQ+PGtleXdv

cmQ+SU1NVU5PR0xPQlVMSU48L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5vZ2xvYnVsaW4gY2xhc3Mg

c3dpdGNoaW5nPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0dMT0JVTElOIEU8L2tleXdvcmQ+PGtl

eXdvcmQ+SW1tdW5vZ2xvYnVsaW4gZXBzaWxvbi1DaGFpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SU1N

VU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTVBMSUNBVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+

SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5ESVZJRFVBTFM8L2tleXdvcmQ+PGtleXdvcmQ+bG9uZG9u

PC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2lkIFRpc3N1ZTwva2V5d29yZD48a2V5d29yZD5NQUxF

PC9rZXl3b3JkPjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNN

PC9rZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJU008L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9r

ZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPm1STkE8L2tleXdvcmQ+

PGtleXdvcmQ+TVVDT1NBPC9rZXl3b3JkPjxrZXl3b3JkPk5BU0FMPC9rZXl3b3JkPjxrZXl3b3Jk

Pm5hc2FsIG11Y29zYTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29y

ZD5QUk9TUEVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjb21iaW5hdGlvbixHZW5ldGljPC9rZXl3

b3JkPjxrZXl3b3JkPlJlc3BpcmF0b3J5IE11Y29zYTwva2V5d29yZD48a2V5d29yZD5SaGluaXRp

czwva2V5d29yZD48a2V5d29yZD5STkEsTWVzc2VuZ2VyPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpF

Q1RTPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDA3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MS8yMDA3PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPlRBS0hBUjIwMDc8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWtoYXI8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS

ZWNOdW0+MTAwMjA8L1JlY051bT48RGlzcGxheVRleHQ+WzcxXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMDAyMDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTc5Ij4xMDAyMDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+VGFraGFyLFAuPC9hdXRob3I+PGF1dGhvcj5Db3JyaWdhbixDLkouPC9hdXRob3I+PGF1dGhv

cj5TbXVydGh3YWl0ZSxMLjwvYXV0aG9yPjxhdXRob3I+TyZhcG9zO0Nvbm5vcixCLkouPC9hdXRo

b3I+PGF1dGhvcj5EdXJoYW0sUy5SLjwvYXV0aG9yPjxhdXRob3I+TGVlLFQuSC48L2F1dGhvcj48

YXV0aG9yPkdvdWxkLEguSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxl

cz48dGl0bGU+Q2xhc3Mgc3dpdGNoIHJlY29tYmluYXRpb24gdG8gSWdFIGluIHRoZSBicm9uY2hp

YWwgbXVjb3NhIG9mIGF0b3BpYyBhbmQgbm9uYXRvcGljIHBhdGllbnRzIHdpdGggYXN0aG1hPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVub2wuPC9zZWNvbmRhcnkt

dGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbGxlcmd5IENsaW4uSW1t

dW5vbC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yMTMtMjE4PC9wYWdlcz48dm9s

dW1lPjExOTwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGlu

IEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QURVTFQ8L2tleXdvcmQ+

PGtleXdvcmQ+QUxMRVJHSUM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3

b3JkPkFUT1BJQzwva2V5d29yZD48a2V5d29yZD5CLUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Qmlv

cGh5c2ljczwva2V5d29yZD48a2V5d29yZD5CSU9QU0lFUzwva2V5d29yZD48a2V5d29yZD5CSU9Q

U1k8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNISTwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8

L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48

a2V5d29yZD5DSEFJTjwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29y

ZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkN5dGlkaW5lIERlYW1pbmFzZTwva2V5d29yZD48

a2V5d29yZD5FTkNPRElORzwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxr

ZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HRU5FPC9rZXl3b3JkPjxrZXl3b3JkPkdF

TkVUSUNTPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29yZD5oeXBlcnNl

bnNpdGl2aXR5LGltbWVkaWF0ZTwva2V5d29yZD48a2V5d29yZD5JZ0U8L2tleXdvcmQ+PGtleXdv

cmQ+SU1NVU5PR0xPQlVMSU48L2tleXdvcmQ+PGtleXdvcmQ+aW1tdW5vZ2xvYnVsaW4gY2xhc3Mg

c3dpdGNoaW5nPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0dMT0JVTElOIEU8L2tleXdvcmQ+PGtl

eXdvcmQ+SW1tdW5vZ2xvYnVsaW4gZXBzaWxvbi1DaGFpbnM8L2tleXdvcmQ+PGtleXdvcmQ+SU1N

VU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTVBMSUNBVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+

SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5ESVZJRFVBTFM8L2tleXdvcmQ+PGtleXdvcmQ+bG9uZG9u

PC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2lkIFRpc3N1ZTwva2V5d29yZD48a2V5d29yZD5NQUxF

PC9rZXl3b3JkPjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNN

PC9rZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJU008L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9r

ZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tl

eXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPm1STkE8L2tleXdvcmQ+

PGtleXdvcmQ+TVVDT1NBPC9rZXl3b3JkPjxrZXl3b3JkPk5BU0FMPC9rZXl3b3JkPjxrZXl3b3Jk

Pm5hc2FsIG11Y29zYTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29y

ZD5QUk9TUEVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+UmVjb21iaW5hdGlvbixHZW5ldGljPC9rZXl3

b3JkPjxrZXl3b3JkPlJlc3BpcmF0b3J5IE11Y29zYTwva2V5d29yZD48a2V5d29yZD5SaGluaXRp

czwva2V5d29yZD48a2V5d29yZD5STkEsTWVzc2VuZ2VyPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpF

Q1RTPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDA3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MS8yMDA3PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPlRBS0hBUjIwMDc8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48

L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [71]. B-cell activating factor of the TNF family (BAFF) is increased after allergen challenge in asthmatic patients many may play a role in increasing IgE production PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXRvPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

TnVtPjExMjE0PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3Ml08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTEyMTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk5OCI+MTEyMTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkthdG8sQS48L2F1dGhvcj48YXV0aG9yPlhpYW8sSC48L2F1dGhvcj48YXV0aG9yPkNodXN0eixS

LlQuPC9hdXRob3I+PGF1dGhvcj5MaXUsTS5DLjwvYXV0aG9yPjxhdXRob3I+U2NobGVpbWVyLFIu

UC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TG9jYWwg

cmVsZWFzZSBvZiBCIGNlbGwtYWN0aXZhdGluZyBmYWN0b3Igb2YgdGhlIFRORiBmYW1pbHkgYWZ0

ZXIgc2VnbWVudGFsIGFsbGVyZ2VuIGNoYWxsZW5nZSBvZiBhbGxlcmdpYyBzdWJqZWN0czwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsbGVyZ3kgQ2xpbi5JbW11bm9sLjwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVu

b2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzY5LTM3NTwvcGFnZXM+PHZvbHVt

ZT4xMjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdv

cmQ+QURVTFQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndh

eXM8L2tleXdvcmQ+PGtleXdvcmQ+QUxCVU1JTjwva2V5d29yZD48a2V5d29yZD5BTExFUkdFTjwv

a2V5d29yZD48a2V5d29yZD5BTExFUkdFTlM8L2tleXdvcmQ+PGtleXdvcmQ+QUxMRVJHSUM8L2tl

eXdvcmQ+PGtleXdvcmQ+QWxsZXJneTwva2V5d29yZD48a2V5d29yZD5BbGxlcmd5IGFuZCBJbW11

bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFOVElHRU4tSU5EVUNFRDwva2V5d29yZD48a2V5d29y

ZD5BU1NBWTwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+Qi1DRUxM

PC9rZXl3b3JkPjxrZXl3b3JkPkItQ2VsbCBBY3RpdmF0aW5nIEZhY3Rvcjwva2V5d29yZD48a2V5

d29yZD5iLWx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPkJBTDwva2V5d29yZD48a2V5d29y

ZD5CaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFSPC9rZXl3b3Jk

PjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUiBMQVZBR0U8L2tleXdvcmQ+PGtleXdvcmQ+YnJvbmNo

b2FsdmVvbGFyIGxhdmFnZSBmbHVpZDwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxr

ZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdv

cmQ+Q0hBTExFTkdFPC9rZXl3b3JkPjxrZXl3b3JkPkNPTkNFTlRSQVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+Q1lUT0tJTkU8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3

b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+

ZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkVMSVNBPC9rZXl3b3JkPjxrZXl3b3JkPmVv

c2lub3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkZBTUlMWTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+RkxVSUQ8L2tleXdvcmQ+PGtleXdvcmQ+R0VORVRJQ1M8L2tleXdv

cmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklHQTwva2V5d29yZD48a2V5d29y

ZD5JZ0U8L2tleXdvcmQ+PGtleXdvcmQ+SUwtMTM8L2tleXdvcmQ+PGtleXdvcmQ+SUwtNjwva2V5

d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PR0xPQlVMSU48L2tl

eXdvcmQ+PGtleXdvcmQ+aW1tdW5vZ2xvYnVsaW4gY2xhc3Mgc3dpdGNoaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPkltbXVub2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3

b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5

d29yZD5pbnRlcmxldWtpbi0xMzwva2V5d29yZD48a2V5d29yZD5JTlRFUkxFVUtJTi02PC9rZXl3

b3JkPjxrZXl3b3JkPkxBVkFHRTwva2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3Jk

PjxrZXl3b3JkPkx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdv

cmQ+PGtleXdvcmQ+TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48

a2V5d29yZD5NRURJQ0lORTwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdv

cmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJFUlM8L2tleXdvcmQ+PGtleXdvcmQ+

cGF0aG9nZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBST0RVQ1RJT048L2tleXdvcmQ+PGtleXdv

cmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlJo

aW5pdGlzLEFsbGVyZ2ljLFNlYXNvbmFsPC9rZXl3b3JkPjxrZXl3b3JkPlNDSE9PTDwva2V5d29y

ZD48a2V5d29yZD5TSVRFUzwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5

d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNV

QkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNZTlRIRVNJUzwva2V5d29yZD48a2V5d29yZD5UTkY8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjIvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5LQVRPMjAwOTwvbGFi

ZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXRvPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

TnVtPjExMjE0PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3Ml08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTEyMTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk5OCI+MTEyMTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkthdG8sQS48L2F1dGhvcj48YXV0aG9yPlhpYW8sSC48L2F1dGhvcj48YXV0aG9yPkNodXN0eixS

LlQuPC9hdXRob3I+PGF1dGhvcj5MaXUsTS5DLjwvYXV0aG9yPjxhdXRob3I+U2NobGVpbWVyLFIu

UC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TG9jYWwg

cmVsZWFzZSBvZiBCIGNlbGwtYWN0aXZhdGluZyBmYWN0b3Igb2YgdGhlIFRORiBmYW1pbHkgYWZ0

ZXIgc2VnbWVudGFsIGFsbGVyZ2VuIGNoYWxsZW5nZSBvZiBhbGxlcmdpYyBzdWJqZWN0czwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KIEFsbGVyZ3kgQ2xpbi5JbW11bm9sLjwvc2Vjb25kYXJ5LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVu

b2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzY5LTM3NTwvcGFnZXM+PHZvbHVt

ZT4xMjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdv

cmQ+QURVTFQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndh

eXM8L2tleXdvcmQ+PGtleXdvcmQ+QUxCVU1JTjwva2V5d29yZD48a2V5d29yZD5BTExFUkdFTjwv

a2V5d29yZD48a2V5d29yZD5BTExFUkdFTlM8L2tleXdvcmQ+PGtleXdvcmQ+QUxMRVJHSUM8L2tl

eXdvcmQ+PGtleXdvcmQ+QWxsZXJneTwva2V5d29yZD48a2V5d29yZD5BbGxlcmd5IGFuZCBJbW11

bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFOVElHRU4tSU5EVUNFRDwva2V5d29yZD48a2V5d29y

ZD5BU1NBWTwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+Qi1DRUxM

PC9rZXl3b3JkPjxrZXl3b3JkPkItQ2VsbCBBY3RpdmF0aW5nIEZhY3Rvcjwva2V5d29yZD48a2V5

d29yZD5iLWx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPkJBTDwva2V5d29yZD48a2V5d29y

ZD5CaW9zeW50aGVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFSPC9rZXl3b3Jk

PjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUiBMQVZBR0U8L2tleXdvcmQ+PGtleXdvcmQ+YnJvbmNo

b2FsdmVvbGFyIGxhdmFnZSBmbHVpZDwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxr

ZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdv

cmQ+Q0hBTExFTkdFPC9rZXl3b3JkPjxrZXl3b3JkPkNPTkNFTlRSQVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+Q1lUT0tJTkU8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3

b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+

ZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkVMSVNBPC9rZXl3b3JkPjxrZXl3b3JkPmVv

c2lub3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+RW9zaW5vcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+

RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkZBTUlMWTwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8

L2tleXdvcmQ+PGtleXdvcmQ+RkxVSUQ8L2tleXdvcmQ+PGtleXdvcmQ+R0VORVRJQ1M8L2tleXdv

cmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklHQTwva2V5d29yZD48a2V5d29y

ZD5JZ0U8L2tleXdvcmQ+PGtleXdvcmQ+SUwtMTM8L2tleXdvcmQ+PGtleXdvcmQ+SUwtNjwva2V5

d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PR0xPQlVMSU48L2tl

eXdvcmQ+PGtleXdvcmQ+aW1tdW5vZ2xvYnVsaW4gY2xhc3Mgc3dpdGNoaW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPkltbXVub2dsb2J1bGluczwva2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3

b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5

d29yZD5pbnRlcmxldWtpbi0xMzwva2V5d29yZD48a2V5d29yZD5JTlRFUkxFVUtJTi02PC9rZXl3

b3JkPjxrZXl3b3JkPkxBVkFHRTwva2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3Jk

PjxrZXl3b3JkPkx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdv

cmQ+PGtleXdvcmQ+TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48

a2V5d29yZD5NRURJQ0lORTwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdv

cmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJFUlM8L2tleXdvcmQ+PGtleXdvcmQ+

cGF0aG9nZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBST0RVQ1RJT048L2tleXdvcmQ+PGtleXdv

cmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlJo

aW5pdGlzLEFsbGVyZ2ljLFNlYXNvbmFsPC9rZXl3b3JkPjxrZXl3b3JkPlNDSE9PTDwva2V5d29y

ZD48a2V5d29yZD5TSVRFUzwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5

d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNV

QkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNZTlRIRVNJUzwva2V5d29yZD48a2V5d29yZD5UTkY8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxk

YXRlPjIvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5LQVRPMjAwOTwvbGFi

ZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [72]. B-lymphocytes are also increased in COPD lungs, particularly in severe disease. B cells are organized into lymphoid follicles, which are located in peripheral airways and lung parenchyma PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2dnPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj

TnVtPjg4MzU8L1JlY051bT48RGlzcGxheVRleHQ+WzI1XTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj44ODM1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NTkiPjg4MzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhv

Z2csSi5DLjwvYXV0aG9yPjxhdXRob3I+Q2h1LEYuPC9hdXRob3I+PGF1dGhvcj5VdG9rYXBhcmNo

LFMuPC9hdXRob3I+PGF1dGhvcj5Xb29kcyxSLjwvYXV0aG9yPjxhdXRob3I+RWxsaW90dCxXLk0u

PC9hdXRob3I+PGF1dGhvcj5CdXphdHUsTC48L2F1dGhvcj48YXV0aG9yPkNoZXJuaWFjayxSLk0u

PC9hdXRob3I+PGF1dGhvcj5Sb2dlcnMsUi5NLjwvYXV0aG9yPjxhdXRob3I+U2NpdXJiYSxGLkMu

PC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+UGFyZSxQLkQuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBuYXR1cmUg

b2Ygc21hbGwtYWlyd2F5IG9ic3RydWN0aW9uIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9u

YXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TiBFbmdsIEogTWVkPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjY0NS0yNjUzPC9wYWdlcz48dm9sdW1lPjM1

MDwvdm9sdW1lPjxudW1iZXI+MjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdvcmQ+

MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPjM8L2tleXdvcmQ+PGtleXdv

cmQ+QUNDVU1VTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48a2V5d29yZD5CLUNFTEw8L2tleXdvcmQ+PGtleXdv

cmQ+Q0Q0PC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q0hBTkdFUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3Jk

PjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBP

QlNUUlVDVElWRSBMVU5HIERJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGFzc2lmaWNhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPVVBMRUQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdv

cmQ+RUZGRUNUUzwva2V5d29yZD48a2V5d29yZD5FVk9MVVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

RVhQT1NVUkU8L2tleXdvcmQ+PGtleXdvcmQ+RVhVREFURVM8L2tleXdvcmQ+PGtleXdvcmQ+R0FT

RVM8L2tleXdvcmQ+PGtleXdvcmQ+Z2xvYmFsPC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdv

cmQ+PGtleXdvcmQ+SEVBTFRIPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVORTwva2V5d29yZD48a2V5

d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5JTkNS

RUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmlu

ZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5MT05HIFRFUk08L2tleXdvcmQ+PGtleXdvcmQ+

TE9ORy1URVJNPC9rZXl3b3JkPjxrZXl3b3JkPkxVTUVOPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8

L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdl

czwva2V5d29yZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NVUNPVVM8L2tleXdvcmQ+PGtl

eXdvcmQ+bmV1dHJvcGhpbDwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElPTjwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5QQVJUSUNMRVM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+

PGtleXdvcmQ+UE9MWU1PUlBIT05VQ0xFQVI8L2tleXdvcmQ+PGtleXdvcmQ+UFJPQkxFTTwva2V5

d29yZD48a2V5d29yZD5QdWJsaWMgSGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwv

a2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48

a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5USVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+

Vk9MVU1FPC9rZXl3b3JkPjxrZXl3b3JkPldBTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjQvMjAwNDwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5IT0dHMjAwNDwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2dnPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj

TnVtPjg4MzU8L1JlY051bT48RGlzcGxheVRleHQ+WzI1XTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj44ODM1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NTkiPjg4MzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkhv

Z2csSi5DLjwvYXV0aG9yPjxhdXRob3I+Q2h1LEYuPC9hdXRob3I+PGF1dGhvcj5VdG9rYXBhcmNo

LFMuPC9hdXRob3I+PGF1dGhvcj5Xb29kcyxSLjwvYXV0aG9yPjxhdXRob3I+RWxsaW90dCxXLk0u

PC9hdXRob3I+PGF1dGhvcj5CdXphdHUsTC48L2F1dGhvcj48YXV0aG9yPkNoZXJuaWFjayxSLk0u

PC9hdXRob3I+PGF1dGhvcj5Sb2dlcnMsUi5NLjwvYXV0aG9yPjxhdXRob3I+U2NpdXJiYSxGLkMu

PC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+UGFyZSxQLkQuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlRoZSBuYXR1cmUg

b2Ygc21hbGwtYWlyd2F5IG9ic3RydWN0aW9uIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9u

YXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TiBFbmdsIEogTWVkPC9zZWNvbmRh

cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TiBFbmdsIEogTWVkPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MjY0NS0yNjUzPC9wYWdlcz48dm9sdW1lPjM1

MDwvdm9sdW1lPjxudW1iZXI+MjY8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdvcmQ+

MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPjM8L2tleXdvcmQ+PGtleXdv

cmQ+QUNDVU1VTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48a2V5d29yZD5CLUNFTEw8L2tleXdvcmQ+PGtleXdv

cmQ+Q0Q0PC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q0hBTkdFUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3Jk

PjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBP

QlNUUlVDVElWRSBMVU5HIERJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGFzc2lmaWNhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPVVBMRUQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdv

cmQ+RUZGRUNUUzwva2V5d29yZD48a2V5d29yZD5FVk9MVVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

RVhQT1NVUkU8L2tleXdvcmQ+PGtleXdvcmQ+RVhVREFURVM8L2tleXdvcmQ+PGtleXdvcmQ+R0FT

RVM8L2tleXdvcmQ+PGtleXdvcmQ+Z2xvYmFsPC9rZXl3b3JkPjxrZXl3b3JkPkdPTEQ8L2tleXdv

cmQ+PGtleXdvcmQ+SEVBTFRIPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVORTwva2V5d29yZD48a2V5

d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5JTkNS

RUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmlu

ZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5MT05HIFRFUk08L2tleXdvcmQ+PGtleXdvcmQ+

TE9ORy1URVJNPC9rZXl3b3JkPjxrZXl3b3JkPkxVTUVOPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8

L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdl

czwva2V5d29yZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRVRIT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5NVUNPVVM8L2tleXdvcmQ+PGtl

eXdvcmQ+bmV1dHJvcGhpbDwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElPTjwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5QQVJUSUNMRVM8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+

PGtleXdvcmQ+UE9MWU1PUlBIT05VQ0xFQVI8L2tleXdvcmQ+PGtleXdvcmQ+UFJPQkxFTTwva2V5

d29yZD48a2V5d29yZD5QdWJsaWMgSGVhbHRoPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwv

a2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48

a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5USVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+

Vk9MVU1FPC9rZXl3b3JkPjxrZXl3b3JkPldBTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+

PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjYvMjQvMjAwNDwvZGF0ZT48L3B1Yi1k

YXRlcz48L2RhdGVzPjxsYWJlbD5IT0dHMjAwNDwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [25]. BAFF, an important regulator of B-cell function and hyperplasia, is increased in lymphoid follicles of COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXlzPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

TnVtPjEyNzczPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3M108L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTI3NzM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTQ1OTg3NjE3NiI+MTI3NzM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlNleXMsIEwuIEouPC9hdXRob3I+PGF1dGhvcj5WZXJoYW1tZSwgRi4gTS48L2F1dGhvcj48YXV0

aG9yPlNjaGlud2FsZCwgQS48L2F1dGhvcj48YXV0aG9yPkhhbW1hZCwgSC48L2F1dGhvcj48YXV0

aG9yPkN1bm9vc2FteSwgRC4gTS48L2F1dGhvcj48YXV0aG9yPkJhbnRzaW1iYS1NYWxhbmRhLCBD

LjwvYXV0aG9yPjxhdXRob3I+U2FiaXJzaCwgQS48L2F1dGhvcj48YXV0aG9yPk1jQ2FsbCwgRS48

L2F1dGhvcj48YXV0aG9yPkZsYXZlbGwsIEwuPC9hdXRob3I+PGF1dGhvcj5IZXJic3QsIFIuPC9h

dXRob3I+PGF1dGhvcj5Qcm92b29zdCwgUy48L2F1dGhvcj48YXV0aG9yPkxhbWJyZWNodCwgQi4g

Ti48L2F1dGhvcj48YXV0aG9yPkpvb3MsIEcuIEYuPC9hdXRob3I+PGF1dGhvcj5CcnVzc2VsbGUs

IEcuIEcuPC9hdXRob3I+PGF1dGhvcj5CcmFja2UsIEsuIFIuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MSBMYWJvcmF0b3J5IGZvciBUcmFuc2xhdGlvbmFs

IFJlc2VhcmNoIGluIE9ic3RydWN0aXZlIFB1bG1vbmFyeSBEaXNlYXNlcywgRGVwYXJ0bWVudCBv

ZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3NwaXRhbCwgR2hlbnQs

IEJlbGdpdW0uJiN4RDsyIEFzdHJhWmVuZWNhIFJlc3BpcmF0b3J5LCBJbmZsYW1tYXRpb24gYW5k

IEF1dG9pbW11bmUgaU1lZCwgTW9sbmRhbCwgU3dlZGVuLiYjeEQ7MyBMYWJvcmF0b3J5IG9mIElt

bXVub3JlZ3VsYXRpb24gYW5kIE11Y29zYWwgSW1tdW5pdHksIERlcGFydG1lbnQgZm9yIE1vbGVj

dWxhciBCaW9tZWRpY2FsIFJlc2VhcmNoLCBWSUIsIEdoZW50LCBCZWxnaXVtLiYjeEQ7NCBEZXBh

cnRtZW50IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHaGVudCBVbml2ZXJzaXR5IEhvc3BpdGFs

LCBHaGVudCwgQmVsZ2l1bS4mI3hEOzUgRGVwYXJ0bWVudCBvZiBSZXNlYXJjaCwgTWVkSW1tdW5l

LCBMTEMsIEdhaXRoZXJzYnVyZywgTWFyeWxhbmQuJiN4RDs2IEFzdHJhWmVuZWNhIENhcmRpb3Zh

c2N1bGFyIGFuZCBNZXRhYm9saWMgRGlzZWFzZSBpTWVkLCBNb2xuZGFsLCBTd2VkZW47IGFuZC4m

I3hEOzcgQXN0cmFaZW5lY2EgRGlzY292ZXJ5IFNjaWVuY2VzIGlNZWQsIEFsZGVybGV5IFBhcmss

IFVuaXRlZCBLaW5nZG9tLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlJvbGUgb2YgQiBj

ZWxsLWFjdGl2YXRpbmcgZmFjdG9yIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZDwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiByZXNwaXJhdG9y

eSBhbmQgY3JpdGljYWwgY2FyZSBtZWRpY2luZTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz43MDYtMTg8L3BhZ2VzPjx2b2x1bWU+MTkyPC92b2x1bWU+PG51bWJl

cj42PC9udW1iZXI+PGVkaXRpb24+MjAxNS8wOC8xMzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWRhcHRpdmUgSW1tdW5pdHk8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5

d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkItQ2VsbCBBY3RpdmF0aW5nIEZhY3Rvci9h

bnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2ltbXVub2xvZ3kvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Qi1MeW1waG9jeXRlcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+RW56eW1lLUxpbmtlZCBJbW11bm9zb3JiZW50IEFzc2F5PC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+THVuZy9pbW11bm9sb2d5LyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2lkIFRpc3N1ZS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPk1hY3JvcGhhZ2VzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlj

ZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxr

ZXl3b3JkPlB1bG1vbmFyeSBEaXNlYXNlLCBDaHJvbmljIE9ic3RydWN0aXZlL2ltbXVub2xvZ3kv

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmV2ZXJzZSBUcmFuc2NyaXB0YXNlIFBvbHlt

ZXJhc2UgQ2hhaW4gUmVhY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+U21va2UvYWR2ZXJzZSBlZmZl

Y3RzPC9rZXl3b3JkPjxrZXl3b3JkPlNtb2tpbmcvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPkIgY2VsbC1hY3RpdmF0aW5nIGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5CIGx5bXBo

b2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPkNvcGQ8L2tleXdvcmQ+PGtleXdvcmQ+bHltcGhvaWQg

Zm9sbGljbGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5TZXAgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDcz

LTQ0OXg8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjYyNjY4Mjc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTY0L3JjY20uMjAxNTAxLTAxMDNP

QzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08

L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXlzPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

TnVtPjEyNzczPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3M108L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTI3NzM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTQ1OTg3NjE3NiI+MTI3NzM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PlNleXMsIEwuIEouPC9hdXRob3I+PGF1dGhvcj5WZXJoYW1tZSwgRi4gTS48L2F1dGhvcj48YXV0

aG9yPlNjaGlud2FsZCwgQS48L2F1dGhvcj48YXV0aG9yPkhhbW1hZCwgSC48L2F1dGhvcj48YXV0

aG9yPkN1bm9vc2FteSwgRC4gTS48L2F1dGhvcj48YXV0aG9yPkJhbnRzaW1iYS1NYWxhbmRhLCBD

LjwvYXV0aG9yPjxhdXRob3I+U2FiaXJzaCwgQS48L2F1dGhvcj48YXV0aG9yPk1jQ2FsbCwgRS48

L2F1dGhvcj48YXV0aG9yPkZsYXZlbGwsIEwuPC9hdXRob3I+PGF1dGhvcj5IZXJic3QsIFIuPC9h

dXRob3I+PGF1dGhvcj5Qcm92b29zdCwgUy48L2F1dGhvcj48YXV0aG9yPkxhbWJyZWNodCwgQi4g

Ti48L2F1dGhvcj48YXV0aG9yPkpvb3MsIEcuIEYuPC9hdXRob3I+PGF1dGhvcj5CcnVzc2VsbGUs

IEcuIEcuPC9hdXRob3I+PGF1dGhvcj5CcmFja2UsIEsuIFIuPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+MSBMYWJvcmF0b3J5IGZvciBUcmFuc2xhdGlvbmFs

IFJlc2VhcmNoIGluIE9ic3RydWN0aXZlIFB1bG1vbmFyeSBEaXNlYXNlcywgRGVwYXJ0bWVudCBv

ZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3NwaXRhbCwgR2hlbnQs

IEJlbGdpdW0uJiN4RDsyIEFzdHJhWmVuZWNhIFJlc3BpcmF0b3J5LCBJbmZsYW1tYXRpb24gYW5k

IEF1dG9pbW11bmUgaU1lZCwgTW9sbmRhbCwgU3dlZGVuLiYjeEQ7MyBMYWJvcmF0b3J5IG9mIElt

bXVub3JlZ3VsYXRpb24gYW5kIE11Y29zYWwgSW1tdW5pdHksIERlcGFydG1lbnQgZm9yIE1vbGVj

dWxhciBCaW9tZWRpY2FsIFJlc2VhcmNoLCBWSUIsIEdoZW50LCBCZWxnaXVtLiYjeEQ7NCBEZXBh

cnRtZW50IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHaGVudCBVbml2ZXJzaXR5IEhvc3BpdGFs

LCBHaGVudCwgQmVsZ2l1bS4mI3hEOzUgRGVwYXJ0bWVudCBvZiBSZXNlYXJjaCwgTWVkSW1tdW5l

LCBMTEMsIEdhaXRoZXJzYnVyZywgTWFyeWxhbmQuJiN4RDs2IEFzdHJhWmVuZWNhIENhcmRpb3Zh

c2N1bGFyIGFuZCBNZXRhYm9saWMgRGlzZWFzZSBpTWVkLCBNb2xuZGFsLCBTd2VkZW47IGFuZC4m

I3hEOzcgQXN0cmFaZW5lY2EgRGlzY292ZXJ5IFNjaWVuY2VzIGlNZWQsIEFsZGVybGV5IFBhcmss

IFVuaXRlZCBLaW5nZG9tLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlJvbGUgb2YgQiBj

ZWxsLWFjdGl2YXRpbmcgZmFjdG9yIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZDwv

c2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiByZXNwaXJhdG9y

eSBhbmQgY3JpdGljYWwgY2FyZSBtZWRpY2luZTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz43MDYtMTg8L3BhZ2VzPjx2b2x1bWU+MTkyPC92b2x1bWU+PG51bWJl

cj42PC9udW1iZXI+PGVkaXRpb24+MjAxNS8wOC8xMzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdv

cmQ+QWRhcHRpdmUgSW1tdW5pdHk8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5

d29yZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkItQ2VsbCBBY3RpdmF0aW5nIEZhY3Rvci9h

bnRhZ29uaXN0cyAmYW1wOyBpbmhpYml0b3JzL2ltbXVub2xvZ3kvKm1ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+Qi1MeW1waG9jeXRlcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+

PGtleXdvcmQ+RW56eW1lLUxpbmtlZCBJbW11bm9zb3JiZW50IEFzc2F5PC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW1t

dW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+THVuZy9pbW11bm9sb2d5LyptZXRh

Ym9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2lkIFRpc3N1ZS9tZXRhYm9saXNtPC9rZXl3

b3JkPjxrZXl3b3JkPk1hY3JvcGhhZ2VzL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48

a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdvcmQ+TWlj

ZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxr

ZXl3b3JkPlB1bG1vbmFyeSBEaXNlYXNlLCBDaHJvbmljIE9ic3RydWN0aXZlL2ltbXVub2xvZ3kv

Km1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmV2ZXJzZSBUcmFuc2NyaXB0YXNlIFBvbHlt

ZXJhc2UgQ2hhaW4gUmVhY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+U21va2UvYWR2ZXJzZSBlZmZl

Y3RzPC9rZXl3b3JkPjxrZXl3b3JkPlNtb2tpbmcvYWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPkIgY2VsbC1hY3RpdmF0aW5nIGZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5CIGx5bXBo

b2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPkNvcGQ8L2tleXdvcmQ+PGtleXdvcmQ+bHltcGhvaWQg

Zm9sbGljbGVzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT5TZXAgMTU8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xMDcz

LTQ0OXg8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjYyNjY4Mjc8L2FjY2Vzc2lvbi1udW0+PHVybHM+

PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTY0L3JjY20uMjAxNTAxLTAxMDNP

QzwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5OTE08

L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [73]. T-lymphocytes are increased in lung parenchyma and airways of COPD patients with a greater increase in CD8+ than CD4+ cells QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\0DGRUMELLI2004A.Grumelli, Corry, et al. 2004 GRUMELLI2004A /id\00.\00 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2dnPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj

TnVtPjg4MzU8L1JlY051bT48RGlzcGxheVRleHQ+WzI1LCA0NF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+ODgzNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTU5Ij44ODM1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5Ib2dnLEouQy48L2F1dGhvcj48YXV0aG9yPkNodSxGLjwvYXV0aG9yPjxhdXRob3I+VXRva2Fw

YXJjaCxTLjwvYXV0aG9yPjxhdXRob3I+V29vZHMsUi48L2F1dGhvcj48YXV0aG9yPkVsbGlvdHQs

Vy5NLjwvYXV0aG9yPjxhdXRob3I+QnV6YXR1LEwuPC9hdXRob3I+PGF1dGhvcj5DaGVybmlhY2ss

Ui5NLjwvYXV0aG9yPjxhdXRob3I+Um9nZXJzLFIuTS48L2F1dGhvcj48YXV0aG9yPlNjaXVyYmEs

Ri5DLjwvYXV0aG9yPjxhdXRob3I+Q294c29uLEguTy48L2F1dGhvcj48YXV0aG9yPlBhcmUsUC5E

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UaGUgbmF0

dXJlIG9mIHNtYWxsLWFpcndheSBvYnN0cnVjdGlvbiBpbiBjaHJvbmljIG9ic3RydWN0aXZlIHB1

bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk4gRW5nbCBKIE1l

ZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI2NDUtMjY1MzwvcGFnZXM+PHZvbHVt

ZT4zNTA8L3ZvbHVtZT48bnVtYmVyPjI2PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4g

RmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4wPC9rZXl3b3JkPjxrZXl3

b3JkPjE8L2tleXdvcmQ+PGtleXdvcmQ+Mjwva2V5d29yZD48a2V5d29yZD4zPC9rZXl3b3JkPjxr

ZXl3b3JkPkFDQ1VNVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtl

eXdvcmQ+QWlyd2F5IG9ic3RydWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdv

cmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+Qi1DRUxMPC9rZXl3b3JkPjxr

ZXl3b3JkPkNENDwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExT

PC9rZXl3b3JkPjxrZXl3b3JkPkNIQU5HRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9O

SUMgT0JTVFJVQ1RJVkUgTFVORyBESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2Jz

dHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2xhc3NpZmljYXRp

b248L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5DT1VQTEVEPC9rZXl3

b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxr

ZXl3b3JkPkVGRkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+RVZPTFVUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkVYUE9TVVJFPC9rZXl3b3JkPjxrZXl3b3JkPkVYVURBVEVTPC9rZXl3b3JkPjxrZXl3b3Jk

PkdBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPmdsb2JhbDwva2V5d29yZD48a2V5d29yZD5HT0xEPC9r

ZXl3b3JkPjxrZXl3b3JkPkhFQUxUSDwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+

PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0U8L2tleXdvcmQ+PGtleXdvcmQ+

SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORklMVFJBVElPTjwva2V5d29yZD48a2V5d29y

ZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+TE9ORyBURVJNPC9rZXl3b3JkPjxrZXl3

b3JkPkxPTkctVEVSTTwva2V5d29yZD48a2V5d29yZD5MVU1FTjwva2V5d29yZD48a2V5d29yZD5M

dW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9w

aGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9r

ZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TVVDT1VTPC9rZXl3b3Jk

PjxrZXl3b3JkPm5ldXRyb3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+TmV1dHJvcGhpbHM8L2tleXdv

cmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFSVElDTEVTPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3

b3JkPjxrZXl3b3JkPlBPTFlNT1JQSE9OVUNMRUFSPC9rZXl3b3JkPjxrZXl3b3JkPlBST0JMRU08

L2tleXdvcmQ+PGtleXdvcmQ+UHVibGljIEhlYWx0aDwva2V5d29yZD48a2V5d29yZD5QVUxNT05B

Ulk8L2tleXdvcmQ+PGtleXdvcmQ+cmlzazwva2V5d29yZD48a2V5d29yZD5TRVZFUkU8L2tleXdv

cmQ+PGtleXdvcmQ+U01BTEw8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VFPC9rZXl3b3JkPjxrZXl3

b3JkPlZPTFVNRTwva2V5d29yZD48a2V5d29yZD5XQUxMPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT42LzI0LzIwMDQ8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+SE9HRzIwMDQ8L2xhYmVsPjx1cmxzPjwvdXJscz48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HcnVtZWxsaTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1ll

YXI+PFJlY051bT45MDA2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj45MDA2PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJw

N3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEzNzg0Nzg5NjIiPjkwMDY8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdydW1lbGxpLFMuPC9hdXRob3I+PGF1dGhv

cj5Db3JyeSxELkIuPC9hdXRob3I+PGF1dGhvcj5Tb25nLEwtWC48L2F1dGhvcj48YXV0aG9yPlNv

bmcsTC48L2F1dGhvcj48YXV0aG9yPkdyZWVuLEwuPC9hdXRob3I+PGF1dGhvcj5IdWgsSi48L2F1

dGhvcj48YXV0aG9yPkhhY2NrZW4sSi48L2F1dGhvcj48YXV0aG9yPkVzcGFkYSxSLjwvYXV0aG9y

PjxhdXRob3I+QmFnLFIuPC9hdXRob3I+PGF1dGhvcj5MZXdpcyxELkUuPC9hdXRob3I+PGF1dGhv

cj5LaGVyYWRtYW5kLEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+

PHRpdGxlPkFuIGltbXVuZSBiYXNpcyBmb3IgbHVuZyBwYXJlbmNoeW1hbCBkZXN0cnVjdGlvbiBp

biBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlIGFuZCBlbXBoeXNlbWE8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjc1LTgzPC9wYWdlcz48dm9sdW1lPjE8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5v

dCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPklNTVVORTwva2V5

d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48

a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVNUEhZU0VNQTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwNDwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5HUlVNRUxMSTIwMDRBPC9sYWJlbD48dXJscz48

L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2dnPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj

TnVtPjg4MzU8L1JlY051bT48RGlzcGxheVRleHQ+WzI1LCA0NF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+ODgzNTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTU5Ij44ODM1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5Ib2dnLEouQy48L2F1dGhvcj48YXV0aG9yPkNodSxGLjwvYXV0aG9yPjxhdXRob3I+VXRva2Fw

YXJjaCxTLjwvYXV0aG9yPjxhdXRob3I+V29vZHMsUi48L2F1dGhvcj48YXV0aG9yPkVsbGlvdHQs

Vy5NLjwvYXV0aG9yPjxhdXRob3I+QnV6YXR1LEwuPC9hdXRob3I+PGF1dGhvcj5DaGVybmlhY2ss

Ui5NLjwvYXV0aG9yPjxhdXRob3I+Um9nZXJzLFIuTS48L2F1dGhvcj48YXV0aG9yPlNjaXVyYmEs

Ri5DLjwvYXV0aG9yPjxhdXRob3I+Q294c29uLEguTy48L2F1dGhvcj48YXV0aG9yPlBhcmUsUC5E

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UaGUgbmF0

dXJlIG9mIHNtYWxsLWFpcndheSBvYnN0cnVjdGlvbiBpbiBjaHJvbmljIG9ic3RydWN0aXZlIHB1

bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5nbCBKIE1lZDwvc2Vj

b25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk4gRW5nbCBKIE1l

ZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI2NDUtMjY1MzwvcGFnZXM+PHZvbHVt

ZT4zNTA8L3ZvbHVtZT48bnVtYmVyPjI2PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4g

RmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4wPC9rZXl3b3JkPjxrZXl3

b3JkPjE8L2tleXdvcmQ+PGtleXdvcmQ+Mjwva2V5d29yZD48a2V5d29yZD4zPC9rZXl3b3JkPjxr

ZXl3b3JkPkFDQ1VNVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtl

eXdvcmQ+QWlyd2F5IG9ic3RydWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdv

cmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+Qi1DRUxMPC9rZXl3b3JkPjxr

ZXl3b3JkPkNENDwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExT

PC9rZXl3b3JkPjxrZXl3b3JkPkNIQU5HRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9O

SUMgT0JTVFJVQ1RJVkUgTFVORyBESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2Jz

dHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2xhc3NpZmljYXRp

b248L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5DT1VQTEVEPC9rZXl3

b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxr

ZXl3b3JkPkVGRkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+RVZPTFVUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkVYUE9TVVJFPC9rZXl3b3JkPjxrZXl3b3JkPkVYVURBVEVTPC9rZXl3b3JkPjxrZXl3b3Jk

PkdBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPmdsb2JhbDwva2V5d29yZD48a2V5d29yZD5HT0xEPC9r

ZXl3b3JkPjxrZXl3b3JkPkhFQUxUSDwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdvcmQ+

PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0U8L2tleXdvcmQ+PGtleXdvcmQ+

SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORklMVFJBVElPTjwva2V5d29yZD48a2V5d29y

ZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+TE9ORyBURVJNPC9rZXl3b3JkPjxrZXl3

b3JkPkxPTkctVEVSTTwva2V5d29yZD48a2V5d29yZD5MVU1FTjwva2V5d29yZD48a2V5d29yZD5M

dW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9w

aGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9r

ZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TVVDT1VTPC9rZXl3b3Jk

PjxrZXl3b3JkPm5ldXRyb3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+TmV1dHJvcGhpbHM8L2tleXdv

cmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFSVElDTEVTPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3

b3JkPjxrZXl3b3JkPlBPTFlNT1JQSE9OVUNMRUFSPC9rZXl3b3JkPjxrZXl3b3JkPlBST0JMRU08

L2tleXdvcmQ+PGtleXdvcmQ+UHVibGljIEhlYWx0aDwva2V5d29yZD48a2V5d29yZD5QVUxNT05B

Ulk8L2tleXdvcmQ+PGtleXdvcmQ+cmlzazwva2V5d29yZD48a2V5d29yZD5TRVZFUkU8L2tleXdv

cmQ+PGtleXdvcmQ+U01BTEw8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VFPC9rZXl3b3JkPjxrZXl3

b3JkPlZPTFVNRTwva2V5d29yZD48a2V5d29yZD5XQUxMPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDQ8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT42LzI0LzIwMDQ8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+SE9HRzIwMDQ8L2xhYmVsPjx1cmxzPjwvdXJscz48L3Jl

Y29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5HcnVtZWxsaTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1ll

YXI+PFJlY051bT45MDA2PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj45MDA2PC9yZWMtbnVt

YmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJw

N3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEzNzg0Nzg5NjIiPjkwMDY8L2tleT48L2Zv

cmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+

PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdydW1lbGxpLFMuPC9hdXRob3I+PGF1dGhv

cj5Db3JyeSxELkIuPC9hdXRob3I+PGF1dGhvcj5Tb25nLEwtWC48L2F1dGhvcj48YXV0aG9yPlNv

bmcsTC48L2F1dGhvcj48YXV0aG9yPkdyZWVuLEwuPC9hdXRob3I+PGF1dGhvcj5IdWgsSi48L2F1

dGhvcj48YXV0aG9yPkhhY2NrZW4sSi48L2F1dGhvcj48YXV0aG9yPkVzcGFkYSxSLjwvYXV0aG9y

PjxhdXRob3I+QmFnLFIuPC9hdXRob3I+PGF1dGhvcj5MZXdpcyxELkUuPC9hdXRob3I+PGF1dGhv

cj5LaGVyYWRtYW5kLEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+

PHRpdGxlPkFuIGltbXVuZSBiYXNpcyBmb3IgbHVuZyBwYXJlbmNoeW1hbCBkZXN0cnVjdGlvbiBp

biBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlIGFuZCBlbXBoeXNlbWE8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+UExvUyBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjc1LTgzPC9wYWdlcz48dm9sdW1lPjE8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5v

dCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPklNTVVORTwva2V5

d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48

a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVNUEhZU0VNQTwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDA0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAwNDwvZGF0

ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5HUlVNRUxMSTIwMDRBPC9sYWJlbD48dXJscz48

L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [25, 44]. The numbers of T-cells correlate with the amount of alveolar destruction and the severity of airflow obstruction. The major difference in the inflammatory cell infiltrate in asymptomatic smokers and smokers with COPD is an increase in T-cells, mainly Tc1 cells, in patients with COPD, so they may play a role in amplifying and maintaining inflammation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWV0dGE8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS

ZWNOdW0+NjE1MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNzRdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjYxNTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODkxNSI+NjE1Mzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

U2FldHRhLE0uPC9hdXRob3I+PGF1dGhvcj5EaSBTdGVmYW5vLEEuPC9hdXRob3I+PGF1dGhvcj5U

dXJhdG8sRy48L2F1dGhvcj48YXV0aG9yPkZhY2NoaW5pLEYuTS48L2F1dGhvcj48YXV0aG9yPkNv

cmJpbm8sTC48L2F1dGhvcj48YXV0aG9yPk1hcHAsQy5FLjwvYXV0aG9yPjxhdXRob3I+TWFlc3Ry

ZWxsaSxQLjwvYXV0aG9yPjxhdXRob3I+Q2lhY2NpYSxBLjwvYXV0aG9yPjxhdXRob3I+RmFiYnJp

LEwuTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Q0Q4

KyBULWx5bXBob2N5dGVzIGluIHBlcmlwaGVyYWwgYWlyd2F5cyBvZiBzbW9rZXJzIHdpdGggY2hy

b25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbS5KLlJlc3Bpci5Dcml0LkNhcmUgTWVkLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtLkouUmVzcGlyLkNyaXQuQ2FyZSBNZWQuPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ODIyLTgyNjwvcGFnZXM+PHZvbHVtZT4xNTc8L3ZvbHVt

ZT48bnVtYmVyPjMgUHQgMTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3Jl

cHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+Q0Q4Kzwva2V5d29yZD48a2V5d29yZD5U

LWx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPlBFUklQ

SEVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48a2V5d29yZD5DSFJPTklD

PC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFS

WTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdv

cmQ+PGtleXdvcmQ+QWlyd2F5IG9ic3RydWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9H

WTwva2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QlJP

TkNISTwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hJVElTPC9rZXl3b3JkPjxrZXl3b3JkPmNhcmNp

bm9tYTwva2V5d29yZD48a2V5d29yZD5zdXJnZXJ5PC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291

bnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNv

bXBhcmF0aXZlIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3JkPmNkNC1wb3NpdGl2ZSB0LWx5bXBob2N5

dGVzPC9rZXl3b3JkPjxrZXl3b3JkPmNkOC1wb3NpdGl2ZSB0LWx5bXBob2N5dGVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5d29yZD48a2V5d29yZD5waHlz

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPmh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hp

c3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkxldWtvY3l0ZSBDb3VudDwva2V5d29yZD48

a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXMsb2JzdHJ1Y3RpdmU8

L2tleXdvcmQ+PGtleXdvcmQ+THVuZyBOZW9wbGFzbXM8L2tleXdvcmQ+PGtleXdvcmQ+bHltcGhv

Y3l0ZSBjb3VudDwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29y

ZD5NQUxFPC9rZXl3b3JkPjxrZXl3b3JkPm11c2NsZSxzbW9vdGg8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1dHJvcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmVjdG9teTwva2V5d29yZD48a2V5

d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnN1cHBvcnQsbm9uLXUucy5nb3YmYXBvczt0

PC9rZXl3b3JkPjxrZXl3b3JkPlZpdGFsIENhcGFjaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmluZmxh

bW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5TWU1QVE9NUzwva2V5d29yZD48a2V5d29yZD5DSFJP

TklDIEJST05DSElUSVM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxPVzwva2V5d29yZD48a2V5d29y

ZD5MT0NBTElaRUQ8L2tleXdvcmQ+PGtleXdvcmQ+bm9ybWFsPC9rZXl3b3JkPjxrZXl3b3JkPmZ1

bmN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0hJU1RPQ0hFTUlDQUw8L2tleXdvcmQ+PGtl

eXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5DRDQrPC9rZXl3b3JkPjxrZXl3b3JkPlQ8

L2tleXdvcmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5MeW1waG9j

eXRlczwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+V0FMTDwva2V5

d29yZD48a2V5d29yZD5NT1JQSE9NRVRSSUM8L2tleXdvcmQ+PGtleXdvcmQ+TUVBU1VSRTwva2V5

d29yZD48a2V5d29yZD5TTU9PVEg8L2tleXdvcmQ+PGtleXdvcmQ+U21vb3RoIG11c2NsZTwva2V5

d29yZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVSUzwva2V5d29yZD48

a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+VFdPPC9rZXl3b3JkPjxrZXl3b3Jk

PlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtl

eXdvcmQ+T0NDVVBBVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk4PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlNBRVRUQTE5OTg8L2xhYmVsPjx1cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWV0dGE8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS

ZWNOdW0+NjE1MzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNzRdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjYxNTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODkxNSI+NjE1Mzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

U2FldHRhLE0uPC9hdXRob3I+PGF1dGhvcj5EaSBTdGVmYW5vLEEuPC9hdXRob3I+PGF1dGhvcj5U

dXJhdG8sRy48L2F1dGhvcj48YXV0aG9yPkZhY2NoaW5pLEYuTS48L2F1dGhvcj48YXV0aG9yPkNv

cmJpbm8sTC48L2F1dGhvcj48YXV0aG9yPk1hcHAsQy5FLjwvYXV0aG9yPjxhdXRob3I+TWFlc3Ry

ZWxsaSxQLjwvYXV0aG9yPjxhdXRob3I+Q2lhY2NpYSxBLjwvYXV0aG9yPjxhdXRob3I+RmFiYnJp

LEwuTS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+Q0Q4

KyBULWx5bXBob2N5dGVzIGluIHBlcmlwaGVyYWwgYWlyd2F5cyBvZiBzbW9rZXJzIHdpdGggY2hy

b25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5BbS5KLlJlc3Bpci5Dcml0LkNhcmUgTWVkLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxw

ZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtLkouUmVzcGlyLkNyaXQuQ2FyZSBNZWQuPC9mdWxsLXRp

dGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+ODIyLTgyNjwvcGFnZXM+PHZvbHVtZT4xNTc8L3ZvbHVt

ZT48bnVtYmVyPjMgUHQgMTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3Jl

cHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+Q0Q4Kzwva2V5d29yZD48a2V5d29yZD5U

LWx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPlBFUklQ

SEVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48a2V5d29yZD5DSFJPTklD

PC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFS

WTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdv

cmQ+PGtleXdvcmQ+QWlyd2F5IG9ic3RydWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9H

WTwva2V5d29yZD48a2V5d29yZD5waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QlJP

TkNISTwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hJVElTPC9rZXl3b3JkPjxrZXl3b3JkPmNhcmNp

bm9tYTwva2V5d29yZD48a2V5d29yZD5zdXJnZXJ5PC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291

bnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBEaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNv

bXBhcmF0aXZlIFN0dWR5PC9rZXl3b3JkPjxrZXl3b3JkPmNkNC1wb3NpdGl2ZSB0LWx5bXBob2N5

dGVzPC9rZXl3b3JkPjxrZXl3b3JkPmNkOC1wb3NpdGl2ZSB0LWx5bXBob2N5dGVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5d29yZD48a2V5d29yZD5waHlz

aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPmh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hp

c3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3JkPkxldWtvY3l0ZSBDb3VudDwva2V5d29yZD48

a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXMsb2JzdHJ1Y3RpdmU8

L2tleXdvcmQ+PGtleXdvcmQ+THVuZyBOZW9wbGFzbXM8L2tleXdvcmQ+PGtleXdvcmQ+bHltcGhv

Y3l0ZSBjb3VudDwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29y

ZD5NQUxFPC9rZXl3b3JkPjxrZXl3b3JkPm11c2NsZSxzbW9vdGg8L2tleXdvcmQ+PGtleXdvcmQ+

TmV1dHJvcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+UG5ldW1vbmVjdG9teTwva2V5d29yZD48a2V5

d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnN1cHBvcnQsbm9uLXUucy5nb3YmYXBvczt0

PC9rZXl3b3JkPjxrZXl3b3JkPlZpdGFsIENhcGFjaXR5PC9rZXl3b3JkPjxrZXl3b3JkPmluZmxh

bW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5TWU1QVE9NUzwva2V5d29yZD48a2V5d29yZD5DSFJP

TklDIEJST05DSElUSVM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxPVzwva2V5d29yZD48a2V5d29y

ZD5MT0NBTElaRUQ8L2tleXdvcmQ+PGtleXdvcmQ+bm9ybWFsPC9rZXl3b3JkPjxrZXl3b3JkPmZ1

bmN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0hJU1RPQ0hFTUlDQUw8L2tleXdvcmQ+PGtl

eXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5DRDQrPC9rZXl3b3JkPjxrZXl3b3JkPlQ8

L2tleXdvcmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5MeW1waG9j

eXRlczwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+V0FMTDwva2V5

d29yZD48a2V5d29yZD5NT1JQSE9NRVRSSUM8L2tleXdvcmQ+PGtleXdvcmQ+TUVBU1VSRTwva2V5

d29yZD48a2V5d29yZD5TTU9PVEg8L2tleXdvcmQ+PGtleXdvcmQ+U21vb3RoIG11c2NsZTwva2V5

d29yZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVSUzwva2V5d29yZD48

a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+VFdPPC9rZXl3b3JkPjxrZXl3b3Jk

PlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtl

eXdvcmQ+T0NDVVBBVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjwv

a2V5d29yZHM+PGRhdGVzPjx5ZWFyPjE5OTg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xOTk4PC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlNBRVRUQTE5OTg8L2xhYmVsPjx1cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [74]. Th1 cells are also increased in the airways of smokers with COPD and express activated STAT-4, a transcription factor that is essential for activation and commitment of the Th1 lineage ADDIN EN.CITE <EndNote><Cite><Author>Di Stefano</Author><Year>2004</Year><RecNum>8833</RecNum><DisplayText>[75]</DisplayText><record><rec-number>8833</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478959">8833</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Di Stefano,A.</author><author>Caramori,G.</author><author>Capelli,A.</author><author>Gnemmi,I.</author><author>Ricciardolo,F.</author><author>Oates,T.</author><author>Donner,C.F.</author><author>Chung,K.F.</author><author>Barnes,P.J.</author><author>Adcock,I.M.</author></authors></contributors><titles><title>STAT4 activation in smokers and patients with chronic obstructive pulmonary disease</title><secondary-title>Eur Resp J</secondary-title></titles><periodical><full-title>Eur Resp J</full-title></periodical><pages>78-85</pages><volume>24</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>ACTIVATION</keyword><keyword>IN</keyword><keyword>PATIENTS</keyword><keyword>CHRONIC</keyword><keyword>CHRONIC OBSTRUCTIVE</keyword><keyword>Chronic obstructive pulmonary disease</keyword><keyword>OBSTRUCTIVE</keyword><keyword>PULMONARY</keyword><keyword>DISEASE</keyword></keywords><dates><year>2004</year><pub-dates><date>2004</date></pub-dates></dates><label>DISTEFANO2004</label><urls></urls></record></Cite></EndNote>[75]. Th17 cells, which secrete IL-17A and IL-22, are also increased in airways of COPD patients and may play a role in orchestrating neutrophilic inflammation QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\0CPRIDGEON2011.Pridgeon, Bugeon, et al. 2011 PRIDGEON2011 /id\00.\00 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaSBTdGVmYW5vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh

cj48UmVjTnVtPjEwNzkxPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3NiwgNzddPC9EaXNwbGF5VGV4

dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNzkxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0

aW1lc3RhbXA9IjEzNzg0Nzg5OTEiPjEwNzkxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5EaSBTdGVmYW5vLEEuPC9hdXRob3I+PGF1dGhvcj5DYXJhbW9yaSxHLjwvYXV0

aG9yPjxhdXRob3I+R25lbW1pLEkuPC9hdXRob3I+PGF1dGhvcj5Db250b2xpLE0uPC9hdXRob3I+

PGF1dGhvcj5WaWNhcmksQy48L2F1dGhvcj48YXV0aG9yPkNhcGVsbGksQS48L2F1dGhvcj48YXV0

aG9yPk1hZ25vLEYuPC9hdXRob3I+PGF1dGhvcj5EJmFwb3M7QW5uYSxTLkUuPC9hdXRob3I+PGF1

dGhvcj5aYW5pbmksQS48L2F1dGhvcj48YXV0aG9yPkJydW4sUC48L2F1dGhvcj48YXV0aG9yPkNh

c29sYXJpLFAuPC9hdXRob3I+PGF1dGhvcj5DaHVuZyxLLkYuPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjxhdXRob3I+UGFwaSxBLjwvYXV0aG9yPjxhdXRob3I+QWRjb2NrLEku

PC9hdXRob3I+PGF1dGhvcj5CYWxiaSxCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48dGl0bGVzPjx0aXRsZT5UIGhlbHBlciB0eXBlIDE3LXJlbGF0ZWQgY3l0b2tpbmUgZXhwcmVz

c2lvbiBpcyBpbmNyZWFzZWQgaW4gdGhlIGJyb25jaGlhbCBtdWNvc2Egb2Ygc3RhYmxlIGNocm9u

aWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2UgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+Q2xpbiBFeHAgSW1tdW5vbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5DbGluIEV4cCBJbW11bm9sLjwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjMxNi0zMjQ8L3BhZ2VzPjx2b2x1bWU+MTU3PC92b2x1bWU+PG51bWJlcj4y

PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+QklPUFNJRVM8L2tl

eXdvcmQ+PGtleXdvcmQ+QklPUFNZPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlhbDwva2V5d29y

ZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIQUlOPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05J

QyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+

Q09QRDwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lO

RVM8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RPUjwv

a2V5d29yZD48a2V5d29yZD5FTkRPVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lbmRvdGhlbGlh

bCBjZWxsczwva2V5d29yZD48a2V5d29yZD5FcGl0aGVsaXVtPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+SElH

SDwva2V5d29yZD48a2V5d29yZD5JTC0yMzwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2No

ZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5JTU1VTk9SRUFDVElWRTwva2V5d29yZD48a2V5d29y

ZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5J

TlRFUkxFVUtJTjwva2V5d29yZD48a2V5d29yZD5JTlZPTFZFTUVOVDwva2V5d29yZD48a2V5d29y

ZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxZTVBIT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+THlt

cGhvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwva2V5d29yZD48a2V5d29yZD5NVUNPU0E8

L2tleXdvcmQ+PGtleXdvcmQ+bm9ybWFsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJFUlM8L2tleXdv

cmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdv

cmQ+PGtleXdvcmQ+UE9MWU1FUkFTRTwva2V5d29yZD48a2V5d29yZD5Qb2x5bWVyYXNlIENoYWlu

IFJlYWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5R

VUFOVElUQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UkVBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+

cmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29yZD48a2V5d29yZD5SRVBP

UlQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2gg

U3VwcG9ydDwva2V5d29yZD48a2V5d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5TUEVD

SUZJQzwva2V5d29yZD48a2V5d29yZD5TVEFCTEU8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8

L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdv

cmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxsYWJlbD5ESVNURUZBTk8yMDA5QTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPlByaWRnZW9uPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

TnVtPjExMjI0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTIyNDwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRz

a3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxMzc4NDc4OTk4Ij4xMTIyNDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UHJpZGdlb24sQy48L2F1dGhvcj48YXV0aG9yPkJ1

Z2VvbixMLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC48L2F1dGhvcj48YXV0aG9yPlN0cmFz

Y2hpbCxVLjwvYXV0aG9yPjxhdXRob3I+VHVkaG9wZSxTLkouPC9hdXRob3I+PGF1dGhvcj5GZW53

aWNrLFAuPC9hdXRob3I+PGF1dGhvcj5MYW1iLEouUi48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQ

LkouPC9hdXRob3I+PGF1dGhvcj5EYWxsbWFuLE0uSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+UmVndWxhdGlvbiBvZiBJTC0xNyBpbiBjaHJvbmljIGlu

ZmxhbW1hdGlvbiBpbiB0aGUgaHVtYW4gbHVuZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DbGlu

LlNjaS4oTG9uZCkuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+Q2xpbi5TY2kuKExvbmQpLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUx

NS01MjQ8L3BhZ2VzPjx2b2x1bWU+MTIwPC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4g

RmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdv

cmQ+PGtleXdvcmQ+Qmlvc3ludGhlc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+

PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29y

ZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3Rp

dmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5

d29yZD5ESUZGRVJFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdv

cmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+

RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RP

UlM8L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tl

eXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklMLTIzPC9rZXl3b3JkPjxr

ZXl3b3JkPklMLTU8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5J

TkhJQklUPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TU9OT05VQ0xF

QVI8L2tleXdvcmQ+PGtleXdvcmQ+Tk88L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVSUzwva2V5d29y

ZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29y

ZD48a2V5d29yZD5QUk9EVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlByb2xpZmVyYXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+UFVSSUZJRUQ8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdvcmQ+

PGtleXdvcmQ+UkVHVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5SRUdVTEFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFUE9SVDwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5

d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNPTFVCTEU8L2tleXdvcmQ+PGtleXdvcmQ+U1BF

Q0lGSUM8L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tleXdv

cmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29yZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtl

eXdvcmQ+VGgxNzwva2V5d29yZD48a2V5d29yZD5UaDE3IENlbGxzPC9rZXl3b3JkPjxrZXl3b3Jk

PlRoMjwva2V5d29yZD48a2V5d29yZD50aDIgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VF

PC9rZXl3b3JkPjxrZXl3b3JkPlRSQU5TQ1JJUFRJT048L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNj

cmlwdGlvbiBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzYvMjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD5QUklER0VPTjIwMTE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaSBTdGVmYW5vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh

cj48UmVjTnVtPjEwNzkxPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3NiwgNzddPC9EaXNwbGF5VGV4

dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNzkxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0

aW1lc3RhbXA9IjEzNzg0Nzg5OTEiPjEwNzkxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5EaSBTdGVmYW5vLEEuPC9hdXRob3I+PGF1dGhvcj5DYXJhbW9yaSxHLjwvYXV0

aG9yPjxhdXRob3I+R25lbW1pLEkuPC9hdXRob3I+PGF1dGhvcj5Db250b2xpLE0uPC9hdXRob3I+

PGF1dGhvcj5WaWNhcmksQy48L2F1dGhvcj48YXV0aG9yPkNhcGVsbGksQS48L2F1dGhvcj48YXV0

aG9yPk1hZ25vLEYuPC9hdXRob3I+PGF1dGhvcj5EJmFwb3M7QW5uYSxTLkUuPC9hdXRob3I+PGF1

dGhvcj5aYW5pbmksQS48L2F1dGhvcj48YXV0aG9yPkJydW4sUC48L2F1dGhvcj48YXV0aG9yPkNh

c29sYXJpLFAuPC9hdXRob3I+PGF1dGhvcj5DaHVuZyxLLkYuPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjxhdXRob3I+UGFwaSxBLjwvYXV0aG9yPjxhdXRob3I+QWRjb2NrLEku

PC9hdXRob3I+PGF1dGhvcj5CYWxiaSxCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48dGl0bGVzPjx0aXRsZT5UIGhlbHBlciB0eXBlIDE3LXJlbGF0ZWQgY3l0b2tpbmUgZXhwcmVz

c2lvbiBpcyBpbmNyZWFzZWQgaW4gdGhlIGJyb25jaGlhbCBtdWNvc2Egb2Ygc3RhYmxlIGNocm9u

aWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2UgcGF0aWVudHM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+Q2xpbiBFeHAgSW1tdW5vbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5DbGluIEV4cCBJbW11bm9sLjwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PHBhZ2VzPjMxNi0zMjQ8L3BhZ2VzPjx2b2x1bWU+MTU3PC92b2x1bWU+PG51bWJlcj4y

PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxr

ZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+QklPUFNJRVM8L2tl

eXdvcmQ+PGtleXdvcmQ+QklPUFNZPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlhbDwva2V5d29y

ZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIQUlOPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05J

QyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1v

bmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tleXdvcmQ+PGtleXdvcmQ+

Q09QRDwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lO

RVM8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RPUjwv

a2V5d29yZD48a2V5d29yZD5FTkRPVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lbmRvdGhlbGlh

bCBjZWxsczwva2V5d29yZD48a2V5d29yZD5FcGl0aGVsaXVtPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+SElH

SDwva2V5d29yZD48a2V5d29yZD5JTC0yMzwva2V5d29yZD48a2V5d29yZD5JbW11bm9oaXN0b2No

ZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5JTU1VTk9SRUFDVElWRTwva2V5d29yZD48a2V5d29y

ZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5J

TlRFUkxFVUtJTjwva2V5d29yZD48a2V5d29yZD5JTlZPTFZFTUVOVDwva2V5d29yZD48a2V5d29y

ZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxZTVBIT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+THlt

cGhvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwva2V5d29yZD48a2V5d29yZD5NVUNPU0E8

L2tleXdvcmQ+PGtleXdvcmQ+bm9ybWFsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJFUlM8L2tleXdv

cmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdv

cmQ+PGtleXdvcmQ+UE9MWU1FUkFTRTwva2V5d29yZD48a2V5d29yZD5Qb2x5bWVyYXNlIENoYWlu

IFJlYWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5R

VUFOVElUQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UkVBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+

cmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29yZD48a2V5d29yZD5SRVBP

UlQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2gg

U3VwcG9ydDwva2V5d29yZD48a2V5d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5TUEVD

SUZJQzwva2V5d29yZD48a2V5d29yZD5TVEFCTEU8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8

L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdv

cmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2Rh

dGVzPjxsYWJlbD5ESVNURUZBTk8yMDA5QTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48Q2l0ZT48QXV0aG9yPlByaWRnZW9uPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

TnVtPjExMjI0PC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTIyNDwvcmVjLW51bWJlcj48

Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRz

a3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxMzc4NDc4OTk4Ij4xMTIyNDwva2V5PjwvZm9yZWln

bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u

dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UHJpZGdlb24sQy48L2F1dGhvcj48YXV0aG9yPkJ1

Z2VvbixMLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC48L2F1dGhvcj48YXV0aG9yPlN0cmFz

Y2hpbCxVLjwvYXV0aG9yPjxhdXRob3I+VHVkaG9wZSxTLkouPC9hdXRob3I+PGF1dGhvcj5GZW53

aWNrLFAuPC9hdXRob3I+PGF1dGhvcj5MYW1iLEouUi48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQ

LkouPC9hdXRob3I+PGF1dGhvcj5EYWxsbWFuLE0uSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+UmVndWxhdGlvbiBvZiBJTC0xNyBpbiBjaHJvbmljIGlu

ZmxhbW1hdGlvbiBpbiB0aGUgaHVtYW4gbHVuZzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DbGlu

LlNjaS4oTG9uZCkuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwt

dGl0bGU+Q2xpbi5TY2kuKExvbmQpLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjUx

NS01MjQ8L3BhZ2VzPjx2b2x1bWU+MTIwPC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4g

RmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdv

cmQ+PGtleXdvcmQ+Qmlvc3ludGhlc2lzPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+

PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29y

ZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3Rp

dmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5

d29yZD5ESUZGRVJFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdv

cmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+

RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RP

UlM8L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tl

eXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklMLTIzPC9rZXl3b3JkPjxr

ZXl3b3JkPklMLTU8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5J

TkhJQklUPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TU9OT05VQ0xF

QVI8L2tleXdvcmQ+PGtleXdvcmQ+Tk88L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVSUzwva2V5d29y

ZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29y

ZD48a2V5d29yZD5QUk9EVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlByb2xpZmVyYXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+UFVSSUZJRUQ8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdvcmQ+

PGtleXdvcmQ+UkVHVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5SRUdVTEFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFUE9SVDwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5

d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNPTFVCTEU8L2tleXdvcmQ+PGtleXdvcmQ+U1BF

Q0lGSUM8L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tleXdv

cmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29yZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtl

eXdvcmQ+VGgxNzwva2V5d29yZD48a2V5d29yZD5UaDE3IENlbGxzPC9rZXl3b3JkPjxrZXl3b3Jk

PlRoMjwva2V5d29yZD48a2V5d29yZD50aDIgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VF

PC9rZXl3b3JkPjxrZXl3b3JkPlRSQU5TQ1JJUFRJT048L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNj

cmlwdGlvbiBGYWN0b3JzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3ll

YXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzYvMjAxMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD5QUklER0VPTjIwMTE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPn==

ADDIN EN.CITE.DATA [76, 77]. Th17 cells may be regulated by IL-6 and IL-23 released from alveolar macrophages. CD4+ and CD8+ T cells in the lung of COPD patients show increased expression of CXCR3, a receptor for CXCL9, CXCL10 and CXCL11, all of which are increased in COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3N0YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT45OTY5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3OF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+OTk2OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTc4Ij45OTY5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

b3N0YSxDLjwvYXV0aG9yPjxhdXRob3I+UnVmaW5vLFIuPC9hdXRob3I+PGF1dGhvcj5UcmF2ZXMs

Uy5MLjwvYXV0aG9yPjxhdXRob3I+TGFwYSBFIFNpbHZhIEpSPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DWENSMyBhbmQgQ0NSNSBjaGVtb2tpbmVzIGlu

IHRoZSBpbmR1Y2VkIHNwdXR1bSBmcm9tIHBhdGllbnRzIHdpdGggQ09QRDwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5DaGVzdC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5DaGVzdC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNi0zMzwv

cGFnZXM+PHZvbHVtZT4xMzM8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdv

cmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbW9raW5lczwva2V5d29yZD48a2V5d29yZD5D

T05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09S

UkVMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09VTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZF

UkVOVElBTDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVMSVNB

PC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tl

eXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxr

ZXl3b3JkPklORFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxr

ZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxZ

TVBIT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+THltcGhvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29y

ZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5OQVRJ

T05BTDwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJF

UlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlJFR1VM

QVRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9rZXl3b3JkPjxrZXl3b3JkPlNN

QUxMPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48

a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVh

cj48cHViLWRhdGVzPjxkYXRlPjIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+

Q09TVEEyMDA3PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3N0YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT45OTY5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3OF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+OTk2OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTc4Ij45OTY5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

b3N0YSxDLjwvYXV0aG9yPjxhdXRob3I+UnVmaW5vLFIuPC9hdXRob3I+PGF1dGhvcj5UcmF2ZXMs

Uy5MLjwvYXV0aG9yPjxhdXRob3I+TGFwYSBFIFNpbHZhIEpSPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DWENSMyBhbmQgQ0NSNSBjaGVtb2tpbmVzIGlu

IHRoZSBpbmR1Y2VkIHNwdXR1bSBmcm9tIHBhdGllbnRzIHdpdGggQ09QRDwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5DaGVzdC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5DaGVzdC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNi0zMzwv

cGFnZXM+PHZvbHVtZT4xMzM8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdv

cmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbW9raW5lczwva2V5d29yZD48a2V5d29yZD5D

T05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09S

UkVMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09VTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZF

UkVOVElBTDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVMSVNB

PC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tl

eXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxr

ZXl3b3JkPklORFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxr

ZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxZ

TVBIT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+THltcGhvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29y

ZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5OQVRJ

T05BTDwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJF

UlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlJFR1VM

QVRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9rZXl3b3JkPjxrZXl3b3JkPlNN

QUxMPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48

a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVh

cj48cHViLWRhdGVzPjxkYXRlPjIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+

Q09TVEEyMDA3PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [78]. There is increased expression of CXCL10 by bronchiolar epithelial cells and this could contribute to the accumulation of CD4+ and CD8+ T-cells, which preferentially express CXCR3 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWV0dGE8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS

ZWNOdW0+Nzk4ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNzldPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjc5ODg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk0NSI+Nzk4ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

U2FldHRhLE0uPC9hdXRob3I+PGF1dGhvcj5NYXJpYW5pLE0uPC9hdXRob3I+PGF1dGhvcj5QYW5p

bmEtQm9yZGlnbm9uLFAuPC9hdXRob3I+PGF1dGhvcj5UdXJhdG8sRy48L2F1dGhvcj48YXV0aG9y

PkJ1b25zYW50aSxDLjwvYXV0aG9yPjxhdXRob3I+QmFyYWxkbyxTLjwvYXV0aG9yPjxhdXRob3I+

QmVsbGV0dGF0byxDLk0uPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5D

b3JiZXR0YSxMLjwvYXV0aG9yPjxhdXRob3I+WnVpbixSLjwvYXV0aG9yPjxhdXRob3I+U2luaWdh

Z2xpYSxGLjwvYXV0aG9yPjxhdXRob3I+RmFiYnJpLEwuTS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SW5jcmVhc2VkIGV4cHJlc3Npb24gb2YgdGhlIGNo

ZW1va2luZSByZWNlcHRvciBDWENSMyBhbmQgaXRzIGxpZ2FuZCBDWENMMTAgaW4gcGVyaXBoZXJh

bCBhaXJ3YXlzIG9mIHNtb2tlcnMgd2l0aCBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBk

aXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTQwNC0x

NDA5PC9wYWdlcz48dm9sdW1lPjE2NTwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFJUkZMT1c8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndh

eXM8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT1BVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5D

RUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJv

bmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRS

T0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3

b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdv

cmQ+PGtleXdvcmQ+SU1NVU5PUkVBQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29y

ZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5JTlRFUkZFUk9OPC9r

ZXl3b3JkPjxrZXl3b3JkPkxJR0FORDwva2V5d29yZD48a2V5d29yZD5MT0NBTElaRUQ8L2tleXdv

cmQ+PGtleXdvcmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3JkPjxr

ZXl3b3JkPkx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5

d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5

d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdv

cmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3Jk

PlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+VDwv

a2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29y

ZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdvcmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwv

a2V5d29yZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VC1seW1waG9jeXRlczwv

a2V5d29yZD48a2V5d29yZD5UWVBFIDE8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3b3Jk

PjxrZXl3b3JkPlVOSVRFRCBTVEFURVM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMTUvMjAwMjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5TQUVUVEEyMDAyPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWV0dGE8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS

ZWNOdW0+Nzk4ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bNzldPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjc5ODg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk0NSI+Nzk4ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

U2FldHRhLE0uPC9hdXRob3I+PGF1dGhvcj5NYXJpYW5pLE0uPC9hdXRob3I+PGF1dGhvcj5QYW5p

bmEtQm9yZGlnbm9uLFAuPC9hdXRob3I+PGF1dGhvcj5UdXJhdG8sRy48L2F1dGhvcj48YXV0aG9y

PkJ1b25zYW50aSxDLjwvYXV0aG9yPjxhdXRob3I+QmFyYWxkbyxTLjwvYXV0aG9yPjxhdXRob3I+

QmVsbGV0dGF0byxDLk0uPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5D

b3JiZXR0YSxMLjwvYXV0aG9yPjxhdXRob3I+WnVpbixSLjwvYXV0aG9yPjxhdXRob3I+U2luaWdh

Z2xpYSxGLjwvYXV0aG9yPjxhdXRob3I+RmFiYnJpLEwuTS48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SW5jcmVhc2VkIGV4cHJlc3Npb24gb2YgdGhlIGNo

ZW1va2luZSByZWNlcHRvciBDWENSMyBhbmQgaXRzIGxpZ2FuZCBDWENMMTAgaW4gcGVyaXBoZXJh

bCBhaXJ3YXlzIG9mIHNtb2tlcnMgd2l0aCBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBk

aXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTQwNC0x

NDA5PC9wYWdlcz48dm9sdW1lPjE2NTwvdm9sdW1lPjxudW1iZXI+MTA8L251bWJlcj48cmVwcmlu

dC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3Jk

PkFJUkZMT1c8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndh

eXM8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT1BVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5D

RUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJv

bmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRS

T0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3

b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdv

cmQ+PGtleXdvcmQ+SU1NVU5PUkVBQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29y

ZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5GSUxUUkFUSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5JTlRFUkZFUk9OPC9r

ZXl3b3JkPjxrZXl3b3JkPkxJR0FORDwva2V5d29yZD48a2V5d29yZD5MT0NBTElaRUQ8L2tleXdv

cmQ+PGtleXdvcmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3JkPjxr

ZXl3b3JkPkx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5

d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5

d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdv

cmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3Jk

PlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+VDwv

a2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29y

ZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdvcmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwv

a2V5d29yZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VC1seW1waG9jeXRlczwv

a2V5d29yZD48a2V5d29yZD5UWVBFIDE8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3b3Jk

PjxrZXl3b3JkPlVOSVRFRCBTVEFURVM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAwMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMTUvMjAwMjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5TQUVUVEEyMDAyPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9D

aXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [79]. CD8+ cells are typically increased in response to infections and it is possible that the chronic bacterial colonization of the lower respiratory tract of COPD patients is responsible for this inflammatory response. There is an association between CD8+ cells and alveolar cell apoptosis in emphysema. CD8+ cells are cytotoxic and induce apoptosis through release of perforins, granzyme-B and TNF- PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWpvPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjc4MTY8L1JlY051bT48RGlzcGxheVRleHQ+WzgwXTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj43ODE2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NDIiPjc4MTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1h

am8sSi48L2F1dGhvcj48YXV0aG9yPkdoZXp6byxILjwvYXV0aG9yPjxhdXRob3I+Q29zaW8sTS5H

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5MeW1waG9j

eXRlIHBvcHVsYXRpb24gYW5kIGFwb3B0b3NpcyBpbiB0aGUgbHVuZ3Mgb2Ygc21va2VycyBhbmQg

dGhlaXIgcmVsYXRpb24gdG8gZW1waHlzZW1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBS

ZXNwaXIgSjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkV1ciBSZXNwaXIgSjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjk0Ni05NTM8L3Bh

Z2VzPjx2b2x1bWU+MTc8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48cmVwcmludC1lZGl0aW9u

Pk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjE1PC9rZXl3

b3JkPjxrZXl3b3JkPmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFMVkVPTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCT0RJRVM8L2tleXdv

cmQ+PGtleXdvcmQ+QU5USUJPRFk8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUdFTklDPC9rZXl3b3Jk

PjxrZXl3b3JkPmFwb3B0b3Npczwva2V5d29yZD48a2V5d29yZD5DQVNFPC9rZXl3b3JkPjxrZXl3

b3JkPkNENCs8L2tleXdvcmQ+PGtleXdvcmQ+Q0Q4Kzwva2V5d29yZD48a2V5d29yZD5jZDgtcG9z

aXRpdmUgdC1seW1waG9jeXRlczwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3

b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURTwva2V5d29yZD48a2V5d29yZD5D

WVRPTFlUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVubWFyazwva2V5d29yZD48a2V5d29yZD5ERVZF

TE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5FTVBIWVNFTUE8L2tleXdvcmQ+PGtleXdvcmQ+RVhB

TUlOQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RmFzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5mdW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29y

ZD48a2V5d29yZD5JTU1VTk9DWVRPQ0hFTUlDQUw8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9H

WTwva2V5d29yZD48a2V5d29yZD5pbW11bm9waGVub3R5cGluZzwva2V5d29yZD48a2V5d29yZD5J

Tjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5EVUNFRDwv

a2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0

b3J5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdv

cmQ+PGtleXdvcmQ+TFlNUEhPQ1lURTwva2V5d29yZD48a2V5d29yZD5seW1waG9jeXRlIGNvdW50

PC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3

b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUFURUQ8L2tleXdv

cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZTwva2V5d29yZD48a2V5d29yZD5NT05PQ0xPTkFMPC9rZXl3

b3JkPjxrZXl3b3JkPk5BVFVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+bmV1dHJvcGhpbDwva2V5d29y

ZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5

d29yZD5OVU1CRVJTPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwva2V5d29yZD48a2V5

d29yZD5QQVRIT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdv

cmQ+UEhFTk9UWVBFPC9rZXl3b3JkPjxrZXl3b3JkPlBuZXVtb25lY3RvbXk8L2tleXdvcmQ+PGtl

eXdvcmQ+UE9QVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtl

eXdvcmQ+cHVsbW9uYXJ5IGFsdmVvbGk8L2tleXdvcmQ+PGtleXdvcmQ+cHVsbW9uYXJ5IGVtcGh5

c2VtYTwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5SRUxBVElP

TlNISVA8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+U0lUVTwv

a2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnN0YWluaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPlNUSU1VTEk8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48

a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJKRUNUUzwva2V5d29yZD48a2V5d29y

ZD5zdXBwb3J0LG5vbi11LnMuZ292JmFwb3M7dDwva2V5d29yZD48a2V5d29yZD5zdXJnZXJ5PC9r

ZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3Jk

PjxrZXl3b3JkPlQgbHltcGhvY3l0ZTwva2V5d29yZD48a2V5d29yZD5UIExZTVBIT0NZVEVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48a2V5d29yZD50LWx5bXBob2N5dGUgc3Vi

c2V0czwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPlRF

U1RTPC9rZXl3b3JkPjxrZXl3b3JkPldBTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5NQUpPMjAwMUE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWpvPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

TnVtPjc4MTY8L1JlY051bT48RGlzcGxheVRleHQ+WzgwXTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj43ODE2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NDIiPjc4MTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1h

am8sSi48L2F1dGhvcj48YXV0aG9yPkdoZXp6byxILjwvYXV0aG9yPjxhdXRob3I+Q29zaW8sTS5H

LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5MeW1waG9j

eXRlIHBvcHVsYXRpb24gYW5kIGFwb3B0b3NpcyBpbiB0aGUgbHVuZ3Mgb2Ygc21va2VycyBhbmQg

dGhlaXIgcmVsYXRpb24gdG8gZW1waHlzZW1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ciBS

ZXNwaXIgSjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl

PkV1ciBSZXNwaXIgSjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjk0Ni05NTM8L3Bh

Z2VzPjx2b2x1bWU+MTc8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48cmVwcmludC1lZGl0aW9u

Pk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjE1PC9rZXl3

b3JkPjxrZXl3b3JkPmFkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3

b3JkPjxrZXl3b3JkPkFMVkVPTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCT0RJRVM8L2tleXdv

cmQ+PGtleXdvcmQ+QU5USUJPRFk8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUdFTklDPC9rZXl3b3Jk

PjxrZXl3b3JkPmFwb3B0b3Npczwva2V5d29yZD48a2V5d29yZD5DQVNFPC9rZXl3b3JkPjxrZXl3

b3JkPkNENCs8L2tleXdvcmQ+PGtleXdvcmQ+Q0Q4Kzwva2V5d29yZD48a2V5d29yZD5jZDgtcG9z

aXRpdmUgdC1seW1waG9jeXRlczwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3

b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURTwva2V5d29yZD48a2V5d29yZD5D

WVRPTFlUSUM8L2tleXdvcmQ+PGtleXdvcmQ+ZGVubWFyazwva2V5d29yZD48a2V5d29yZD5ERVZF

TE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5FTVBIWVNFTUE8L2tleXdvcmQ+PGtleXdvcmQ+RVhB

TUlOQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RmFzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwv

a2V5d29yZD48a2V5d29yZD5mdW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29y

ZD48a2V5d29yZD5JTU1VTk9DWVRPQ0hFTUlDQUw8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9H

WTwva2V5d29yZD48a2V5d29yZD5pbW11bm9waGVub3R5cGluZzwva2V5d29yZD48a2V5d29yZD5J

Tjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5EVUNFRDwv

a2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0

b3J5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdv

cmQ+PGtleXdvcmQ+TFlNUEhPQ1lURTwva2V5d29yZD48a2V5d29yZD5seW1waG9jeXRlIGNvdW50

PC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3

b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUFURUQ8L2tleXdv

cmQ+PGtleXdvcmQ+TWlkZGxlIEFnZTwva2V5d29yZD48a2V5d29yZD5NT05PQ0xPTkFMPC9rZXl3

b3JkPjxrZXl3b3JkPk5BVFVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+bmV1dHJvcGhpbDwva2V5d29y

ZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5

d29yZD5OVU1CRVJTPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwva2V5d29yZD48a2V5

d29yZD5QQVRIT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdv

cmQ+UEhFTk9UWVBFPC9rZXl3b3JkPjxrZXl3b3JkPlBuZXVtb25lY3RvbXk8L2tleXdvcmQ+PGtl

eXdvcmQ+UE9QVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtl

eXdvcmQ+cHVsbW9uYXJ5IGFsdmVvbGk8L2tleXdvcmQ+PGtleXdvcmQ+cHVsbW9uYXJ5IGVtcGh5

c2VtYTwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5SRUxBVElP

TlNISVA8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+U0lUVTwv

a2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPnN0YWluaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPlNUSU1VTEk8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48

a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJKRUNUUzwva2V5d29yZD48a2V5d29y

ZD5zdXBwb3J0LG5vbi11LnMuZ292JmFwb3M7dDwva2V5d29yZD48a2V5d29yZD5zdXJnZXJ5PC9r

ZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3Jk

PjxrZXl3b3JkPlQgbHltcGhvY3l0ZTwva2V5d29yZD48a2V5d29yZD5UIExZTVBIT0NZVEVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48a2V5d29yZD50LWx5bXBob2N5dGUgc3Vi

c2V0czwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPlRF

U1RTPC9rZXl3b3JkPjxrZXl3b3JkPldBTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHll

YXI+MjAwMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMjAwMTwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5NQUpPMjAwMUE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [80]. There is evidence for immunosenescence in COPD, with increased numbers of T-cells with no expression of the co-stimulatory receptor CD28 (CD4/CD28null, CD8/CD28null cells) and these cells release increased amounts of perforins and granzyme B QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\09HODGE2011(Hodge, Mukaro, et al. 2011 HODGE2011 /id\00(\00 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW1iZXJzPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

UmVjTnVtPjExNjI2PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4MSwgODJdPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjExNjI2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1l

c3RhbXA9IjEzNzg0NzkwMDQiPjExNjI2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5MYW1iZXJzLEMuPC9hdXRob3I+PGF1dGhvcj5IYWNrZXIsUy48L2F1dGhvcj48YXV0

aG9yPlBvc2NoLE0uPC9hdXRob3I+PGF1dGhvcj5Ib2V0emVuZWNrZXIsSy48L2F1dGhvcj48YXV0

aG9yPlBvbGxyZWlzeixBLjwvYXV0aG9yPjxhdXRob3I+TGljaHRlbmF1ZXIsTS48L2F1dGhvcj48

YXV0aG9yPktsZXBldGtvLFcuPC9hdXRob3I+PGF1dGhvcj5BbmtlcnNtaXQsSC5KLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UIGNlbGwgc2VuZXNjZW5j

ZSBhbmQgY29udHJhY3Rpb24gb2YgVCBjZWxsIHJlcGVydG9pcmUgZGl2ZXJzaXR5IGluIHBhdGll

bnRzIHdpdGggY2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5DbGluLkV4cC5JbW11bm9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNsaW4uRXhwLkltbXVub2wuPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+NDY2LTQ3NTwvcGFnZXM+PHZvbHVtZT4xNTU8L3ZvbHVtZT48bnVt

YmVyPjM8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QU5BTFlTSVM8L2tl

eXdvcmQ+PGtleXdvcmQ+QU5USUdFTjwva2V5d29yZD48a2V5d29yZD5hbnRpZ2VucyxjZDI4PC9r

ZXl3b3JkPjxrZXl3b3JkPkFTU0FZPC9rZXl3b3JkPjxrZXl3b3JkPmF1dG9pbW11bmUgZGlzZWFz

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPmNhc2UtY29udHJvbCBzdHVkaWVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkNEMjg8L2tleXdvcmQ+PGtleXdvcmQ+Y2Q0LXBvc2l0aXZlIHQtbHltcGhvY3l0ZXM8

L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DZWxsIEFnaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIQVJBQ1RFUklTVElDPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElW

RTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBBUklTT048L2tleXdvcmQ+PGtleXdvcmQ+Q09NUEFSSVNP

TlM8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJP

TDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPkNPU1RJTVVMQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3b3JkPkRJQUdOT1NJUzwv

a2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3

b3JkPjxrZXl3b3JkPkVBUkxZPC9rZXl3b3JkPjxrZXl3b3JkPkVOSEFOQ0VEPC9rZXl3b3JkPjxr

ZXl3b3JkPkVuenltZSBMaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29y

ZD5lbnp5bWUtbGlua2VkIGltbXVub3NvcmJlbnQgYXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+RVZB

TFVBVElPTjwva2V5d29yZD48a2V5d29yZD5FWFBPU1VSRTwva2V5d29yZD48a2V5d29yZD5FWFBS

RVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5GTE9XPC9r

ZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPkdyYW56eW1lczwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTVBBSVJFRDwva2V5

d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTiBWSVRSTzwva2V5d29yZD48a2V5

d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJmZXJvbi1nYW1tYTwva2V5d29y

ZD48a2V5d29yZD5JTlRSQUNFTExVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPmtpbGxlciBjZWxscyxu

YXR1cmFsPC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtleXdvcmQ+bG9naXN0aWMg

bW9kZWxzPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5

d29yZD48a2V5d29yZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5

d29yZD48a2V5d29yZD5NRURJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk1JTEQ8L2tleXdvcmQ+PGtl

eXdvcmQ+TU9ERUw8L2tleXdvcmQ+PGtleXdvcmQ+TU9OT05VQ0xFQVI8L2tleXdvcmQ+PGtleXdv

cmQ+TkFUVVJBTDwva2V5d29yZD48a2V5d29yZD5ORUNST1NJUzwva2V5d29yZD48a2V5d29yZD5P

QlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRIT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+

UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UGVyZm9yaW48L2tleXdvcmQ+PGtleXdvcmQ+UEVS

SVBIRVJBTDwva2V5d29yZD48a2V5d29yZD5QSEVOT1RZUEU8L2tleXdvcmQ+PGtleXdvcmQ+cGh5

c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBPUFVMQVRJT048L2tleXdvcmQ+PGtleXdv

cmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29yZD48a2V5d29y

ZD5QdWxtb25hcnkgTWVkaWNpbmU8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdvcmQ+

PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlJvYyBDdXJ2ZTwva2V5d29yZD48

a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPlNN

T0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1VSRkFDRTwva2V5d29yZD48a2V5d29yZD5UPC9rZXl3

b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3JkPjxr

ZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48a2V5d29yZD50LWx5bXBob2N5dGUgc3Vic2V0czwva2V5

d29yZD48a2V5d29yZD5UUklHR0VSSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlRVTU9VUjwva2V5d29y

ZD48a2V5d29yZD5VUC1SRUdVTEFUSU9OPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4zLzIwMDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48bGFiZWw+TEFNQkVSUzIwMDk8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5Ib2RnZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051bT4x

MTYyNzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE2Mjc8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1

d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3OTAwNCI+MTE2Mjc8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvZGdlLEcuPC9hdXRob3I+PGF1dGhvcj5NdWthcm8sVi48

L2F1dGhvcj48YXV0aG9yPlJleW5vbGRzLFAuTi48L2F1dGhvcj48YXV0aG9yPkhvZGdlLFMuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlJvbGUgb2YgaW5j

cmVhc2VkIENEOC9DRDI4KG51bGwpIFQgY2VsbHMgYW5kIGFsdGVybmF0aXZlIGNvLXN0aW11bGF0

b3J5IG1vbGVjdWxlcyBpbiBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNsaW4uRXhwLkltbXVub2wuPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2xpbi5FeHAuSW1tdW5vbC48L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz45NC0xMDI8L3BhZ2VzPjx2b2x1bWU+MTY2PC92b2x1

bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmlu

dC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4xMjwva2V5d29yZD48a2V5d29yZD4xNTwva2V5

d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48

a2V5d29yZD5hbnRpZ2VucyxjZDI4PC9rZXl3b3JkPjxrZXl3b3JkPmFudGlnZW5zLGNkNDwva2V5

d29yZD48a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48a2V5d29yZD5hdXN0cmFsaWE8L2tleXdv

cmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtleXdvcmQ+YnJvbmNob2FsdmVvbGFyIGxhdmFn

ZSBmbHVpZDwva2V5d29yZD48a2V5d29yZD5jYXNlLWNvbnRyb2wgc3R1ZGllczwva2V5d29yZD48

a2V5d29yZD5jYXVzZSBvZiBkZWF0aDwva2V5d29yZD48a2V5d29yZD5jZDQtcG9zaXRpdmUgdC1s

eW1waG9jeXRlczwva2V5d29yZD48a2V5d29yZD5jZDgtcG9zaXRpdmUgdC1seW1waG9jeXRlczwv

a2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxr

ZXl3b3JkPkNIQU5HRVM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3

b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkNJR0FSRVRURTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEUgU01PS0U8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09NUE9ORU5UUzwva2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3

b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09TVElNVUxBVE9SWTwva2V5d29y

ZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORVM8L2tleXdvcmQ+

PGtleXdvcmQ+Y3l0b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+REVBVEg8L2tleXdvcmQ+PGtleXdv

cmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+RVhQ

UkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+Rmxv

dyBDeXRvbWV0cnk8L2tleXdvcmQ+PGtleXdvcmQ+RlVOQ1RJT05BTDwva2V5d29yZD48a2V5d29y

ZD5HZW5lIEV4cHJlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+R0VORVRJQ1M8L2tleXdvcmQ+PGtl

eXdvcmQ+R3Jhbnp5bWVzPC9rZXl3b3JkPjxrZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3

b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNF

RDwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSQUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklO

VEVSQUNUSU9OUzwva2V5d29yZD48a2V5d29yZD5JTlRFUkZFUk9OPC9rZXl3b3JkPjxrZXl3b3Jk

Pkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+THltcGhvY3l0ZXMsTnVsbDwva2V5d29yZD48a2V5d29y

ZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5d29yZD48a2V5d29y

ZD5NRURJQ0lORTwva2V5d29yZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TU9E

RUw8L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEU8L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEVT

PC9rZXl3b3JkPjxrZXl3b3JkPk1VUklORTwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48

a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtl

eXdvcmQ+UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPlBlcmZvcmluPC9rZXl3b3JkPjxrZXl3

b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9EVUNUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPlBST0lORkxBTU1BVE9SWTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+

PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29yZD48

a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SRVNJU1RBTkNFPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48a2V5

d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tJ

Tkc8L2tleXdvcmQ+PGtleXdvcmQ+c291dGggYXVzdHJhbGlhPC9rZXl3b3JkPjxrZXl3b3JkPlNU

SU1VTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+VDwv

a2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29y

ZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VUPC9rZXl3b3JkPjxrZXl3

b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRTwva2V5d29yZD48a2V5d29y

ZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VVAtUkVHVUxBVElPTjwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTAvMjAxMTwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5IT0RHRTIwMTE8L2xhYmVsPjx1cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW1iZXJzPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

UmVjTnVtPjExNjI2PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4MSwgODJdPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjExNjI2PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1l

c3RhbXA9IjEzNzg0NzkwMDQiPjExNjI2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5MYW1iZXJzLEMuPC9hdXRob3I+PGF1dGhvcj5IYWNrZXIsUy48L2F1dGhvcj48YXV0

aG9yPlBvc2NoLE0uPC9hdXRob3I+PGF1dGhvcj5Ib2V0emVuZWNrZXIsSy48L2F1dGhvcj48YXV0

aG9yPlBvbGxyZWlzeixBLjwvYXV0aG9yPjxhdXRob3I+TGljaHRlbmF1ZXIsTS48L2F1dGhvcj48

YXV0aG9yPktsZXBldGtvLFcuPC9hdXRob3I+PGF1dGhvcj5BbmtlcnNtaXQsSC5KLjwvYXV0aG9y

PjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5UIGNlbGwgc2VuZXNjZW5j

ZSBhbmQgY29udHJhY3Rpb24gb2YgVCBjZWxsIHJlcGVydG9pcmUgZGl2ZXJzaXR5IGluIHBhdGll

bnRzIHdpdGggY2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5DbGluLkV4cC5JbW11bm9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNsaW4uRXhwLkltbXVub2wuPC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+NDY2LTQ3NTwvcGFnZXM+PHZvbHVtZT4xNTU8L3ZvbHVtZT48bnVt

YmVyPjM8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QU5BTFlTSVM8L2tl

eXdvcmQ+PGtleXdvcmQ+QU5USUdFTjwva2V5d29yZD48a2V5d29yZD5hbnRpZ2VucyxjZDI4PC9r

ZXl3b3JkPjxrZXl3b3JkPkFTU0FZPC9rZXl3b3JkPjxrZXl3b3JkPmF1dG9pbW11bmUgZGlzZWFz

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzPC9rZXl3b3JkPjxrZXl3b3Jk

PkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPmNhc2UtY29udHJvbCBzdHVkaWVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkNEMjg8L2tleXdvcmQ+PGtleXdvcmQ+Y2Q0LXBvc2l0aXZlIHQtbHltcGhvY3l0ZXM8

L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DZWxsIEFnaW5nPC9rZXl3

b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIQVJBQ1RFUklTVElDPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElW

RTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNl

PC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBBUklTT048L2tleXdvcmQ+PGtleXdvcmQ+Q09NUEFSSVNP

TlM8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJBQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJP

TDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPkNPU1RJTVVMQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3b3JkPkRJQUdOT1NJUzwv

a2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3

b3JkPjxrZXl3b3JkPkVBUkxZPC9rZXl3b3JkPjxrZXl3b3JkPkVOSEFOQ0VEPC9rZXl3b3JkPjxr

ZXl3b3JkPkVuenltZSBMaW5rZWQgSW1tdW5vc29yYmVudCBBc3NheTwva2V5d29yZD48a2V5d29y

ZD5lbnp5bWUtbGlua2VkIGltbXVub3NvcmJlbnQgYXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+RVZB

TFVBVElPTjwva2V5d29yZD48a2V5d29yZD5FWFBPU1VSRTwva2V5d29yZD48a2V5d29yZD5FWFBS

RVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5GTE9XPC9r

ZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9u

PC9rZXl3b3JkPjxrZXl3b3JkPkdyYW56eW1lczwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTVBBSVJFRDwva2V5

d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTiBWSVRSTzwva2V5d29yZD48a2V5

d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJmZXJvbi1nYW1tYTwva2V5d29y

ZD48a2V5d29yZD5JTlRSQUNFTExVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPmtpbGxlciBjZWxscyxu

YXR1cmFsPC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtleXdvcmQ+bG9naXN0aWMg

bW9kZWxzPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5

d29yZD48a2V5d29yZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5

d29yZD48a2V5d29yZD5NRURJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3Jk

PjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPk1JTEQ8L2tleXdvcmQ+PGtl

eXdvcmQ+TU9ERUw8L2tleXdvcmQ+PGtleXdvcmQ+TU9OT05VQ0xFQVI8L2tleXdvcmQ+PGtleXdv

cmQ+TkFUVVJBTDwva2V5d29yZD48a2V5d29yZD5ORUNST1NJUzwva2V5d29yZD48a2V5d29yZD5P

QlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRIT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+

UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UGVyZm9yaW48L2tleXdvcmQ+PGtleXdvcmQ+UEVS

SVBIRVJBTDwva2V5d29yZD48a2V5d29yZD5QSEVOT1RZUEU8L2tleXdvcmQ+PGtleXdvcmQ+cGh5

c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBPUFVMQVRJT048L2tleXdvcmQ+PGtleXdv

cmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29yZD48a2V5d29y

ZD5QdWxtb25hcnkgTWVkaWNpbmU8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdvcmQ+

PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlJvYyBDdXJ2ZTwva2V5d29yZD48

a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPlNN

T0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1VSRkFDRTwva2V5d29yZD48a2V5d29yZD5UPC9rZXl3

b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3JkPjxr

ZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48a2V5d29yZD50LWx5bXBob2N5dGUgc3Vic2V0czwva2V5

d29yZD48a2V5d29yZD5UUklHR0VSSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlRVTU9VUjwva2V5d29y

ZD48a2V5d29yZD5VUC1SRUdVTEFUSU9OPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFy

PjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4zLzIwMDk8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48bGFiZWw+TEFNQkVSUzIwMDk8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5Ib2RnZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051bT4x

MTYyNzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE2Mjc8L3JlYy1udW1iZXI+PGZvcmVp

Z24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1

d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3OTAwNCI+MTE2Mjc8L2tleT48L2ZvcmVpZ24ta2V5

cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1

dG9ycz48YXV0aG9ycz48YXV0aG9yPkhvZGdlLEcuPC9hdXRob3I+PGF1dGhvcj5NdWthcm8sVi48

L2F1dGhvcj48YXV0aG9yPlJleW5vbGRzLFAuTi48L2F1dGhvcj48YXV0aG9yPkhvZGdlLFMuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlJvbGUgb2YgaW5j

cmVhc2VkIENEOC9DRDI4KG51bGwpIFQgY2VsbHMgYW5kIGFsdGVybmF0aXZlIGNvLXN0aW11bGF0

b3J5IG1vbGVjdWxlcyBpbiBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNsaW4uRXhwLkltbXVub2wuPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2xpbi5FeHAuSW1tdW5vbC48L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz45NC0xMDI8L3BhZ2VzPjx2b2x1bWU+MTY2PC92b2x1

bWU+PG51bWJlcj4xPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmlu

dC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4xMjwva2V5d29yZD48a2V5d29yZD4xNTwva2V5

d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48

a2V5d29yZD5hbnRpZ2VucyxjZDI4PC9rZXl3b3JkPjxrZXl3b3JkPmFudGlnZW5zLGNkNDwva2V5

d29yZD48a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48a2V5d29yZD5hdXN0cmFsaWE8L2tleXdv

cmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtleXdvcmQ+YnJvbmNob2FsdmVvbGFyIGxhdmFn

ZSBmbHVpZDwva2V5d29yZD48a2V5d29yZD5jYXNlLWNvbnRyb2wgc3R1ZGllczwva2V5d29yZD48

a2V5d29yZD5jYXVzZSBvZiBkZWF0aDwva2V5d29yZD48a2V5d29yZD5jZDQtcG9zaXRpdmUgdC1s

eW1waG9jeXRlczwva2V5d29yZD48a2V5d29yZD5jZDgtcG9zaXRpdmUgdC1seW1waG9jeXRlczwv

a2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxr

ZXl3b3JkPkNIQU5HRVM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3

b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3Jk

PjxrZXl3b3JkPkNJR0FSRVRURTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEUgU01PS0U8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09NUE9ORU5UUzwva2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3

b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09TVElNVUxBVE9SWTwva2V5d29y

ZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORVM8L2tleXdvcmQ+

PGtleXdvcmQ+Y3l0b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+REVBVEg8L2tleXdvcmQ+PGtleXdv

cmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+RVhQ

UkVTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+Rmxv

dyBDeXRvbWV0cnk8L2tleXdvcmQ+PGtleXdvcmQ+RlVOQ1RJT05BTDwva2V5d29yZD48a2V5d29y

ZD5HZW5lIEV4cHJlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+R0VORVRJQ1M8L2tleXdvcmQ+PGtl

eXdvcmQ+R3Jhbnp5bWVzPC9rZXl3b3JkPjxrZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3

b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNF

RDwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFt

bWF0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSQUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklO

VEVSQUNUSU9OUzwva2V5d29yZD48a2V5d29yZD5JTlRFUkZFUk9OPC9rZXl3b3JkPjxrZXl3b3Jk

Pkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+THltcGhvY3l0ZXMsTnVsbDwva2V5d29yZD48a2V5d29y

ZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5d29yZD48a2V5d29y

ZD5NRURJQ0lORTwva2V5d29yZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+TU9E

RUw8L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEU8L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEVT

PC9rZXl3b3JkPjxrZXl3b3JkPk1VUklORTwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48

a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtl

eXdvcmQ+UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPlBlcmZvcmluPC9rZXl3b3JkPjxrZXl3

b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9EVUNUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPlBST0lORkxBTU1BVE9SWTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+

PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29yZD48

a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SRVNJU1RBTkNFPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48a2V5

d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tJ

Tkc8L2tleXdvcmQ+PGtleXdvcmQ+c291dGggYXVzdHJhbGlhPC9rZXl3b3JkPjxrZXl3b3JkPlNU

SU1VTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+VDwv

a2V5d29yZD48a2V5d29yZD5UIENFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VCBDRUxMUzwva2V5d29y

ZD48a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VUPC9rZXl3b3JkPjxrZXl3

b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRTwva2V5d29yZD48a2V5d29y

ZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VVAtUkVHVUxBVElPTjwva2V5d29yZD48L2tl

eXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTAvMjAxMTwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5IT0RHRTIwMTE8L2xhYmVsPjx1cmxzPjwv

dXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [81, 82]. ILCs also play a role in regulation of lung immunity and may be regulated via danger signals and cell damage ADDIN EN.CITE <EndNote><Cite><Author>Artis</Author><Year>2015</Year><RecNum>12398</RecNum><DisplayText>[83]</DisplayText><record><rec-number>12398</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1441103585">12398</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Artis, D.</author><author>Spits, H.</author></authors></contributors><auth-address>Weill Cornell Medical College, Cornell University, New York, New York 10021, USA.&#xD;Academic Medical Center at the University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.</auth-address><titles><title>The biology of innate lymphoid cells</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title></periodical><alt-periodical><full-title>Nature</full-title></alt-periodical><pages>293-301</pages><volume>517</volume><number>7534</number><edition>2015/01/17</edition><keywords><keyword>Animals</keyword><keyword>Homeostasis/immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate/genetics/*immunology</keyword><keyword>Inflammation/immunology</keyword><keyword>Killer Cells, Natural/cytology/immunology</keyword><keyword>Lymphocytes/*cytology/*immunology/metabolism</keyword><keyword>Transcription, Genetic/immunology</keyword></keywords><dates><year>2015</year><pub-dates><date>Jan 15</date></pub-dates></dates><isbn>0028-0836</isbn><accession-num>25592534</accession-num><urls></urls><electronic-resource-num>10.1038/nature14189</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[83]. In COPD there is an increase in ILC3 cells that are the innate equivalent of Th17 cells that secrete IL-17 and IL-22 and they may also play a role in driving neutrophilic inflammation ADDIN EN.CITE <EndNote><Cite><Author>De Grove</Author><Year>2016</Year><RecNum>12770</RecNum><DisplayText>[84]</DisplayText><record><rec-number>12770</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1459872867">12770</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>De Grove, K. C.</author><author>Provoost, S.</author><author>Verhamme, F. M.</author><author>Bracke, K. R.</author><author>Joos, G. F.</author><author>Maes, T.</author><author>Brusselle, G. G.</author></authors></contributors><auth-address>Department of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Ghent University Hospital, Ghent, Belgium.</auth-address><titles><title>Characterization and quantification of innate lymphoid cell subsets in human lung</title><secondary-title>PLoS One</secondary-title><alt-title>PloS one</alt-title></titles><periodical><full-title>PLoS One</full-title><abbr-1>PloS one</abbr-1></periodical><alt-periodical><full-title>PLoS One</full-title><abbr-1>PloS one</abbr-1></alt-periodical><pages>e0145961</pages><volume>11</volume><number>1</number><edition>2016/01/05</edition><dates><year>2016</year></dates><isbn>1932-6203</isbn><accession-num>26727464</accession-num><urls></urls><custom2>PMC4699688</custom2><electronic-resource-num>10.1371/journal.pone.0145961</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[84].Autoimmune mechanisms may play a role in severe asthma and COPD through the formation of autoantibodies as a result of local tissue damage and defective function of Tregs. Autoantibodies have been described in non-atopic asthma, but their role in disease is uncertain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWhtPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

TnVtPjEwNjk1PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4NV08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTA2OTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk4OSI+MTA2OTU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

Pk5haG0sRC5ILjwvYXV0aG9yPjxhdXRob3I+TGVlLFkuRS48L2F1dGhvcj48YXV0aG9yPllpbSxF

LkouPC9hdXRob3I+PGF1dGhvcj5QYXJrLEguUy48L2F1dGhvcj48YXV0aG9yPllpbSxILjwvYXV0

aG9yPjxhdXRob3I+S2FuZyxZLjwvYXV0aG9yPjxhdXRob3I+S2ltLEouSy48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SWRlbnRpZmljYXRpb24gb2YgY3l0

b2tlcmF0aW4gMTggYXMgYSBicm9uY2hpYWwgZXBpdGhlbGlhbCBhdXRvYW50aWdlbiBhc3NvY2lh

dGVkIHdpdGggbm9uYWxsZXJnaWMgYXN0aG1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEog

UmVzcGlyIENyaXQgQ2FyZSBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZC48L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xNTM2LTE1Mzk8L3BhZ2VzPjx2b2x1bWU+MTY1PC92b2x1bWU+PG51

bWJlcj4xMTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRp

dGlvbj48a2V5d29yZHM+PGtleXdvcmQ+Mjwva2V5d29yZD48a2V5d29yZD4zPC9rZXl3b3JkPjxr

ZXl3b3JkPkFDSUQ8L2tleXdvcmQ+PGtleXdvcmQ+QURVTFQ8L2tleXdvcmQ+PGtleXdvcmQ+QUdF

TlQ8L2tleXdvcmQ+PGtleXdvcmQ+QUdFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5

d29yZD48a2V5d29yZD5BTExFUkdFTjwva2V5d29yZD48a2V5d29yZD5BTExFUkdFTlM8L2tleXdv

cmQ+PGtleXdvcmQ+QUxMRVJHSUM8L2tleXdvcmQ+PGtleXdvcmQ+YWxsZXJnaWMgYXN0aG1hPC9r

ZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkFuYWx5c2lzIG9mIFZh

cmlhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElHRU48L2tleXdvcmQ+PGtleXdvcmQ+QW50aWdl

bnM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkFVVE9BTlRJQk9E

SUVTPC9rZXl3b3JkPjxrZXl3b3JkPmF1dG9hbnRpZ2Vuczwva2V5d29yZD48a2V5d29yZD5BdXRv

aW1tdW5pdHk8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPkJST05DSEk8L2tleXdvcmQ+PGtleXdvcmQ+

YnJvbmNoaWFsPC9rZXl3b3JkPjxrZXl3b3JkPmNhc2UtY29udHJvbCBzdHVkaWVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VsbHMsQ3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Y2hpLXNxdWFyZSBkaXN0cmlidXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+Y2lyY3VsYXRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0

dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q09NUEFSQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q29t

cGFyYXRpdmUgU3R1ZHk8L2tleXdvcmQ+PGtleXdvcmQ+Q1VMVFVSRUQ8L2tleXdvcmQ+PGtleXdv

cmQ+Y3l0b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+REVWRUxPUE1FTlQ8L2tleXdvcmQ+PGtleXdv

cmQ+RElBR05PU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkVQSVRIRUxJQUw8L2tleXdvcmQ+PGtleXdv

cmQ+ZXBpdGhlbGlhbCBjZWxsczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+SEVBTFRIWTwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5I

VU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SURFTlRJRklDQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

SWdHPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2Jsb3R0aW5nPC9rZXl3b3JkPjxrZXl3b3JkPklN

TVVOT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklOVk9MVkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPktlcmF0

aW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNp

czwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5Qcm9iYWJpbGl0

eTwva2V5d29yZD48a2V5d29yZD5QVVJJRklFRDwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2Ug

VmFsdWVzPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJlc2Vh

cmNoIFN1cHBvcnQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+

U2Vuc2l0aXZpdHkgYW5kIFNwZWNpZmljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlNFTlNJVElaQVRJ

T048L2tleXdvcmQ+PGtleXdvcmQ+U0VRVUVOQ0lORzwva2V5d29yZD48a2V5d29yZD5TRVJVTTwv

a2V5d29yZD48a2V5d29yZD5zZXZlcml0eSBvZiBpbGxuZXNzIGluZGV4PC9rZXl3b3JkPjxrZXl3

b3JkPlNJR05JRklDQU5DRTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3

b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNZU1RFTUlDPC9rZXl3b3JkPjxrZXl3b3JkPlZP

TFVOVEVFUlM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjYvMS8yMDAyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPk5B

SE0yMDAyPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWhtPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

TnVtPjEwNjk1PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4NV08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTA2OTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk4OSI+MTA2OTU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

Pk5haG0sRC5ILjwvYXV0aG9yPjxhdXRob3I+TGVlLFkuRS48L2F1dGhvcj48YXV0aG9yPllpbSxF

LkouPC9hdXRob3I+PGF1dGhvcj5QYXJrLEguUy48L2F1dGhvcj48YXV0aG9yPllpbSxILjwvYXV0

aG9yPjxhdXRob3I+S2FuZyxZLjwvYXV0aG9yPjxhdXRob3I+S2ltLEouSy48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+SWRlbnRpZmljYXRpb24gb2YgY3l0

b2tlcmF0aW4gMTggYXMgYSBicm9uY2hpYWwgZXBpdGhlbGlhbCBhdXRvYW50aWdlbiBhc3NvY2lh

dGVkIHdpdGggbm9uYWxsZXJnaWMgYXN0aG1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEog

UmVzcGlyIENyaXQgQ2FyZSBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZC48L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz4xNTM2LTE1Mzk8L3BhZ2VzPjx2b2x1bWU+MTY1PC92b2x1bWU+PG51

bWJlcj4xMTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRp

dGlvbj48a2V5d29yZHM+PGtleXdvcmQ+Mjwva2V5d29yZD48a2V5d29yZD4zPC9rZXl3b3JkPjxr

ZXl3b3JkPkFDSUQ8L2tleXdvcmQ+PGtleXdvcmQ+QURVTFQ8L2tleXdvcmQ+PGtleXdvcmQ+QUdF

TlQ8L2tleXdvcmQ+PGtleXdvcmQ+QUdFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5

d29yZD48a2V5d29yZD5BTExFUkdFTjwva2V5d29yZD48a2V5d29yZD5BTExFUkdFTlM8L2tleXdv

cmQ+PGtleXdvcmQ+QUxMRVJHSUM8L2tleXdvcmQ+PGtleXdvcmQ+YWxsZXJnaWMgYXN0aG1hPC9r

ZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkFuYWx5c2lzIG9mIFZh

cmlhbmNlPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElHRU48L2tleXdvcmQ+PGtleXdvcmQ+QW50aWdl

bnM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkFVVE9BTlRJQk9E

SUVTPC9rZXl3b3JkPjxrZXl3b3JkPmF1dG9hbnRpZ2Vuczwva2V5d29yZD48a2V5d29yZD5BdXRv

aW1tdW5pdHk8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPkJST05DSEk8L2tleXdvcmQ+PGtleXdvcmQ+

YnJvbmNoaWFsPC9rZXl3b3JkPjxrZXl3b3JkPmNhc2UtY29udHJvbCBzdHVkaWVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VsbHMsQ3VsdHVyZWQ8L2tleXdvcmQ+PGtleXdvcmQ+Y2hpLXNxdWFyZSBkaXN0cmlidXRpb248

L2tleXdvcmQ+PGtleXdvcmQ+Y2lyY3VsYXRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Q29ob3J0IFN0

dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q09NUEFSQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q29t

cGFyYXRpdmUgU3R1ZHk8L2tleXdvcmQ+PGtleXdvcmQ+Q1VMVFVSRUQ8L2tleXdvcmQ+PGtleXdv

cmQ+Y3l0b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+REVWRUxPUE1FTlQ8L2tleXdvcmQ+PGtleXdv

cmQ+RElBR05PU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkVQSVRIRUxJQUw8L2tleXdvcmQ+PGtleXdv

cmQ+ZXBpdGhlbGlhbCBjZWxsczwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtl

eXdvcmQ+SEVBTFRIWTwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5I

VU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SURFTlRJRklDQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

SWdHPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2Jsb3R0aW5nPC9rZXl3b3JkPjxrZXl3b3JkPklN

TVVOT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0

aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklOVk9MVkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPktlcmF0

aW5zPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNp

czwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5Qcm9iYWJpbGl0

eTwva2V5d29yZD48a2V5d29yZD5QVVJJRklFRDwva2V5d29yZD48a2V5d29yZD5SZWZlcmVuY2Ug

VmFsdWVzPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJlc2Vh

cmNoIFN1cHBvcnQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+

U2Vuc2l0aXZpdHkgYW5kIFNwZWNpZmljaXR5PC9rZXl3b3JkPjxrZXl3b3JkPlNFTlNJVElaQVRJ

T048L2tleXdvcmQ+PGtleXdvcmQ+U0VRVUVOQ0lORzwva2V5d29yZD48a2V5d29yZD5TRVJVTTwv

a2V5d29yZD48a2V5d29yZD5zZXZlcml0eSBvZiBpbGxuZXNzIGluZGV4PC9rZXl3b3JkPjxrZXl3

b3JkPlNJR05JRklDQU5DRTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3

b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNZU1RFTUlDPC9rZXl3b3JkPjxrZXl3b3JkPlZP

TFVOVEVFUlM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMjwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjYvMS8yMDAyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPk5B

SE0yMDAyPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [85]. Cigarette smoke may damage lung interstitial and structural cells and make them antigenic. Oxidative stress leads to the formation of carbonylated proteins that are antigenic; several anti-carbonylated protein antibodies have been found in the circulation of COPD patients, particularly in severe disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXJraGFtPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMzM1PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTEzMzU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMCI+MTEzMzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPktpcmtoYW0sUC5BLjwvYXV0aG9yPjxhdXRob3I+Q2FyYW1vcmksRy48L2F1dGhvcj48YXV0

aG9yPkNhc29sYXJpLFAuPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5F

ZHdhcmRzLE0uPC9hdXRob3I+PGF1dGhvcj5TaGFtamksQi48L2F1dGhvcj48YXV0aG9yPlRyaWFu

dGFwaHlsbG9wb3Vsb3MsSy48L2F1dGhvcj48YXV0aG9yPkh1c3NhaW4sRi48L2F1dGhvcj48YXV0

aG9yPlBpbmFydCxNLjwvYXV0aG9yPjxhdXRob3I+S2hhbixZLjwvYXV0aG9yPjxhdXRob3I+SGVp

bmVtYW5uLEwuPC9hdXRob3I+PGF1dGhvcj5TdGV2ZW5zLEwuPC9hdXRob3I+PGF1dGhvcj5ZZWFk

b24sTS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5DaHVuZyxL

LkYuPC9hdXRob3I+PGF1dGhvcj5BZGNvY2ssSS5NLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5PeGlkYXRpdmUgc3RyZXNzLWluZHVjZWQgYW50aWJvZGll

cyB0byBjYXJib255bC1tb2RpZmllZCBwcm90ZWluIGNvcnJlbGF0ZSB3aXRoIHNldmVyaXR5IG9m

IENPUEQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZC48

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3BpciBDcml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjc5Ni04

MDI8L3BhZ2VzPjx2b2x1bWU+MTg0PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+

PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5BR0U8L2tleXdvcmQ+PGtleXdv

cmQ+QUlSPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCT0RJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUJPRFk8

L2tleXdvcmQ+PGtleXdvcmQ+QU5USUdFTjwva2V5d29yZD48a2V5d29yZD5BTlRJR0VOLVBSRVNF

TlRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkFVVE9BTlRJ

Qk9ESUVTPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21lZGljYWwgUmVzZWFyY2g8L2tleXdvcmQ+PGtl

eXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvbXBsZW1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5

d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+RUxJU0E8L2tleXdvcmQ+PGtleXdvcmQ+

RU5ET1RIRUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZW5kb3RoZWxpYWwgY2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQT1NVUkU8L2tleXdvcmQ+PGtl

eXdvcmQ+Rk9STUFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5F

PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5MZWFkPC9r

ZXl3b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TU9ERUw8L2tleXdvcmQ+PGtleXdvcmQ+TVVSSU5FPC9r

ZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29y

ZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwv

a2V5d29yZD48a2V5d29yZD5PWk9ORTwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5

d29yZD48a2V5d29yZD5QRVJTSVNURU5UPC9rZXl3b3JkPjxrZXl3b3JkPlBSRVZBTEVOQ0U8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QUk9URUlOPC9rZXl3

b3JkPjxrZXl3b3JkPlBST1RFSU5TPC9rZXl3b3JkPjxrZXl3b3JkPlJFQUNUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48

a2V5d29yZD5TRU5TSVRJWkVEPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48a2V5

d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5d29yZD5WRVNTRUxT

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT42LzE2LzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+S0lSS0hBTTIw

MTE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXJraGFtPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMzM1PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTEzMzU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMCI+MTEzMzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPktpcmtoYW0sUC5BLjwvYXV0aG9yPjxhdXRob3I+Q2FyYW1vcmksRy48L2F1dGhvcj48YXV0

aG9yPkNhc29sYXJpLFAuPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5F

ZHdhcmRzLE0uPC9hdXRob3I+PGF1dGhvcj5TaGFtamksQi48L2F1dGhvcj48YXV0aG9yPlRyaWFu

dGFwaHlsbG9wb3Vsb3MsSy48L2F1dGhvcj48YXV0aG9yPkh1c3NhaW4sRi48L2F1dGhvcj48YXV0

aG9yPlBpbmFydCxNLjwvYXV0aG9yPjxhdXRob3I+S2hhbixZLjwvYXV0aG9yPjxhdXRob3I+SGVp

bmVtYW5uLEwuPC9hdXRob3I+PGF1dGhvcj5TdGV2ZW5zLEwuPC9hdXRob3I+PGF1dGhvcj5ZZWFk

b24sTS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5DaHVuZyxL

LkYuPC9hdXRob3I+PGF1dGhvcj5BZGNvY2ssSS5NLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5PeGlkYXRpdmUgc3RyZXNzLWluZHVjZWQgYW50aWJvZGll

cyB0byBjYXJib255bC1tb2RpZmllZCBwcm90ZWluIGNvcnJlbGF0ZSB3aXRoIHNldmVyaXR5IG9m

IENPUEQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZC48

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3BpciBDcml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjc5Ni04

MDI8L3BhZ2VzPjx2b2x1bWU+MTg0PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+

PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5BR0U8L2tleXdvcmQ+PGtleXdv

cmQ+QUlSPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCT0RJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUJPRFk8

L2tleXdvcmQ+PGtleXdvcmQ+QU5USUdFTjwva2V5d29yZD48a2V5d29yZD5BTlRJR0VOLVBSRVNF

TlRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkFVVE9BTlRJ

Qk9ESUVTPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21lZGljYWwgUmVzZWFyY2g8L2tleXdvcmQ+PGtl

eXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvbXBsZW1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5

d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+RUxJU0E8L2tleXdvcmQ+PGtleXdvcmQ+

RU5ET1RIRUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZW5kb3RoZWxpYWwgY2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQT1NVUkU8L2tleXdvcmQ+PGtl

eXdvcmQ+Rk9STUFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5F

PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5MZWFkPC9r

ZXl3b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TU9ERUw8L2tleXdvcmQ+PGtleXdvcmQ+TVVSSU5FPC9r

ZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29y

ZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwv

a2V5d29yZD48a2V5d29yZD5PWk9ORTwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5

d29yZD48a2V5d29yZD5QRVJTSVNURU5UPC9rZXl3b3JkPjxrZXl3b3JkPlBSRVZBTEVOQ0U8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QUk9URUlOPC9rZXl3

b3JkPjxrZXl3b3JkPlBST1RFSU5TPC9rZXl3b3JkPjxrZXl3b3JkPlJFQUNUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48

a2V5d29yZD5TRU5TSVRJWkVEPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48a2V5

d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5d29yZD5WRVNTRUxT

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT42LzE2LzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+S0lSS0hBTTIw

MTE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [86]. Anti-endothelial antibodies have also been detected QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\0CKIRKHAM2011A/Kirkham, Caramori, et al. 2011 KIRKHAM2011A /id\00/\00 in COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJheWFtYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4xMTQ5NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bODddPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjExNDk3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0NzkwMDIiPjExNDk3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5LYXJheWFtYSxNLjwvYXV0aG9yPjxhdXRob3I+SW51aSxOLjwvYXV0aG9yPjxhdXRob3I+

U3VkYSxULjwvYXV0aG9yPjxhdXRob3I+TmFrYW11cmEsWS48L2F1dGhvcj48YXV0aG9yPk5ha2Ft

dXJhLEguPC9hdXRob3I+PGF1dGhvcj5DaGlkYSxLLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BbnRpZW5kb3RoZWxpYWwgQ2VsbCBBbnRpYm9kaWVzIGlu

IFBhdGllbnRzIFdpdGggQ09QRDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DaGVzdC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdC48L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzAzLTEzMDg8L3BhZ2VzPjx2b2x1bWU+MTM4PC92

b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVw

cmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BTlRJQk9ESUVTPC9rZXl3b3JkPjxrZXl3

b3JkPkFOVElCT0RZPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElHRU48L2tleXdvcmQ+PGtleXdvcmQ+

QW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdvcmQ+PGtleXdvcmQ+QVVUT0FO

VElCT0RJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPmNhc2UtY29udHJvbCBzdHVkaWVzPC9rZXl3

b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdv

cmQ+Q0VMTFVMQVI8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5D

SFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkUg

TFVORyBESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPmNpcmN1bGF0aW5nPC9rZXl3b3JkPjxrZXl3

b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkNPTExBR0VOPC9rZXl3b3JkPjxrZXl3b3Jk

PkNPTkNFTlRSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5E

QU1BR0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNF

Uzwva2V5d29yZD48a2V5d29yZD5FTkRPVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lbmRvdGhl

bGlhbCBjZWxsczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgTGlua2VkIEltbXVub3NvcmJlbnQg

QXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+ZW56eW1lLWxpbmtlZCBpbW11bm9zb3JiZW50IGFzc2F5

PC9rZXl3b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPmdsb2JhbDwva2V5d29y

ZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdv

cmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTlZP

TFZFTUVOVDwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVESUNJTkU8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3Jk

PjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+bm9ybWFsPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxr

ZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBPUFVMQVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+UFJPR05PU0lTPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5

d29yZD5QdWxtb25hcnkgRGlzZWFzZSxDaHJvbmljIE9ic3RydWN0aXZlPC9rZXl3b3JkPjxrZXl3

b3JkPnJhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlJlZmVyZW5jZSBWYWx1ZXM8L2tleXdv

cmQ+PGtleXdvcmQ+UmVzcGlyYXRvcnkgRnVuY3Rpb24gVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+

U0NIT09MPC9rZXl3b3JkPjxrZXl3b3JkPlNFQ09ORDwva2V5d29yZD48a2V5d29yZD5TRVJVTTwv

a2V5d29yZD48a2V5d29yZD5zZXZlcml0eSBvZiBpbGxuZXNzIGluZGV4PC9rZXl3b3JkPjxrZXl3

b3JkPlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U3Bpcm9tZXRyeTwva2V5d29yZD48a2V5d29y

ZD5zdGF0aXN0aWNzLG5vbnBhcmFtZXRyaWM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5

d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJKRUNUUzwva2V5d29yZD48

a2V5d29yZD5TWVNURU1JQzwva2V5d29yZD48a2V5d29yZD50b21vZ3JhcGh5LHgtcmF5IGNvbXB1

dGVkPC9rZXl3b3JkPjxrZXl3b3JkPlZBU0NVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPlZhc2N1bGFy

IERpc2Vhc2VzPC9rZXl3b3JkPjxrZXl3b3JkPlZhc2N1bGl0aXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjEyLzIwMTA8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+S0FSQVlBTUEyMDEwPC9sYWJlbD48dXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJheWFtYTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+

PFJlY051bT4xMTQ5NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bODddPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjExNDk3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0NzkwMDIiPjExNDk3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5LYXJheWFtYSxNLjwvYXV0aG9yPjxhdXRob3I+SW51aSxOLjwvYXV0aG9yPjxhdXRob3I+

U3VkYSxULjwvYXV0aG9yPjxhdXRob3I+TmFrYW11cmEsWS48L2F1dGhvcj48YXV0aG9yPk5ha2Ft

dXJhLEguPC9hdXRob3I+PGF1dGhvcj5DaGlkYSxLLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BbnRpZW5kb3RoZWxpYWwgQ2VsbCBBbnRpYm9kaWVzIGlu

IFBhdGllbnRzIFdpdGggQ09QRDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5DaGVzdC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdC48L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMzAzLTEzMDg8L3BhZ2VzPjx2b2x1bWU+MTM4PC92

b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVw

cmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29yZD5BTlRJQk9ESUVTPC9rZXl3b3JkPjxrZXl3

b3JkPkFOVElCT0RZPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElHRU48L2tleXdvcmQ+PGtleXdvcmQ+

QW50aWdlbnM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdvcmQ+PGtleXdvcmQ+QVVUT0FO

VElCT0RJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QmlvbG9naWNhbCBNYXJrZXJzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPmNhc2UtY29udHJvbCBzdHVkaWVzPC9rZXl3

b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdv

cmQ+Q0VMTFVMQVI8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5D

SFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkUg

TFVORyBESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPmNpcmN1bGF0aW5nPC9rZXl3b3JkPjxrZXl3

b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkNPTExBR0VOPC9rZXl3b3JkPjxrZXl3b3Jk

PkNPTkNFTlRSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5E

QU1BR0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNF

Uzwva2V5d29yZD48a2V5d29yZD5FTkRPVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lbmRvdGhl

bGlhbCBjZWxsczwva2V5d29yZD48a2V5d29yZD5Fbnp5bWUgTGlua2VkIEltbXVub3NvcmJlbnQg

QXNzYXk8L2tleXdvcmQ+PGtleXdvcmQ+ZW56eW1lLWxpbmtlZCBpbW11bm9zb3JiZW50IGFzc2F5

PC9rZXl3b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048

L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPmdsb2JhbDwva2V5d29y

ZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdv

cmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTlZP

TFZFTUVOVDwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVESUNJTkU8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3Jk

PjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+bm9ybWFsPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxr

ZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBPUFVMQVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+UFJPR05PU0lTPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5

d29yZD5QdWxtb25hcnkgRGlzZWFzZSxDaHJvbmljIE9ic3RydWN0aXZlPC9rZXl3b3JkPjxrZXl3

b3JkPnJhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlJlZmVyZW5jZSBWYWx1ZXM8L2tleXdv

cmQ+PGtleXdvcmQ+UmVzcGlyYXRvcnkgRnVuY3Rpb24gVGVzdHM8L2tleXdvcmQ+PGtleXdvcmQ+

U0NIT09MPC9rZXl3b3JkPjxrZXl3b3JkPlNFQ09ORDwva2V5d29yZD48a2V5d29yZD5TRVJVTTwv

a2V5d29yZD48a2V5d29yZD5zZXZlcml0eSBvZiBpbGxuZXNzIGluZGV4PC9rZXl3b3JkPjxrZXl3

b3JkPlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U3Bpcm9tZXRyeTwva2V5d29yZD48a2V5d29y

ZD5zdGF0aXN0aWNzLG5vbnBhcmFtZXRyaWM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5

d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJKRUNUUzwva2V5d29yZD48

a2V5d29yZD5TWVNURU1JQzwva2V5d29yZD48a2V5d29yZD50b21vZ3JhcGh5LHgtcmF5IGNvbXB1

dGVkPC9rZXl3b3JkPjxrZXl3b3JkPlZBU0NVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPlZhc2N1bGFy

IERpc2Vhc2VzPC9rZXl3b3JkPjxrZXl3b3JkPlZhc2N1bGl0aXM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjEyLzIwMTA8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+S0FSQVlBTUEyMDEwPC9sYWJlbD48dXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [87] Autoantibodies may cause cell damage through the binding of complement, which is deposited in the lungs of COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXJraGFtPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMzM1PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTEzMzU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMCI+MTEzMzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPktpcmtoYW0sUC5BLjwvYXV0aG9yPjxhdXRob3I+Q2FyYW1vcmksRy48L2F1dGhvcj48YXV0

aG9yPkNhc29sYXJpLFAuPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5F

ZHdhcmRzLE0uPC9hdXRob3I+PGF1dGhvcj5TaGFtamksQi48L2F1dGhvcj48YXV0aG9yPlRyaWFu

dGFwaHlsbG9wb3Vsb3MsSy48L2F1dGhvcj48YXV0aG9yPkh1c3NhaW4sRi48L2F1dGhvcj48YXV0

aG9yPlBpbmFydCxNLjwvYXV0aG9yPjxhdXRob3I+S2hhbixZLjwvYXV0aG9yPjxhdXRob3I+SGVp

bmVtYW5uLEwuPC9hdXRob3I+PGF1dGhvcj5TdGV2ZW5zLEwuPC9hdXRob3I+PGF1dGhvcj5ZZWFk

b24sTS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5DaHVuZyxL

LkYuPC9hdXRob3I+PGF1dGhvcj5BZGNvY2ssSS5NLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5PeGlkYXRpdmUgc3RyZXNzLWluZHVjZWQgYW50aWJvZGll

cyB0byBjYXJib255bC1tb2RpZmllZCBwcm90ZWluIGNvcnJlbGF0ZSB3aXRoIHNldmVyaXR5IG9m

IENPUEQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZC48

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3BpciBDcml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjc5Ni04

MDI8L3BhZ2VzPjx2b2x1bWU+MTg0PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+

PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5BR0U8L2tleXdvcmQ+PGtleXdv

cmQ+QUlSPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCT0RJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUJPRFk8

L2tleXdvcmQ+PGtleXdvcmQ+QU5USUdFTjwva2V5d29yZD48a2V5d29yZD5BTlRJR0VOLVBSRVNF

TlRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkFVVE9BTlRJ

Qk9ESUVTPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21lZGljYWwgUmVzZWFyY2g8L2tleXdvcmQ+PGtl

eXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvbXBsZW1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5

d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+RUxJU0E8L2tleXdvcmQ+PGtleXdvcmQ+

RU5ET1RIRUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZW5kb3RoZWxpYWwgY2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQT1NVUkU8L2tleXdvcmQ+PGtl

eXdvcmQ+Rk9STUFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5F

PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5MZWFkPC9r

ZXl3b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TU9ERUw8L2tleXdvcmQ+PGtleXdvcmQ+TVVSSU5FPC9r

ZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29y

ZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwv

a2V5d29yZD48a2V5d29yZD5PWk9ORTwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5

d29yZD48a2V5d29yZD5QRVJTSVNURU5UPC9rZXl3b3JkPjxrZXl3b3JkPlBSRVZBTEVOQ0U8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QUk9URUlOPC9rZXl3

b3JkPjxrZXl3b3JkPlBST1RFSU5TPC9rZXl3b3JkPjxrZXl3b3JkPlJFQUNUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48

a2V5d29yZD5TRU5TSVRJWkVEPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48a2V5

d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5d29yZD5WRVNTRUxT

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT42LzE2LzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+S0lSS0hBTTIw

MTE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXJraGFtPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMzM1PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls4Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTEzMzU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMCI+MTEzMzU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPktpcmtoYW0sUC5BLjwvYXV0aG9yPjxhdXRob3I+Q2FyYW1vcmksRy48L2F1dGhvcj48YXV0

aG9yPkNhc29sYXJpLFAuPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5F

ZHdhcmRzLE0uPC9hdXRob3I+PGF1dGhvcj5TaGFtamksQi48L2F1dGhvcj48YXV0aG9yPlRyaWFu

dGFwaHlsbG9wb3Vsb3MsSy48L2F1dGhvcj48YXV0aG9yPkh1c3NhaW4sRi48L2F1dGhvcj48YXV0

aG9yPlBpbmFydCxNLjwvYXV0aG9yPjxhdXRob3I+S2hhbixZLjwvYXV0aG9yPjxhdXRob3I+SGVp

bmVtYW5uLEwuPC9hdXRob3I+PGF1dGhvcj5TdGV2ZW5zLEwuPC9hdXRob3I+PGF1dGhvcj5ZZWFk

b24sTS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5DaHVuZyxL

LkYuPC9hdXRob3I+PGF1dGhvcj5BZGNvY2ssSS5NLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRy

aWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5PeGlkYXRpdmUgc3RyZXNzLWluZHVjZWQgYW50aWJvZGll

cyB0byBjYXJib255bC1tb2RpZmllZCBwcm90ZWluIGNvcnJlbGF0ZSB3aXRoIHNldmVyaXR5IG9m

IENPUEQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZC48

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3BpciBDcml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjc5Ni04

MDI8L3BhZ2VzPjx2b2x1bWU+MTg0PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+

PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5BR0U8L2tleXdvcmQ+PGtleXdv

cmQ+QUlSPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlz

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCT0RJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUJPRFk8

L2tleXdvcmQ+PGtleXdvcmQ+QU5USUdFTjwva2V5d29yZD48a2V5d29yZD5BTlRJR0VOLVBSRVNF

TlRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkFVVE9BTlRJ

Qk9ESUVTPC9rZXl3b3JkPjxrZXl3b3JkPkJpb21lZGljYWwgUmVzZWFyY2g8L2tleXdvcmQ+PGtl

eXdvcmQ+QkxPT0Q8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNvbXBsZW1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5

d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+RElTRUFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+RUxJU0E8L2tleXdvcmQ+PGtleXdvcmQ+

RU5ET1RIRUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZW5kb3RoZWxpYWwgY2VsbHM8L2tleXdvcmQ+

PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQT1NVUkU8L2tleXdvcmQ+PGtl

eXdvcmQ+Rk9STUFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPkdPTEQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5F

PC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlzdHJ5PC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5MZWFkPC9r

ZXl3b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+TU9ERUw8L2tleXdvcmQ+PGtleXdvcmQ+TVVSSU5FPC9r

ZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29y

ZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwv

a2V5d29yZD48a2V5d29yZD5PWk9ORTwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5

d29yZD48a2V5d29yZD5QRVJTSVNURU5UPC9rZXl3b3JkPjxrZXl3b3JkPlBSRVZBTEVOQ0U8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QUk9URUlOPC9rZXl3

b3JkPjxrZXl3b3JkPlBST1RFSU5TPC9rZXl3b3JkPjxrZXl3b3JkPlJFQUNUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3Jk

PjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFUzwva2V5d29yZD48

a2V5d29yZD5TRU5TSVRJWkVEPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSRTwva2V5d29yZD48a2V5

d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5d29yZD5WRVNTRUxT

PC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTE8L3llYXI+PHB1Yi1kYXRlcz48

ZGF0ZT42LzE2LzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+S0lSS0hBTTIw

MTE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [86]. Citrullinated proteins are also described in the lungs of COPD patients and may induce autoantibody formation, as found in rheumatoid arthritis ADDIN EN.CITE <EndNote><Cite><Author>Klareskog</Author><Year>2015</Year><RecNum>12816</RecNum><DisplayText>[88]</DisplayText><record><rec-number>12816</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1462952905">12816</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Klareskog, L.</author><author>Catrina, A. I.</author></authors></contributors><auth-address>Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, 171 76 Stockholm, Sweden.</auth-address><titles><title>Autoimmunity: lungs and citrullination</title><secondary-title>Nat Rev Rheumatol</secondary-title><alt-title>Nature reviews. Rheumatology</alt-title></titles><periodical><full-title>Nat Rev Rheumatol</full-title><abbr-1>Nature reviews. Rheumatology</abbr-1></periodical><alt-periodical><full-title>Nat Rev Rheumatol</full-title><abbr-1>Nature reviews. Rheumatology</abbr-1></alt-periodical><pages>261-2</pages><volume>11</volume><number>5</number><edition>2015/03/18</edition><keywords><keyword>Arthritis, Rheumatoid/immunology</keyword><keyword>Autoimmunity/*immunology</keyword><keyword>Citrulline/*immunology</keyword><keyword>Humans</keyword><keyword>Lung/*immunology/metabolism/pathology</keyword><keyword>Pneumonia/*immunology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/immunology/metabolism</keyword><keyword>Smoking/immunology</keyword></keywords><dates><year>2015</year><pub-dates><date>May</date></pub-dates></dates><isbn>1759-4790</isbn><accession-num>25776950</accession-num><urls></urls><electronic-resource-num>10.1038/nrrheum.2015.38</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[88].Structural cellsStructural cells of the airways, including epithelial cells, endothelial cells, fibroblasts and airway smooth muscle cells, are also important sources of inflammatory mediators such as cytokines and lipid mediators in asthma and COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1tYWQ8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTIzNjE8L1JlY051bT48RGlzcGxheVRleHQ+WzUwLCA4OV08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTIzNjE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQzODE2NTIzMiI+MTIzNjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkhhbW1hZCwgSC48L2F1dGhvcj48YXV0aG9yPkxhbWJyZWNodCwgQi4gTi48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5WSUIgSW5mbGFtbWF0aW9u

IFJlc2VhcmNoIENlbnRlciwgVGVjaG5vbG9naWVwYXJrIDkyNywgOTA1MiBHaGVudCwgQmVsZ2l1

bTsgTGFib3JhdG9yeSBvZiBJbW11bm9yZWd1bGF0aW9uIGFuZCBNdWNvc2FsIEltbXVub2xvZ3ks

IERlcGFydG1lbnQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEdoZW50IFVuaXZlcnNpdHksIERl

IFBpbnRlbGFhbiAxODUsIDkwMDAgR2hlbnQsIEJlbGdpdW0uIEVsZWN0cm9uaWMgYWRkcmVzczog

aGFtaWRhLmhhbW1hZEBpcmMudmliLXVnZW50LmJlLiYjeEQ7VklCIEluZmxhbW1hdGlvbiBSZXNl

YXJjaCBDZW50ZXIsIFRlY2hub2xvZ2llcGFyayA5MjcsIDkwNTIgR2hlbnQsIEJlbGdpdW07IExh

Ym9yYXRvcnkgb2YgSW1tdW5vcmVndWxhdGlvbiBhbmQgTXVjb3NhbCBJbW11bm9sb2d5LCBEZXBh

cnRtZW50IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHaGVudCBVbml2ZXJzaXR5LCBEZSBQaW50

ZWxhYW4gMTg1LCA5MDAwIEdoZW50LCBCZWxnaXVtOyBEZXBhcnRtZW50IG9mIFB1bG1vbmFyeSBN

ZWRpY2luZSwgRXJhc211c01DLCBEciBNb2xld2F0ZXJwbGVpbiA1MCwgMzAxNSBHRSBSb3R0ZXJk

YW0sIHRoZSBOZXRoZXJsYW5kcy4gRWxlY3Ryb25pYyBhZGRyZXNzOiBiYXJ0LmxhbWJyZWNodEBp

cmMudmliLXVnZW50LmJlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJhcnJpZXIgZXBp

dGhlbGlhbCBjZWxscyBhbmQgdGhlIGNvbnRyb2wgb2YgdHlwZSAyIGltbXVuaXR5PC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkltbXVuaXR5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5JbW11

bml0eTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkltbXVuaXR5

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SW1t

dW5pdHk8L2Z1bGwtdGl0bGU+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MjktNDA8L3BhZ2VzPjx2

b2x1bWU+NDM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE1LzA3LzIzPC9l

ZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsIDIxPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA3NC03NjEzPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjI2MjAwMDExPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMTAxNi9qLmltbXVuaS4yMDE1LjA3LjAwNzwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5ObG08L3JlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5HYW88L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MTIzNTE8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyMzUxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0MzUwNTk2MzEiPjEyMzUxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5HYW8sIFcuPC9hdXRob3I+PGF1dGhvcj5MaSwgTC48L2F1dGhvcj48YXV0aG9yPldhbmcs

IFkuPC9hdXRob3I+PGF1dGhvcj5aaGFuZywgUy48L2F1dGhvcj48YXV0aG9yPkFkY29jaywgSS4g

TS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcywgUC4gSi48L2F1dGhvcj48YXV0aG9yPkh1YW5nLCBN

LjwvYXV0aG9yPjxhdXRob3I+WWFvLCBYLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIFRoZSBG

aXJzdCBBZmZpbGlhdGVkIEhvc3BpdGFsIG9mIE5hbmppbmcgTWVkaWNhbCBVbml2ZXJzaXR5LCBO

YW5qaW5nLCBDaGluYS4mI3hEO0FpcndheSBEaXNlYXNlIFNlY3Rpb24sIE5hdGlvbmFsIEhlYXJ0

IGFuZCBMdW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSwgTG9uZG9uLCBVSy48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Ccm9uY2hpYWwgZXBpdGhlbGlhbCBjZWxsczogVGhlIGtl

eSBlZmZlY3RvciBjZWxscyBpbiB0aGUgcGF0aG9nZW5lc2lzIG9mIGNocm9uaWMgb2JzdHJ1Y3Rp

dmUgcHVsbW9uYXJ5IGRpc2Vhc2U/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJlc3Bpcm9sb2d5

PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5SZXNwaXJvbG9neSAoQ2FybHRvbiwgVmljLik8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5SZXNwaXJvbG9neTwv

ZnVsbC10aXRsZT48YWJici0xPlJlc3Bpcm9sb2d5IChDYXJsdG9uLCBWaWMuKTwvYWJici0xPjwv

cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UmVzcGlyb2xvZ3k8L2Z1bGwt

dGl0bGU+PGFiYnItMT5SZXNwaXJvbG9neSAoQ2FybHRvbiwgVmljLik8L2FiYnItMT48L2FsdC1w

ZXJpb2RpY2FsPjxwYWdlcz43MjItOTwvcGFnZXM+PHZvbHVtZT4yMDwvdm9sdW1lPjxudW1iZXI+

NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDQvMTU8L2VkaXRpb24+PGRhdGVzPjx5ZWFyPjIwMTU8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xMzIzLTc3OTk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU4Njg4NDI8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL3Jlc3AuMTI1NDI8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TmxtPC9y

ZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1tYWQ8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

ZWNOdW0+MTIzNjE8L1JlY051bT48RGlzcGxheVRleHQ+WzUwLCA4OV08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTIzNjE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQzODE2NTIzMiI+MTIzNjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkhhbW1hZCwgSC48L2F1dGhvcj48YXV0aG9yPkxhbWJyZWNodCwgQi4gTi48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5WSUIgSW5mbGFtbWF0aW9u

IFJlc2VhcmNoIENlbnRlciwgVGVjaG5vbG9naWVwYXJrIDkyNywgOTA1MiBHaGVudCwgQmVsZ2l1

bTsgTGFib3JhdG9yeSBvZiBJbW11bm9yZWd1bGF0aW9uIGFuZCBNdWNvc2FsIEltbXVub2xvZ3ks

IERlcGFydG1lbnQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEdoZW50IFVuaXZlcnNpdHksIERl

IFBpbnRlbGFhbiAxODUsIDkwMDAgR2hlbnQsIEJlbGdpdW0uIEVsZWN0cm9uaWMgYWRkcmVzczog

aGFtaWRhLmhhbW1hZEBpcmMudmliLXVnZW50LmJlLiYjeEQ7VklCIEluZmxhbW1hdGlvbiBSZXNl

YXJjaCBDZW50ZXIsIFRlY2hub2xvZ2llcGFyayA5MjcsIDkwNTIgR2hlbnQsIEJlbGdpdW07IExh

Ym9yYXRvcnkgb2YgSW1tdW5vcmVndWxhdGlvbiBhbmQgTXVjb3NhbCBJbW11bm9sb2d5LCBEZXBh

cnRtZW50IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHaGVudCBVbml2ZXJzaXR5LCBEZSBQaW50

ZWxhYW4gMTg1LCA5MDAwIEdoZW50LCBCZWxnaXVtOyBEZXBhcnRtZW50IG9mIFB1bG1vbmFyeSBN

ZWRpY2luZSwgRXJhc211c01DLCBEciBNb2xld2F0ZXJwbGVpbiA1MCwgMzAxNSBHRSBSb3R0ZXJk

YW0sIHRoZSBOZXRoZXJsYW5kcy4gRWxlY3Ryb25pYyBhZGRyZXNzOiBiYXJ0LmxhbWJyZWNodEBp

cmMudmliLXVnZW50LmJlLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkJhcnJpZXIgZXBp

dGhlbGlhbCBjZWxscyBhbmQgdGhlIGNvbnRyb2wgb2YgdHlwZSAyIGltbXVuaXR5PC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkltbXVuaXR5PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5JbW11

bml0eTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkltbXVuaXR5

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SW1t

dW5pdHk8L2Z1bGwtdGl0bGU+PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MjktNDA8L3BhZ2VzPjx2

b2x1bWU+NDM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE1LzA3LzIzPC9l

ZGl0aW9uPjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVsIDIxPC9k

YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA3NC03NjEzPC9pc2JuPjxhY2Nlc3Npb24t

bnVtPjI2MjAwMDExPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNv

dXJjZS1udW0+MTAuMTAxNi9qLmltbXVuaS4yMDE1LjA3LjAwNzwvZWxlY3Ryb25pYy1yZXNvdXJj

ZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5ObG08L3JlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhv

cj5HYW88L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNOdW0+MTIzNTE8L1JlY051bT48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyMzUxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0MzUwNTk2MzEiPjEyMzUxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5HYW8sIFcuPC9hdXRob3I+PGF1dGhvcj5MaSwgTC48L2F1dGhvcj48YXV0aG9yPldhbmcs

IFkuPC9hdXRob3I+PGF1dGhvcj5aaGFuZywgUy48L2F1dGhvcj48YXV0aG9yPkFkY29jaywgSS4g

TS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcywgUC4gSi48L2F1dGhvcj48YXV0aG9yPkh1YW5nLCBN

LjwvYXV0aG9yPjxhdXRob3I+WWFvLCBYLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIFRoZSBG

aXJzdCBBZmZpbGlhdGVkIEhvc3BpdGFsIG9mIE5hbmppbmcgTWVkaWNhbCBVbml2ZXJzaXR5LCBO

YW5qaW5nLCBDaGluYS4mI3hEO0FpcndheSBEaXNlYXNlIFNlY3Rpb24sIE5hdGlvbmFsIEhlYXJ0

IGFuZCBMdW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSwgTG9uZG9uLCBVSy48L2F1dGgt

YWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Ccm9uY2hpYWwgZXBpdGhlbGlhbCBjZWxsczogVGhlIGtl

eSBlZmZlY3RvciBjZWxscyBpbiB0aGUgcGF0aG9nZW5lc2lzIG9mIGNocm9uaWMgb2JzdHJ1Y3Rp

dmUgcHVsbW9uYXJ5IGRpc2Vhc2U/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlJlc3Bpcm9sb2d5

PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5SZXNwaXJvbG9neSAoQ2FybHRvbiwgVmljLik8

L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5SZXNwaXJvbG9neTwv

ZnVsbC10aXRsZT48YWJici0xPlJlc3Bpcm9sb2d5IChDYXJsdG9uLCBWaWMuKTwvYWJici0xPjwv

cGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+UmVzcGlyb2xvZ3k8L2Z1bGwt

dGl0bGU+PGFiYnItMT5SZXNwaXJvbG9neSAoQ2FybHRvbiwgVmljLik8L2FiYnItMT48L2FsdC1w

ZXJpb2RpY2FsPjxwYWdlcz43MjItOTwvcGFnZXM+PHZvbHVtZT4yMDwvdm9sdW1lPjxudW1iZXI+

NTwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDQvMTU8L2VkaXRpb24+PGRhdGVzPjx5ZWFyPjIwMTU8

L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNi

bj4xMzIzLTc3OTk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjU4Njg4NDI8L2FjY2Vzc2lvbi1udW0+

PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTExL3Jlc3AuMTI1NDI8

L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TmxtPC9y

ZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+

PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [50, 89]. Epithelial cells play a key role in translating inhaled environmental signals into an airway inflammatory response, and are probably major target cells for inhaled corticosteroids in asthma. Inflammatory mediatorsOver 100 inflammatory mediators have been implicated in asthma and COPD, and they may have a variety of effects on the airways that in combination account for the pathological features of these diseases. Mast cell derived mediators, histamine, PGD2, and cys-LTs, contract airway smooth muscle, increase microvascular leakage, increase airway mucus secretion, and attract other inflammatory cells. Because each mediator has many effects, the role of individual mediators in the pathophysiology of asthma and COPD is not always clear. The multiplicity and redundancy of effects of mediators means that preventing the synthesis or action of a single mediator is unlikely to have a major clinical effect in asthma or COPD. However, in certain patients blocking a critical mediator may be of clinical value if this mediator is predominant or high is a cascade of mediators. For example, blocking IL-5 may be clinically useful in asthmatic patients with high eosinophils, despite high doses of corticosteroids PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcnRlZ2E8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MTIyNTU8L1JlY051bT48RGlzcGxheVRleHQ+WzU2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMjI1NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxNDI4MjI0OTIwIj4xMjI1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+T3J0ZWdhLCBILiBHLjwvYXV0aG9yPjxhdXRob3I+TGl1LCBNLiBDLjwvYXV0aG9yPjxhdXRo

b3I+UGF2b3JkLCBJLiBELjwvYXV0aG9yPjxhdXRob3I+QnJ1c3NlbGxlLCBHLiBHLjwvYXV0aG9y

PjxhdXRob3I+Rml0ekdlcmFsZCwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkNoZXR0YSwgQS48L2F1

dGhvcj48YXV0aG9yPkh1bWJlcnQsIE0uPC9hdXRob3I+PGF1dGhvcj5LYXR6LCBMLiBFLjwvYXV0

aG9yPjxhdXRob3I+S2VlbmUsIE8uIE4uPC9hdXRob3I+PGF1dGhvcj5ZYW5jZXksIFMuIFcuPC9h

dXRob3I+PGF1dGhvcj5DaGFuZXosIFAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RnJvbSB0aGUgUmVzcGlyYXRvcnkgVGhlcmFwZXV0aWMgQXJlYSBVbml0

LCBHbGF4b1NtaXRoS2xpbmUsIFJlc2VhcmNoIFRyaWFuZ2xlIFBhcmssIE5DIChILkcuTy4sIEwu

RS5LLiwgUy5XLlkuKTsgSm9obnMgSG9wa2lucyBBc3RobWEgYW5kIEFsbGVyZ3kgQ2VudGVyLCBC

YWx0aW1vcmUgKE0uQy5MLik7IFJlc3BpcmF0b3J5IE1lZGljaW5lIFVuaXQsIE51ZmZpZWxkIERl

cGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgT3hmb3JkLCBPeGZvcmQgKEkuRC5Q

LiksIGFuZCBDbGluaWNhbCBTdGF0aXN0aWNzLCBHbGF4b1NtaXRoS2xpbmUsIFN0b2NrbGV5IFBh

cmssIE1pZGRsZXNleCAoTy5OLksuKSAtIGJvdGggaW4gdGhlIFVuaXRlZCBLaW5nZG9tOyB0aGUg

RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgR2hlbnQsIEJlbGdpdW0gKEcuRy5CLik7IHRoZSBMdW5nIENlbnRyZSwgSW5zdGl0dXRl

IGZvciBIZWFydCBhbmQgTHVuZyBIZWFsdGgsIFZhbmNvdXZlciwgQkMsIENhbmFkYSAoSi5NLkYu

KTsgdGhlIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgYW5kIEV4cGVyaW1lbnRhbCBNZWRpY2luZSwg

VW5pdmVyc2l0eSBvZiBQYXJtYSwgUGFybWEsIEl0YWx5IChBLkMuKTsgYW5kIEFzc2lzdGFuY2Ug

UHVibGlxdWUtSG9waXRhdXggZGUgUGFyaXMsIERlcGFydGVtZW50IEhvc3BpdGFsby1Vbml2ZXJz

aXRhaXJlIFRob3JheCBJbm5vdmF0aW9uLCBTZXJ2aWNlIGRlIFBuZXVtb2xvZ2llLCBIb3BpdGFs

IEJpY2V0cmUsIFVuaXZlcnNpdGUgUGFyaXMtU3VkLCBhbmQgSU5TRVJNIFVuaXRlIE1peHRlIGRl

IFJlY2hlcmNoZSA5OTksIExlIEtyZW1saW4tQmljZXRyZSAoTS5ILiksIGFuZCBVbml0ZXMgTWl4

dGVzIGRlIFJlY2hlcmNoZSBJTlNFUk0gVW5pdGUgMTA2NyBDZW50cmUgTmF0aW9uYWxlIGRlIGxh

IFJlY2hlcmNoZSBTY2llbnRpZmlxdWUgNzczMywgQWl4LU1hcnNlaWxsZSBVbml2ZXJzaXRlLCBE

ZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IERpc2Vhc2VzIGFuZCBDbGluaWNhbCBJbnZlc3RpZ2F0

aW9uIENlbnRlciwgQXNzaXN0YW5jZSBQdWJsaXF1ZS1Ib3BpdGF1eCBkZSBNYXJzZWlsbGUsIEhv

cGl0YWwgTm9yZCwgTWFyc2VpbGxlIChQLkMuKSAtIGJvdGggaW4gRnJhbmNlLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPk1lcG9saXp1bWFiIHRyZWF0bWVudCBpbiBwYXRpZW50cyB3aXRo

IHNldmVyZSBlb3Npbm9waGlsaWMgYXN0aG1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5n

bCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJu

YWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTk4LTIwNzwv

cGFnZXM+PHZvbHVtZT4zNzE8L3ZvbHVtZT48bnVtYmVyPjEzPC9udW1iZXI+PGVkaXRpb24+MjAx

NC8wOS8xMDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWRtaW5pc3RyYXRpb24sIE9yYWw8

L2tleXdvcmQ+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5

d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9r

ZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50cy8qYWRtaW5pc3RyYXRpb24gJmFt

cDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBN

b25vY2xvbmFsLCBIdW1hbml6ZWQvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZlcnNl

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hLypkcnVnIHRoZXJhcHkvaW1tdW5vbG9n

eS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdv

cmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHksIENv

bWJpbmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipFb3Npbm9waGlsaWE8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5

d29yZD48a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBJ

bnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBTdWJjdXRhbmVvdXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y

ZD48a2V5d29yZD5RdWFsaXR5IG9mIExpZmU8L2tleXdvcmQ+PGtleXdvcmQ+UXVlc3Rpb25uYWly

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+U2Vjb25kYXJ5IFByZXZlbnRpb248L2tleXdvcmQ+PGtleXdv

cmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMjgtNDc5MzwvaXNibj48YWNjZXNzaW9uLW51bT4yNTE5OTA1OTwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTQwMzI5

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5ObG08

L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PcnRlZ2E8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

ZWNOdW0+MTIyNTU8L1JlY051bT48RGlzcGxheVRleHQ+WzU2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMjI1NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxNDI4MjI0OTIwIj4xMjI1NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+T3J0ZWdhLCBILiBHLjwvYXV0aG9yPjxhdXRob3I+TGl1LCBNLiBDLjwvYXV0aG9yPjxhdXRo

b3I+UGF2b3JkLCBJLiBELjwvYXV0aG9yPjxhdXRob3I+QnJ1c3NlbGxlLCBHLiBHLjwvYXV0aG9y

PjxhdXRob3I+Rml0ekdlcmFsZCwgSi4gTS48L2F1dGhvcj48YXV0aG9yPkNoZXR0YSwgQS48L2F1

dGhvcj48YXV0aG9yPkh1bWJlcnQsIE0uPC9hdXRob3I+PGF1dGhvcj5LYXR6LCBMLiBFLjwvYXV0

aG9yPjxhdXRob3I+S2VlbmUsIE8uIE4uPC9hdXRob3I+PGF1dGhvcj5ZYW5jZXksIFMuIFcuPC9h

dXRob3I+PGF1dGhvcj5DaGFuZXosIFAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3Jz

PjxhdXRoLWFkZHJlc3M+RnJvbSB0aGUgUmVzcGlyYXRvcnkgVGhlcmFwZXV0aWMgQXJlYSBVbml0

LCBHbGF4b1NtaXRoS2xpbmUsIFJlc2VhcmNoIFRyaWFuZ2xlIFBhcmssIE5DIChILkcuTy4sIEwu

RS5LLiwgUy5XLlkuKTsgSm9obnMgSG9wa2lucyBBc3RobWEgYW5kIEFsbGVyZ3kgQ2VudGVyLCBC

YWx0aW1vcmUgKE0uQy5MLik7IFJlc3BpcmF0b3J5IE1lZGljaW5lIFVuaXQsIE51ZmZpZWxkIERl

cGFydG1lbnQgb2YgTWVkaWNpbmUsIFVuaXZlcnNpdHkgb2YgT3hmb3JkLCBPeGZvcmQgKEkuRC5Q

LiksIGFuZCBDbGluaWNhbCBTdGF0aXN0aWNzLCBHbGF4b1NtaXRoS2xpbmUsIFN0b2NrbGV5IFBh

cmssIE1pZGRsZXNleCAoTy5OLksuKSAtIGJvdGggaW4gdGhlIFVuaXRlZCBLaW5nZG9tOyB0aGUg

RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgR2hlbnQsIEJlbGdpdW0gKEcuRy5CLik7IHRoZSBMdW5nIENlbnRyZSwgSW5zdGl0dXRl

IGZvciBIZWFydCBhbmQgTHVuZyBIZWFsdGgsIFZhbmNvdXZlciwgQkMsIENhbmFkYSAoSi5NLkYu

KTsgdGhlIERlcGFydG1lbnQgb2YgQ2xpbmljYWwgYW5kIEV4cGVyaW1lbnRhbCBNZWRpY2luZSwg

VW5pdmVyc2l0eSBvZiBQYXJtYSwgUGFybWEsIEl0YWx5IChBLkMuKTsgYW5kIEFzc2lzdGFuY2Ug

UHVibGlxdWUtSG9waXRhdXggZGUgUGFyaXMsIERlcGFydGVtZW50IEhvc3BpdGFsby1Vbml2ZXJz

aXRhaXJlIFRob3JheCBJbm5vdmF0aW9uLCBTZXJ2aWNlIGRlIFBuZXVtb2xvZ2llLCBIb3BpdGFs

IEJpY2V0cmUsIFVuaXZlcnNpdGUgUGFyaXMtU3VkLCBhbmQgSU5TRVJNIFVuaXRlIE1peHRlIGRl

IFJlY2hlcmNoZSA5OTksIExlIEtyZW1saW4tQmljZXRyZSAoTS5ILiksIGFuZCBVbml0ZXMgTWl4

dGVzIGRlIFJlY2hlcmNoZSBJTlNFUk0gVW5pdGUgMTA2NyBDZW50cmUgTmF0aW9uYWxlIGRlIGxh

IFJlY2hlcmNoZSBTY2llbnRpZmlxdWUgNzczMywgQWl4LU1hcnNlaWxsZSBVbml2ZXJzaXRlLCBE

ZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IERpc2Vhc2VzIGFuZCBDbGluaWNhbCBJbnZlc3RpZ2F0

aW9uIENlbnRlciwgQXNzaXN0YW5jZSBQdWJsaXF1ZS1Ib3BpdGF1eCBkZSBNYXJzZWlsbGUsIEhv

cGl0YWwgTm9yZCwgTWFyc2VpbGxlIChQLkMuKSAtIGJvdGggaW4gRnJhbmNlLjwvYXV0aC1hZGRy

ZXNzPjx0aXRsZXM+PHRpdGxlPk1lcG9saXp1bWFiIHRyZWF0bWVudCBpbiBwYXRpZW50cyB3aXRo

IHNldmVyZSBlb3Npbm9waGlsaWMgYXN0aG1hPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk4gRW5n

bCBKIE1lZDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+VGhlIE5ldyBFbmdsYW5kIGpvdXJu

YWwgb2YgbWVkaWNpbmU8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OIEVuZ2wgSiBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTk4LTIwNzwv

cGFnZXM+PHZvbHVtZT4zNzE8L3ZvbHVtZT48bnVtYmVyPjEzPC9udW1iZXI+PGVkaXRpb24+MjAx

NC8wOS8xMDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QWRtaW5pc3RyYXRpb24sIE9yYWw8

L2tleXdvcmQ+PGtleXdvcmQ+QWRvbGVzY2VudDwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5

d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQsIDgwIGFuZCBvdmVyPC9r

ZXl3b3JkPjxrZXl3b3JkPkFudGktQXN0aG1hdGljIEFnZW50cy8qYWRtaW5pc3RyYXRpb24gJmFt

cDsgZG9zYWdlL2FkdmVyc2UgZWZmZWN0czwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzLCBN

b25vY2xvbmFsLCBIdW1hbml6ZWQvKmFkbWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS9hZHZlcnNl

IGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hLypkcnVnIHRoZXJhcHkvaW1tdW5vbG9n

eS9waHlzaW9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2hpbGQ8L2tleXdvcmQ+PGtleXdv

cmQ+RG91YmxlLUJsaW5kIE1ldGhvZDwva2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHksIENv

bWJpbmF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPipFb3Npbm9waGlsaWE8L2tleXdvcmQ+PGtleXdv

cmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5

d29yZD48a2V5d29yZD5HbHVjb2NvcnRpY29pZHMvYWRtaW5pc3RyYXRpb24gJmFtcDsgZG9zYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBJ

bnRyYXZlbm91czwva2V5d29yZD48a2V5d29yZD5JbmplY3Rpb25zLCBTdWJjdXRhbmVvdXM8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29y

ZD48a2V5d29yZD5RdWFsaXR5IG9mIExpZmU8L2tleXdvcmQ+PGtleXdvcmQ+UXVlc3Rpb25uYWly

ZXM8L2tleXdvcmQ+PGtleXdvcmQ+U2Vjb25kYXJ5IFByZXZlbnRpb248L2tleXdvcmQ+PGtleXdv

cmQ+WW91bmcgQWR1bHQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVh

cj48cHViLWRhdGVzPjxkYXRlPlNlcCAyNTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2Ju

PjAwMjgtNDc5MzwvaXNibj48YWNjZXNzaW9uLW51bT4yNTE5OTA1OTwvYWNjZXNzaW9uLW51bT48

dXJscz48L3VybHM+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwNTYvTkVKTW9hMTQwMzI5

MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj5ObG08

L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFnZT48L3JlY29y

ZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [56].Lipid mediatorsMultiple lipid mediators derived from arachidonic acid, including prostaglandins and cys-LTs are released in asthma and COPD. Cys-LTs, particularly LTD4, released from mast cells are important bronchoconstrictors in asthma, but antagonism of cys-LT1-receptors is much less effective in bronchodilatation than β2-agonists, indicating that there are additional bronchoconstrictor mediators. PGD2 is predominantly released from mast cells and is a potent bronchoconstrictor, but is also chemotactic for Th2 cells, eosinophils and mast cells through binding to DP2-receptors (also called CRTh2) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXR0aXBoZXI8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy

PjxSZWNOdW0+MTAxMTg8L1JlY051bT48RGlzcGxheVRleHQ+WzkwXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDExODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTgwIj4xMDExODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+UGV0dGlwaGVyLFIuPC9hdXRob3I+PGF1dGhvcj5IYW5zZWwsVC5ULjwvYXV0aG9yPjxh

dXRob3I+QXJtZXIsUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+QW50YWdvbmlzbSBvZiB0aGUgcHJvc3RhZ2xhbmRpbiBEMiByZWNlcHRvcnMgRFAxIGFu

ZCBDUlRIMiBhcyBhbiBhcHByb2FjaCB0byB0cmVhdCBhbGxlcmdpYyBkaXNlYXNlczwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IERydWcgRGlzY292Ljwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdCBSZXYgRHJ1ZyBEaXNjb3YuPC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzEzLTMyNTwvcGFnZXM+PHZvbHVtZT42PC92b2x1

bWU+PG51bWJlcj40PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmlu

dC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+QUNU

SU9OUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVVRF

PC9rZXl3b3JkPjxrZXl3b3JkPkFMTEVSR0lDPC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVyZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QU5BTFlTSVM8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5BTlRBR09OSVNNPC9rZXl3b3JkPjxrZXl3b3JkPkFOVEFHT05JU1Q8L2tleXdv

cmQ+PGtleXdvcmQ+QU5UQUdPTklTVFM8L2tleXdvcmQ+PGtleXdvcmQ+YW50YWdvbmlzdHMgJmFt

cDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5BUFBST0FDSEVTPC9rZXl3b3JkPjxrZXl3

b3JkPkFTUEVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkNF

TEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5

d29yZD48a2V5d29yZD5ERVZFTE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPmRydWcgdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SFlQRVJTRU5TSVRJVklUWTwv

a2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5NQUlOVEVOQU5DRTwv

a2V5d29yZD48a2V5d29yZD5NQVNUPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1QgQ0VMTDwva2V5d29y

ZD48a2V5d29yZD5tYXN0IGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElBVElORzwva2V5d29y

ZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9naWNhbDwv

a2V5d29yZD48a2V5d29yZD5waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBST1NUQUdMQU5ESU48L2tleXdvcmQ+PGtleXdvcmQ+

cHJvc3RhZ2xhbmRpbiBhbnRhZ29uaXN0czwva2V5d29yZD48a2V5d29yZD5QUk9TVEFHTEFORElO

IEQyPC9rZXl3b3JkPjxrZXl3b3JkPnByb3N0YWdsYW5kaW4gRDIgcmVjZXB0b3I8L2tleXdvcmQ+

PGtleXdvcmQ+cHJvc3Rhbm9pZCBEIHJlY2VwdG9yIDEsaHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+

UkVDRU5UPC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9yczwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcnMsaW1tdW5vbG9naWM8L2tleXdvcmQ+PGtl

eXdvcmQ+UmVjZXB0b3JzLFByb3N0YWdsYW5kaW48L2tleXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9r

ZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8L2tleXdvcmQ+PGtl

eXdvcmQ+U0VMRUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdv

cmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRo

ZXJhcHk8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNzwveWVhcj48cHViLWRh

dGVzPjxkYXRlPjQvMjAwNzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5QRVRUSVBI

RVIyMDA3PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXR0aXBoZXI8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFy

PjxSZWNOdW0+MTAxMTg8L1JlY051bT48RGlzcGxheVRleHQ+WzkwXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDExODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTgwIj4xMDExODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+UGV0dGlwaGVyLFIuPC9hdXRob3I+PGF1dGhvcj5IYW5zZWwsVC5ULjwvYXV0aG9yPjxh

dXRob3I+QXJtZXIsUi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48

dGl0bGU+QW50YWdvbmlzbSBvZiB0aGUgcHJvc3RhZ2xhbmRpbiBEMiByZWNlcHRvcnMgRFAxIGFu

ZCBDUlRIMiBhcyBhbiBhcHByb2FjaCB0byB0cmVhdCBhbGxlcmdpYyBkaXNlYXNlczwvdGl0bGU+

PHNlY29uZGFyeS10aXRsZT5OYXQgUmV2IERydWcgRGlzY292Ljwvc2Vjb25kYXJ5LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPk5hdCBSZXYgRHJ1ZyBEaXNjb3YuPC9mdWxs

LXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzEzLTMyNTwvcGFnZXM+PHZvbHVtZT42PC92b2x1

bWU+PG51bWJlcj40PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmlu

dC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+QUNU

SU9OUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVVRF

PC9rZXl3b3JkPjxrZXl3b3JkPkFMTEVSR0lDPC9rZXl3b3JkPjxrZXl3b3JkPkFsbGVyZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+QU5BTFlTSVM8L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y

ZD48a2V5d29yZD5BTlRBR09OSVNNPC9rZXl3b3JkPjxrZXl3b3JkPkFOVEFHT05JU1Q8L2tleXdv

cmQ+PGtleXdvcmQ+QU5UQUdPTklTVFM8L2tleXdvcmQ+PGtleXdvcmQ+YW50YWdvbmlzdHMgJmFt

cDsgaW5oaWJpdG9yczwva2V5d29yZD48a2V5d29yZD5BUFBST0FDSEVTPC9rZXl3b3JkPjxrZXl3

b3JkPkFTUEVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkNF

TEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5

d29yZD48a2V5d29yZD5ERVZFTE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPmRydWcgdGhlcmFweTwva2V5

d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SFlQRVJTRU5TSVRJVklUWTwv

a2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5NQUlOVEVOQU5DRTwv

a2V5d29yZD48a2V5d29yZD5NQVNUPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1QgQ0VMTDwva2V5d29y

ZD48a2V5d29yZD5tYXN0IGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElBVElORzwva2V5d29y

ZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9naWNhbDwv

a2V5d29yZD48a2V5d29yZD5waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0

aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBST1NUQUdMQU5ESU48L2tleXdvcmQ+PGtleXdvcmQ+

cHJvc3RhZ2xhbmRpbiBhbnRhZ29uaXN0czwva2V5d29yZD48a2V5d29yZD5QUk9TVEFHTEFORElO

IEQyPC9rZXl3b3JkPjxrZXl3b3JkPnByb3N0YWdsYW5kaW4gRDIgcmVjZXB0b3I8L2tleXdvcmQ+

PGtleXdvcmQ+cHJvc3Rhbm9pZCBEIHJlY2VwdG9yIDEsaHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+

UkVDRU5UPC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9yczwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcnMsaW1tdW5vbG9naWM8L2tleXdvcmQ+PGtl

eXdvcmQ+UmVjZXB0b3JzLFByb3N0YWdsYW5kaW48L2tleXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9r

ZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8L2tleXdvcmQ+PGtl

eXdvcmQ+U0VMRUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdv

cmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRo

ZXJhcHk8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwNzwveWVhcj48cHViLWRh

dGVzPjxkYXRlPjQvMjAwNzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5QRVRUSVBI

RVIyMDA3PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [90]. Several DP2-receptor antagonists have been developed and reduce eosinophils in the airways, although their clinical benefit is so far uncertain ADDIN EN.CITE <EndNote><Cite><Author>Gonem</Author><Year>2016</Year><RecNum>12882</RecNum><DisplayText>[91]</DisplayText><record><rec-number>12882</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1472055286">12882</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gonem, S.</author><author>Berair, R.</author><author>Singapuri, A.</author><author>Hartley, R.</author><author>Laurencin, M. F.</author><author>Bacher, G.</author><author>Holzhauer, B.</author><author>Bourne, M.</author><author>Mistry, V.</author><author>Pavord, I. D.</author><author>Mansur, A. H.</author><author>Wardlaw, A. J.</author><author>Siddiqui, S. H.</author><author>Kay, R. A.</author><author>Brightling, C. E.</author></authors></contributors><auth-address>University of Leicester, Leicester, UK.&#xD;Novartis, Basel, Switzerland.&#xD;University of Oxford, Oxford, UK.&#xD;Birmingham Heartlands Hospital, Birmingham, UK.&#xD;University of Leicester, Leicester, UK. Electronic address: ceb17@le.ac.uk.</auth-address><titles><title>Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial</title><secondary-title>Lancet Respir Med</secondary-title><alt-title>The Lancet. Respiratory medicine</alt-title></titles><periodical><full-title>Lancet Respir Med</full-title><abbr-1>The lancet. Respiratory medicine</abbr-1></periodical><alt-periodical><full-title>Lancet Respir Med</full-title><abbr-1>The lancet. Respiratory medicine</abbr-1></alt-periodical><pages>699-707</pages><number>4</number><edition>2016/08/10</edition><dates><year>2016</year><pub-dates><date>Aug 5</date></pub-dates></dates><isbn>2213-2600</isbn><accession-num>27503237</accession-num><urls></urls><electronic-resource-num>10.1016/s2213-2600(16)30179-5</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[91].The profile of lipid mediators in COPD differs from asthma. In exhaled breath condensate there is a significant increase in PGE2, PGF2α and LTB4 but not in cys-LTs, whereas in asthma, thromboxane and cys-LTs predominate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb250dXNjaGk8L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFy

PjxSZWNOdW0+ODI5MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bOTJdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjgyOTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk0OSI+ODI5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+TW9udHVzY2hpLFAuPC9hdXRob3I+PGF1dGhvcj5LaGFyaXRvbm92LFMuQS48L2F1dGhvcj48

YXV0aG9yPkNpYWJhdHRvbmksRy48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkV4aGFsZWQgbGV1a290cmll

bmVzIGFuZCBwcm9zdGFnbGFuZGlucyBpbiBDT1BEPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlRo

b3JheDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRo

b3JheDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU4NS01ODg8L3BhZ2VzPjx2b2x1

bWU+NTg8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdv

cmQ+MTU8L2tleXdvcmQ+PGtleXdvcmQ+QUdFPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRS

T0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5DT1JUSUNPU1RFUk9J

RDwva2V5d29yZD48a2V5d29yZD5Db3J0aWNvc3Rlcm9pZHM8L2tleXdvcmQ+PGtleXdvcmQ+REVT

SUdOPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFT

RTwva2V5d29yZD48a2V5d29yZD5FSUNPU0FOT0lEPC9rZXl3b3JkPjxrZXl3b3JkPkVpY29zYW5v

aWRzPC9rZXl3b3JkPjxrZXl3b3JkPmV4aGFsZWQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBTFRIWTwv

a2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48

a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5IQUxFRDwva2V5d29yZD48a2V5

d29yZD5MRVVLT1RSSUVORTwva2V5d29yZD48a2V5d29yZD5MRVVLT1RSSUVORVM8L2tleXdvcmQ+

PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdv

cmQ+TUlMRDwva2V5d29yZD48a2V5d29yZD5NT0RFUkFURTwva2V5d29yZD48a2V5d29yZD5PQlNU

UlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QUk9T

VEFHTEFORElOPC9rZXl3b3JkPjxrZXl3b3JkPlByb3N0YWdsYW5kaW5zPC9rZXl3b3JkPjxrZXl3

b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNF

Q1JFVElPTjwva2V5d29yZD48a2V5d29yZD5TRUNSRVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPlNF

TEVDVElWRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJM

RTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tl

eXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+

PGtleXdvcmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtl

eXdvcmQ+VGhyb21ib3hhbmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjcvMjAwMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD5NT05UVVNDSEkyMDAzQjwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb250dXNjaGk8L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFy

PjxSZWNOdW0+ODI5MjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bOTJdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjgyOTI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk0OSI+ODI5Mjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+TW9udHVzY2hpLFAuPC9hdXRob3I+PGF1dGhvcj5LaGFyaXRvbm92LFMuQS48L2F1dGhvcj48

YXV0aG9yPkNpYWJhdHRvbmksRy48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkV4aGFsZWQgbGV1a290cmll

bmVzIGFuZCBwcm9zdGFnbGFuZGlucyBpbiBDT1BEPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlRo

b3JheDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRo

b3JheDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU4NS01ODg8L3BhZ2VzPjx2b2x1

bWU+NTg8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdvcmQ+PGtleXdv

cmQ+MTU8L2tleXdvcmQ+PGtleXdvcmQ+QUdFPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRS

T0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5DT1JUSUNPU1RFUk9J

RDwva2V5d29yZD48a2V5d29yZD5Db3J0aWNvc3Rlcm9pZHM8L2tleXdvcmQ+PGtleXdvcmQ+REVT

SUdOPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFT

RTwva2V5d29yZD48a2V5d29yZD5FSUNPU0FOT0lEPC9rZXl3b3JkPjxrZXl3b3JkPkVpY29zYW5v

aWRzPC9rZXl3b3JkPjxrZXl3b3JkPmV4aGFsZWQ8L2tleXdvcmQ+PGtleXdvcmQ+SEVBTFRIWTwv

a2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48

a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5IQUxFRDwva2V5d29yZD48a2V5

d29yZD5MRVVLT1RSSUVORTwva2V5d29yZD48a2V5d29yZD5MRVVLT1RSSUVORVM8L2tleXdvcmQ+

PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdv

cmQ+TUlMRDwva2V5d29yZD48a2V5d29yZD5NT0RFUkFURTwva2V5d29yZD48a2V5d29yZD5PQlNU

UlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QUk9T

VEFHTEFORElOPC9rZXl3b3JkPjxrZXl3b3JkPlByb3N0YWdsYW5kaW5zPC9rZXl3b3JkPjxrZXl3

b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNF

Q1JFVElPTjwva2V5d29yZD48a2V5d29yZD5TRUNSRVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPlNF

TEVDVElWRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJM

RTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tl

eXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+

PGtleXdvcmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtl

eXdvcmQ+VGhyb21ib3hhbmU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwMzwv

eWVhcj48cHViLWRhdGVzPjxkYXRlPjcvMjAwMzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD5NT05UVVNDSEkyMDAzQjwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48

L0VuZE5vdGU+

ADDIN EN.CITE.DATA [92]. LTB4 concentrations are increased in induced sputum of COPD patients and further increased in sputum and exhaled breath condensate during acute exacerbations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWVoPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjgyMzg8L1JlY051bT48RGlzcGxheVRleHQ+WzkzLCA5NF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+ODIzODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQ5Ij44MjM4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CZWVoLEsuTS48L2F1dGhvcj48YXV0aG9yPktvcm5tYW5uLE8uPC9hdXRob3I+PGF1dGhvcj5C

dWhsLFIuPC9hdXRob3I+PGF1dGhvcj5DdWxwaXR0LFMuVi48L2F1dGhvcj48YXV0aG9yPkdpZW1i

eWN6LE0uQS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPk5ldXRyb3BoaWwgY2hlbW90YWN0aWMgYWN0aXZp

dHkgb2Ygc3B1dHVtIGZyb20gcGF0aWVudHMgd2l0aCBDT1BEOiByb2xlIG9mIGludGVybGV1a2lu

IDggYW5kIGxldWtvdHJpZW5lIEI0PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNoZXN0PC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3Q8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjQwLTEyNDc8L3BhZ2VzPjx2b2x1bWU+MTIzPC92

b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVw

cmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4yMjU3MDc2Nzwva2V5d29yZD48a2V5d29y

ZD5BQ1RJVklUSUVTPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWSVRZPC9rZXl3b3JkPjxrZXl3b3Jk

PkFOVEFHT05JU1Q8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUJPRElFUzwva2V5d29yZD48a2V5d29y

ZD5BTlRJQk9EWTwva2V5d29yZD48a2V5d29yZD5BU1NBWTwva2V5d29yZD48a2V5d29yZD5icm9u

Y2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5

d29yZD48a2V5d29yZD5DSEVNT1RBQ1RJQzwva2V5d29yZD48a2V5d29yZD5DaGVtb3RheGlzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+REVTSUdOPC9rZXl3b3JkPjxr

ZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+

RkFDVE9SUzwva2V5d29yZD48a2V5d29yZD5JTC04PC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPklOSElCSVRPUjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1JTPC9r

ZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybGV1a2lu

IDg8L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJMRVVLSU4tODwva2V5d29yZD48a2V5d29yZD5MRVVL

T1RSSUVORTwva2V5d29yZD48a2V5d29yZD5MdW1pbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+

TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+TUVBU1VSRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+bmV1

dHJvcGhpbDwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5Q

QVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tleXdvcmQ+PGtleXdvcmQ+UFJF

VFJFQVRNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlFVQU5USUZJQ0FUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3Jk

PlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0IgMjAxMTQ2PC9rZXl3b3JkPjxrZXl3b3JkPlNFQ1JF

VElPTjwva2V5d29yZD48a2V5d29yZD5TRUNSRVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPlNFTEVD

VElWRTwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5d29yZD5TUFVUVU08

L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29y

ZD48a2V5d29yZD5TVVBQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

NC8yMDAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkJFRUgyMDAzPC9sYWJlbD48

dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Qmllcm5hY2tpPC9BdXRo

b3I+PFllYXI+MjAwMzwvWWVhcj48UmVjTnVtPjgyMzI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjgyMzI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0

cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3ODk0

OSI+ODIzMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Qmllcm5hY2tp

LFcuQS48L2F1dGhvcj48YXV0aG9yPktoYXJpdG9ub3YsUy5BLjwvYXV0aG9yPjxhdXRob3I+QmFy

bmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

SW5jcmVhc2VkIGxldWtvdHJpZW5lIEI0IGFuZCA4LWlzb3Byb3N0YW5lIGluIGV4aGFsZWQgYnJl

YXRoIGNvbmRlbnNhdGUgb2YgcGF0aWVudHMgd2l0aCBleGFjZXJiYXRpb25zIG9mIENPUEQ8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+VGhvcmF4PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+VGhvcmF4PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+Mjk0LTI5ODwvcGFnZXM+PHZvbHVtZT41ODwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxy

ZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+MTE8L2tleXdvcmQ+PGtleXdvcmQ+MTI8L2tleXdvcmQ+PGtleXdvcmQ+Mjwva2V5d29y

ZD48a2V5d29yZD4yMjU1NTY2Mjwva2V5d29yZD48a2V5d29yZD5BR0U8L2tleXdvcmQ+PGtleXdv

cmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCSU9USUNTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkNPTkNFTlRSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTjwva2V5d29yZD48a2V5

d29yZD5FWEFDRVJCQVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPmV4aGFsZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+ZmFsbDwva2V5d29yZD48a2V5d29yZD5IRUFMVEg8L2tleXdvcmQ+PGtleXdvcmQ+aGVh

bHRoIGNhcmUgY29zdHM8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5D

UkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5M

QVJHRTwva2V5d29yZD48a2V5d29yZD5MRVVLT1RSSUVORTwva2V5d29yZD48a2V5d29yZD5sZXVr

b3RyaWVuZSBCNDwva2V5d29yZD48a2V5d29yZD5MVEI0PC9rZXl3b3JkPjxrZXl3b3JkPk1FVEhP

RDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3Jk

PjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwva2V5

d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+c3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxr

ZXl3b3JkPlRSRUFUTUVOVDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAzPC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+NC8yMDAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxh

YmVsPkJJRVJOQUNLSTIwMDM8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWVoPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjgyMzg8L1JlY051bT48RGlzcGxheVRleHQ+WzkzLCA5NF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+ODIzODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQ5Ij44MjM4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5CZWVoLEsuTS48L2F1dGhvcj48YXV0aG9yPktvcm5tYW5uLE8uPC9hdXRob3I+PGF1dGhvcj5C

dWhsLFIuPC9hdXRob3I+PGF1dGhvcj5DdWxwaXR0LFMuVi48L2F1dGhvcj48YXV0aG9yPkdpZW1i

eWN6LE0uQS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwv

Y29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPk5ldXRyb3BoaWwgY2hlbW90YWN0aWMgYWN0aXZp

dHkgb2Ygc3B1dHVtIGZyb20gcGF0aWVudHMgd2l0aCBDT1BEOiByb2xlIG9mIGludGVybGV1a2lu

IDggYW5kIGxldWtvdHJpZW5lIEI0PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNoZXN0PC9zZWNv

bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3Q8L2Z1bGwt

dGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMjQwLTEyNDc8L3BhZ2VzPjx2b2x1bWU+MTIzPC92

b2x1bWU+PG51bWJlcj40PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVw

cmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4yMjU3MDc2Nzwva2V5d29yZD48a2V5d29y

ZD5BQ1RJVklUSUVTPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWSVRZPC9rZXl3b3JkPjxrZXl3b3Jk

PkFOVEFHT05JU1Q8L2tleXdvcmQ+PGtleXdvcmQ+QU5USUJPRElFUzwva2V5d29yZD48a2V5d29y

ZD5BTlRJQk9EWTwva2V5d29yZD48a2V5d29yZD5BU1NBWTwva2V5d29yZD48a2V5d29yZD5icm9u

Y2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5

d29yZD48a2V5d29yZD5DSEVNT1RBQ1RJQzwva2V5d29yZD48a2V5d29yZD5DaGVtb3RheGlzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+REVTSUdOPC9rZXl3b3JkPjxr

ZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+

RkFDVE9SUzwva2V5d29yZD48a2V5d29yZD5JTC04PC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPklOSElCSVRPUjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1JTPC9r

ZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3JkPkludGVybGV1a2lu

IDg8L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJMRVVLSU4tODwva2V5d29yZD48a2V5d29yZD5MRVVL

T1RSSUVORTwva2V5d29yZD48a2V5d29yZD5MdW1pbmVzY2VuY2U8L2tleXdvcmQ+PGtleXdvcmQ+

TUFKT1I8L2tleXdvcmQ+PGtleXdvcmQ+TUVBU1VSRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+bmV1

dHJvcGhpbDwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5Q

QVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QT1RFTlRJQUw8L2tleXdvcmQ+PGtleXdvcmQ+UFJF

VFJFQVRNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlFVQU5USUZJQ0FUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3Jk

PlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0IgMjAxMTQ2PC9rZXl3b3JkPjxrZXl3b3JkPlNFQ1JF

VElPTjwva2V5d29yZD48a2V5d29yZD5TRUNSRVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPlNFTEVD

VElWRTwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5d29yZD5TUFVUVU08

L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29y

ZD48a2V5d29yZD5TVVBQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

NC8yMDAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkJFRUgyMDAzPC9sYWJlbD48

dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+Qmllcm5hY2tpPC9BdXRo

b3I+PFllYXI+MjAwMzwvWWVhcj48UmVjTnVtPjgyMzI8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjgyMzI8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0

cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3ODk0

OSI+ODIzMjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+Qmllcm5hY2tp

LFcuQS48L2F1dGhvcj48YXV0aG9yPktoYXJpdG9ub3YsUy5BLjwvYXV0aG9yPjxhdXRob3I+QmFy

bmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+

SW5jcmVhc2VkIGxldWtvdHJpZW5lIEI0IGFuZCA4LWlzb3Byb3N0YW5lIGluIGV4aGFsZWQgYnJl

YXRoIGNvbmRlbnNhdGUgb2YgcGF0aWVudHMgd2l0aCBleGFjZXJiYXRpb25zIG9mIENPUEQ8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+VGhvcmF4PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+VGhvcmF4PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+Mjk0LTI5ODwvcGFnZXM+PHZvbHVtZT41ODwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVyPjxy

ZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtl

eXdvcmQ+MTE8L2tleXdvcmQ+PGtleXdvcmQ+MTI8L2tleXdvcmQ+PGtleXdvcmQ+Mjwva2V5d29y

ZD48a2V5d29yZD4yMjU1NTY2Mjwva2V5d29yZD48a2V5d29yZD5BR0U8L2tleXdvcmQ+PGtleXdv

cmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFOVElCSU9USUNTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxr

ZXl3b3JkPkNPTkNFTlRSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTjwva2V5d29yZD48a2V5

d29yZD5FWEFDRVJCQVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPmV4aGFsZWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+ZmFsbDwva2V5d29yZD48a2V5d29yZD5IRUFMVEg8L2tleXdvcmQ+PGtleXdvcmQ+aGVh

bHRoIGNhcmUgY29zdHM8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5D

UkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5M

QVJHRTwva2V5d29yZD48a2V5d29yZD5MRVVLT1RSSUVORTwva2V5d29yZD48a2V5d29yZD5sZXVr

b3RyaWVuZSBCNDwva2V5d29yZD48a2V5d29yZD5MVEI0PC9rZXl3b3JkPjxrZXl3b3JkPk1FVEhP

RDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3Jk

PjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48

a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwva2V5

d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+c3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxr

ZXl3b3JkPlRSRUFUTUVOVDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAzPC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+NC8yMDAzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxh

YmVsPkJJRVJOQUNLSTIwMDM8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE.DATA [93, 94]. LTB4 is a potent chemoattractant of neutrophils via high affinity BLT1-receptors. A BLT1-receptor antagonist reduces the neutrophil chemotactic activity of sputum by approximately 25% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWVoPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjgyMzg8L1JlY051bT48RGlzcGxheVRleHQ+WzkzXTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj44MjM4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NDkiPjgyMzg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJl

ZWgsSy5NLjwvYXV0aG9yPjxhdXRob3I+S29ybm1hbm4sTy48L2F1dGhvcj48YXV0aG9yPkJ1aGws

Ui48L2F1dGhvcj48YXV0aG9yPkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRob3I+R2llbWJ5Y3os

TS5BLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmV1dHJvcGhpbCBjaGVtb3RhY3RpYyBhY3Rpdml0eSBv

ZiBzcHV0dW0gZnJvbSBwYXRpZW50cyB3aXRoIENPUEQ6IHJvbGUgb2YgaW50ZXJsZXVraW4gOCBh

bmQgbGV1a290cmllbmUgQjQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2hlc3Q8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEyNDAtMTI0NzwvcGFnZXM+PHZvbHVtZT4xMjM8L3ZvbHVt

ZT48bnVtYmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50

LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjIyNTcwNzY3PC9rZXl3b3JkPjxrZXl3b3JkPkFD

VElWSVRJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJVFk8L2tleXdvcmQ+PGtleXdvcmQ+QU5U

QUdPTklTVDwva2V5d29yZD48a2V5d29yZD5BTlRJQk9ESUVTPC9rZXl3b3JkPjxrZXl3b3JkPkFO

VElCT0RZPC9rZXl3b3JkPjxrZXl3b3JkPkFTU0FZPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlh

bDwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3Jk

PjxrZXl3b3JkPkNIRU1PVEFDVElDPC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1vdGF4aXM8L2tleXdv

cmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ERVNJR048L2tleXdvcmQ+PGtleXdv

cmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNU

T1JTPC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+

PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklOSElCSVRJT048L2tleXdv

cmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3JkPklOSElCSVRPUlM8L2tleXdv

cmQ+PGtleXdvcmQ+SU5URVJMRVVLSU48L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVraW4gODwv

a2V5d29yZD48a2V5d29yZD5JTlRFUkxFVUtJTi04PC9rZXl3b3JkPjxrZXl3b3JkPkxFVUtPVFJJ

RU5FPC9rZXl3b3JkPjxrZXl3b3JkPkx1bWluZXNjZW5jZTwva2V5d29yZD48a2V5d29yZD5NQUpP

Ujwva2V5d29yZD48a2V5d29yZD5NRUFTVVJFTUVOVDwva2V5d29yZD48a2V5d29yZD5uZXV0cm9w

aGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElF

TlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUkVUUkVB

VE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+UVVBTlRJRklDQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

cmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+Uk9M

RTwva2V5d29yZD48a2V5d29yZD5TQiAyMDExNDY8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPlNFQ1JFVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+U0VMRUNUSVZF

PC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5

d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxr

ZXl3b3JkPlNVUFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT40LzIw

MDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+QkVFSDIwMDM8L2xhYmVsPjx1cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWVoPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48UmVj

TnVtPjgyMzg8L1JlY051bT48RGlzcGxheVRleHQ+WzkzXTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj44MjM4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBk

Yi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjEz

Nzg0Nzg5NDkiPjgyMzg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5h

bCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkJl

ZWgsSy5NLjwvYXV0aG9yPjxhdXRob3I+S29ybm1hbm4sTy48L2F1dGhvcj48YXV0aG9yPkJ1aGws

Ui48L2F1dGhvcj48YXV0aG9yPkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRob3I+R2llbWJ5Y3os

TS5BLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250

cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmV1dHJvcGhpbCBjaGVtb3RhY3RpYyBhY3Rpdml0eSBv

ZiBzcHV0dW0gZnJvbSBwYXRpZW50cyB3aXRoIENPUEQ6IHJvbGUgb2YgaW50ZXJsZXVraW4gOCBh

bmQgbGV1a290cmllbmUgQjQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+Q2hlc3Q8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DaGVzdDwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjEyNDAtMTI0NzwvcGFnZXM+PHZvbHVtZT4xMjM8L3ZvbHVt

ZT48bnVtYmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50

LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjIyNTcwNzY3PC9rZXl3b3JkPjxrZXl3b3JkPkFD

VElWSVRJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJVFk8L2tleXdvcmQ+PGtleXdvcmQ+QU5U

QUdPTklTVDwva2V5d29yZD48a2V5d29yZD5BTlRJQk9ESUVTPC9rZXl3b3JkPjxrZXl3b3JkPkFO

VElCT0RZPC9rZXl3b3JkPjxrZXl3b3JkPkFTU0FZPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlh

bDwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3Jk

PjxrZXl3b3JkPkNIRU1PVEFDVElDPC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1vdGF4aXM8L2tleXdv

cmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ERVNJR048L2tleXdvcmQ+PGtleXdv

cmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNU

T1JTPC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+

PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklOSElCSVRJT048L2tleXdv

cmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3JkPklOSElCSVRPUlM8L2tleXdv

cmQ+PGtleXdvcmQ+SU5URVJMRVVLSU48L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJsZXVraW4gODwv

a2V5d29yZD48a2V5d29yZD5JTlRFUkxFVUtJTi04PC9rZXl3b3JkPjxrZXl3b3JkPkxFVUtPVFJJ

RU5FPC9rZXl3b3JkPjxrZXl3b3JkPkx1bWluZXNjZW5jZTwva2V5d29yZD48a2V5d29yZD5NQUpP

Ujwva2V5d29yZD48a2V5d29yZD5NRUFTVVJFTUVOVDwva2V5d29yZD48a2V5d29yZD5uZXV0cm9w

aGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5ldXRyb3BoaWxzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElF

TlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUkVUUkVB

VE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+UVVBTlRJRklDQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+

cmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+Uk9M

RTwva2V5d29yZD48a2V5d29yZD5TQiAyMDExNDY8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPlNFQ1JFVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+U0VMRUNUSVZF

PC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5

d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxr

ZXl3b3JkPlNVUFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3Jk

Pjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT40LzIw

MDM8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+QkVFSDIwMDM8L2xhYmVsPjx1cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [93]. BLT1-receptors have also been identified on T-lymphocytes and there is evidence that LTB4 is also involved in recruitment of T cells.CytokinesMultiple cytokines orchestrate chronic inflammation in asthma and COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

ZWNOdW0+MTAyMjA8L1JlY051bT48RGlzcGxheVRleHQ+Wzk1LCA5Nl08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAyMjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTM3ODQ3ODk4MiI+MTAyMjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPkN5dG9raW5lIG5ldHdvcmtzIGluIGFzdGhtYSBhbmQgY2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIENsaW4gSW52

ZXN0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBD

bGluIEludmVzdDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM1NDYtMzU1NjwvcGFn

ZXM+PHZvbHVtZT4xMTg8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkNZVE9LSU5FPC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hy

b25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5PQlNU

UlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+RElT

RUFTRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+MjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CQVJORVMyMDA4

QTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJhcm5l

czwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJlY051bT4xMDg2NDwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTA4NjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk5MiI+MTA4NjQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlRoZSBjeXRva2luZSBuZXR3b3JrIGluIENPUEQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QW0gSiBSZXNwaXIgQ2VsbCBNb2wgQmlvbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDZWxsIE1vbCBCaW9sLjwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjYzMS02Mzg8L3BhZ2VzPjx2b2x1bWU+NDE8L3ZvbHVtZT48

cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3

b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QU5USS1JTkZMQU1NQVRPUlk8L2tleXdvcmQ+

PGtleXdvcmQ+QVBQUk9BQ0hFUzwva2V5d29yZD48a2V5d29yZD5CTE9DS0lORzwva2V5d29yZD48

a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNI

QU5HRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hBUkFDVEVSSVNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+

Y2hlbW9raW5lczwva2V5d29yZD48a2V5d29yZD5DSVJDVUxBVElPTjwva2V5d29yZD48a2V5d29y

ZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9L

SU5FPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNF

PC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5

d29yZD48a2V5d29yZD5GQUNUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPkdST1dUSDwva2V5d29yZD48

a2V5d29yZD5Hcm93dGggZmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3

b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+

PGtleXdvcmQ+TGVhZDwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxV

TkdTPC9rZXl3b3JkPjxrZXl3b3JkPkxZTVBIT0tJTkU8L2tleXdvcmQ+PGtleXdvcmQ+TFlNUEhP

S0lORVM8L2tleXdvcmQ+PGtleXdvcmQ+TVVMVElQTEU8L2tleXdvcmQ+PGtleXdvcmQ+TkVUV09S

Szwva2V5d29yZD48a2V5d29yZD5QUk9JTkZMQU1NQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwv

a2V5d29yZD48a2V5d29yZD5TVFJVQ1RVUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5

d29yZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3JkPjxrZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48

a2V5d29yZD5UQVJHRVQ8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQRVVUSUM8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjgvMjAw

OTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CQVJORVMyMDA5RjwvbGFiZWw+PHVy

bHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

ZWNOdW0+MTAyMjA8L1JlY051bT48RGlzcGxheVRleHQ+Wzk1LCA5Nl08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTAyMjA8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTM3ODQ3ODk4MiI+MTAyMjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPkN5dG9raW5lIG5ldHdvcmtzIGluIGFzdGhtYSBhbmQgY2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIENsaW4gSW52

ZXN0PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBD

bGluIEludmVzdDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjM1NDYtMzU1NjwvcGFn

ZXM+PHZvbHVtZT4xMTg8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkNZVE9LSU5FPC9rZXl3b3JkPjxrZXl3b3Jk

PklOPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9r

ZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hy

b25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5PQlNU

UlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+RElT

RUFTRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA4PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+MjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CQVJORVMyMDA4

QTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkJhcm5l

czwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJlY051bT4xMDg2NDwvUmVjTnVtPjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTA4NjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk5MiI+MTA4NjQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRp

dGxlPlRoZSBjeXRva2luZSBuZXR3b3JrIGluIENPUEQ8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+

QW0gSiBSZXNwaXIgQ2VsbCBNb2wgQmlvbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDZWxsIE1vbCBCaW9sLjwvZnVsbC10aXRs

ZT48L3BlcmlvZGljYWw+PHBhZ2VzPjYzMS02Mzg8L3BhZ2VzPjx2b2x1bWU+NDE8L3ZvbHVtZT48

cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3

b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QU5USS1JTkZMQU1NQVRPUlk8L2tleXdvcmQ+

PGtleXdvcmQ+QVBQUk9BQ0hFUzwva2V5d29yZD48a2V5d29yZD5CTE9DS0lORzwva2V5d29yZD48

a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNI

QU5HRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hBUkFDVEVSSVNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+

Y2hlbW9raW5lczwva2V5d29yZD48a2V5d29yZD5DSVJDVUxBVElPTjwva2V5d29yZD48a2V5d29y

ZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9L

SU5FPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNF

PC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5

d29yZD48a2V5d29yZD5GQUNUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPkdST1dUSDwva2V5d29yZD48

a2V5d29yZD5Hcm93dGggZmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3

b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+

PGtleXdvcmQ+TGVhZDwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxV

TkdTPC9rZXl3b3JkPjxrZXl3b3JkPkxZTVBIT0tJTkU8L2tleXdvcmQ+PGtleXdvcmQ+TFlNUEhP

S0lORVM8L2tleXdvcmQ+PGtleXdvcmQ+TVVMVElQTEU8L2tleXdvcmQ+PGtleXdvcmQ+TkVUV09S

Szwva2V5d29yZD48a2V5d29yZD5QUk9JTkZMQU1NQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwv

a2V5d29yZD48a2V5d29yZD5TVFJVQ1RVUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5

d29yZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3JkPjxrZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48

a2V5d29yZD5UQVJHRVQ8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQRVVUSUM8L2tleXdvcmQ+PC9r

ZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjgvMjgvMjAw

OTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CQVJORVMyMDA5RjwvbGFiZWw+PHVy

bHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [95, 96]. T2 cytokines (IL-4, IL-5, IL-9, IL-13) mediate allergic inflammation, whereas proinflammatory cytokines such as TNF-α and IL-1β, amplify the inflammatory response and play a role in more severe disease. Blocking antibodies against IL-5 and IL-13 and their receptors have clinical benefits in selected patients ADDIN EN.CITE <EndNote><Cite><Author>Parulekar</Author><Year>2017</Year><RecNum>12935</RecNum><DisplayText>[97]</DisplayText><record><rec-number>12935</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482505497">12935</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parulekar, A. D.</author><author>Diamant, Z.</author><author>Hanania, N. A.</author></authors></contributors><auth-address>aSection of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, Texas, USA bDepartment of Respiratory Medicine and Allergology, Skane University Hospital, Lund, Sweden cDepartment of Clinical Pharmacy &amp; Pharmacology, Department of General Practice &amp; QPS-NL, Groningen, the Netherlands.</auth-address><titles><title>Role of biologics targeting type 2 airway inflammation in asthma: what have we learned so far?</title><secondary-title>Curr Opin Pulm Med</secondary-title><alt-title>Current opinion in pulmonary medicine</alt-title></titles><periodical><full-title>Curr Opin Pulm Med</full-title></periodical><pages>3-11</pages><volume>23</volume><number>1</number><edition>2016/11/08</edition><dates><year>2017</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1070-5287</isbn><accession-num>27820746</accession-num><urls></urls><electronic-resource-num>10.1097/mcp.0000000000000343</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[97]. TSLP is an upstream cytokine released from epithelial cells of asthmatics that orchestrates the release of chemokines that selectively attract T2 cells ADDIN EN.CITE <EndNote><Cite><Author>Mitchell</Author><Year>2016</Year><RecNum>12902</RecNum><DisplayText>[98]</DisplayText><record><rec-number>12902</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1476119625">12902</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitchell, P. D.</author><author>O&apos;Byrne, P. M.</author></authors></contributors><auth-address>Firestone Institute of Respiratory Health, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.&#xD;Firestone Institute of Respiratory Health, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, Michael G DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: obyrnep@mcmaster.ca.</auth-address><titles><title>Biologics and the lung: TSLP and other epithelial cell-derived cytokines in asthma</title><secondary-title>Pharmacol Ther</secondary-title><alt-title>Pharmacology &amp; therapeutics</alt-title></titles><periodical><full-title>Pharmacol Ther</full-title></periodical><alt-periodical><full-title>Pharmacology &amp; Therapeutics</full-title></alt-periodical><edition>2016/07/02</edition><keywords><keyword>Alarmins</keyword><keyword>Asthma</keyword><keyword>Epithelial cell-derived cytokines</keyword><keyword>Il-25</keyword><keyword>Il-33</keyword><keyword>Tslp</keyword></keywords><dates><year>2016</year><pub-dates><date>Jun 27</date></pub-dates></dates><isbn>0163-7258</isbn><accession-num>27365223</accession-num><urls></urls><electronic-resource-num>10.1016/j.pharmthera.2016.06.009</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[98]. Th17 cells release IL-17A/F and IL-22 which are increased in severe asthma and may orchestrate neutrophilic inflammation ADDIN EN.CITE <EndNote><Cite><Author>Halwani</Author><Year>2013</Year><RecNum>12439</RecNum><DisplayText>[69]</DisplayText><record><rec-number>12439</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1446738087">12439</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Halwani, R.</author><author>Al-Muhsen, S.</author><author>Hamid, Q.</author></authors></contributors><auth-address>Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia.</auth-address><titles><title>T helper 17 cells in airway diseases: from laboratory bench to bedside</title><secondary-title>Chest</secondary-title><alt-title>Chest</alt-title></titles><periodical><full-title>Chest</full-title></periodical><alt-periodical><full-title>Chest</full-title></alt-periodical><pages>494-501</pages><volume>143</volume><number>2</number><edition>2013/02/06</edition><keywords><keyword>Asthma/physiopathology</keyword><keyword>Humans</keyword><keyword>Interleukin-17/physiology</keyword><keyword>Lung Diseases/*physiopathology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/physiopathology</keyword><keyword>Th17 Cells/*physiology</keyword><keyword>*Translational Medical Research</keyword></keywords><dates><year>2013</year><pub-dates><date>Feb 1</date></pub-dates></dates><isbn>0012-3692</isbn><accession-num>23381314</accession-num><urls></urls><electronic-resource-num>10.1378/chest.12-0598</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[69]. Some cytokines, such as IL-10 and IL-12, are anti-inflammatory and may be deficient in asthma.There is an increase in concentration of TNF-α in induced sputum in stable COPD, with a further increase during exacerbations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl

Y051bT43NjM5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls5OV08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+NzYzOTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTM5Ij43NjM5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5B

YXJvbixTLkQuPC9hdXRob3I+PGF1dGhvcj5BbmdlbCxKLkIuPC9hdXRob3I+PGF1dGhvcj5MdW5h

dSxNLjwvYXV0aG9yPjxhdXRob3I+V3JpZ2h0LEsuPC9hdXRob3I+PGF1dGhvcj5GZXgsQy48L2F1

dGhvcj48YXV0aG9yPkxlIFNhdXgsTi48L2F1dGhvcj48YXV0aG9yPkRhbGVzLFIuRS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+R3JhbnVsb2N5dGUgaW5m

bGFtbWF0b3J5IG1hcmtlcnMgYW5kIGFpcndheSBpbmZlY3Rpb24gZHVyaW5nIGFjdXRlIGV4YWNl

cmJhdGlvbiBvZiBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUg

TWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzQ5LTM1NTwvcGFnZXM+PHZvbHVt

ZT4xNjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjE8L2tleXdvcmQ+PGtleXdv

cmQ+Mjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVVRF

PC9rZXl3b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdv

cmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48a2V5d29yZD5BU1NBWTwva2V5d29yZD48a2V5

d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5DSEFJTjwva2V5d29y

ZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tl

eXdvcmQ+PGtleXdvcmQ+Q1VMVFVSRTwva2V5d29yZD48a2V5d29yZD5DVUxUVVJFUzwva2V5d29y

ZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORVM8L2tleXdvcmQ+

PGtleXdvcmQ+REVDTElORTwva2V5d29yZD48a2V5d29yZD5ERVRFQ1RJT048L2tleXdvcmQ+PGtl

eXdvcmQ+RElBR05PU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdv

cmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkVYQUNFUkJBVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HUkFOVUxPQ1lURTwva2V5d29yZD48a2V5d29y

ZD5HUkFOVUxPQ1lURVM8L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+

SUwtODwva2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9r

ZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPklORFVDRUQ8L2tleXdv

cmQ+PGtleXdvcmQ+SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklORkVDVElPTlM8L2tleXdv

cmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbiBN

ZWRpYXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3b3Jk

PkludGVybGV1a2luIDg8L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJMRVVLSU4tODwva2V5d29yZD48

a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXMsb2JzdHJ1Y3RpdmU8

L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5NRURJQVRPUjwva2V5d29y

ZD48a2V5d29yZD5tZWRpYXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+TUVUQUJPTElTTTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlPC9rZXl3b3JkPjxrZXl3b3JkPk15ZWxvcGVyb3hpZGFzZTwv

a2V5d29yZD48a2V5d29yZD5ORUNST1NJUzwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwv

a2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwv

a2V5d29yZD48a2V5d29yZD5QQ1I8L2tleXdvcmQ+PGtleXdvcmQ+UEVST1hJREFTRTwva2V5d29y

ZD48a2V5d29yZD5QT0xZTUVSQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltZXJhc2UgQ2hhaW4g

UmVhY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlFV

QU5USVRBVElWRTwva2V5d29yZD48a2V5d29yZD5SRUFDVElPTjwva2V5d29yZD48a2V5d29yZD5S

RVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFDVDwva2V5d29yZD48

a2V5d29yZD5yZXNwaXJhdG9yeSB0cmFjdCBpbmZlY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlJF

U1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlNFUlVNPC9rZXl3b3JkPjxrZXl3b3JkPlNPTFVCTEU8

L2tleXdvcmQ+PGtleXdvcmQ+U1BVVFVNPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29y

ZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3

b3JkPnN1cHBvcnQsbm9uLXUucy5nb3YmYXBvczt0PC9rZXl3b3JkPjxrZXl3b3JkPlRSQUNUPC9r

ZXl3b3JkPjxrZXl3b3JkPlRVTU9SPC9rZXl3b3JkPjxrZXl3b3JkPlRVTU9SIE5FQ1JPU0lTIEZB

Q1RPUjwva2V5d29yZD48a2V5d29yZD5VTklURUQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEIFNU

QVRFUzwva2V5d29yZD48a2V5d29yZD5WSVJBTDwva2V5d29yZD48a2V5d29yZD52aXJ1cyBkaXNl

YXNlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAxPC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+Mi8yMDAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkFBUk9OMjAw

MTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl

Y051bT43NjM5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls5OV08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+NzYzOTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTM5Ij43NjM5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5B

YXJvbixTLkQuPC9hdXRob3I+PGF1dGhvcj5BbmdlbCxKLkIuPC9hdXRob3I+PGF1dGhvcj5MdW5h

dSxNLjwvYXV0aG9yPjxhdXRob3I+V3JpZ2h0LEsuPC9hdXRob3I+PGF1dGhvcj5GZXgsQy48L2F1

dGhvcj48YXV0aG9yPkxlIFNhdXgsTi48L2F1dGhvcj48YXV0aG9yPkRhbGVzLFIuRS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+R3JhbnVsb2N5dGUgaW5m

bGFtbWF0b3J5IG1hcmtlcnMgYW5kIGFpcndheSBpbmZlY3Rpb24gZHVyaW5nIGFjdXRlIGV4YWNl

cmJhdGlvbiBvZiBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUg

TWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MzQ5LTM1NTwvcGFnZXM+PHZvbHVt

ZT4xNjM8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjE8L2tleXdvcmQ+PGtleXdv

cmQ+Mjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVVRF

PC9rZXl3b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QWdlZCw4MCBhbmQgb3Zlcjwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdv

cmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48a2V5d29yZD5BU1NBWTwva2V5d29yZD48a2V5

d29yZD5CYWN0ZXJpYWwgSW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5DSEFJTjwva2V5d29y

ZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tl

eXdvcmQ+PGtleXdvcmQ+Q1VMVFVSRTwva2V5d29yZD48a2V5d29yZD5DVUxUVVJFUzwva2V5d29y

ZD48a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORVM8L2tleXdvcmQ+

PGtleXdvcmQ+REVDTElORTwva2V5d29yZD48a2V5d29yZD5ERVRFQ1RJT048L2tleXdvcmQ+PGtl

eXdvcmQ+RElBR05PU0lTPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdv

cmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkVYQUNFUkJBVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3

b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5HUkFOVUxPQ1lURTwva2V5d29yZD48a2V5d29y

ZD5HUkFOVUxPQ1lURVM8L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+

SUwtODwva2V5d29yZD48a2V5d29yZD5JTU1VTk9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9r

ZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPklORFVDRUQ8L2tleXdv

cmQ+PGtleXdvcmQ+SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPklORkVDVElPTlM8L2tleXdv

cmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1hdGlvbiBN

ZWRpYXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3b3Jk

PkludGVybGV1a2luIDg8L2tleXdvcmQ+PGtleXdvcmQ+SU5URVJMRVVLSU4tODwva2V5d29yZD48

a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXMsb2JzdHJ1Y3RpdmU8

L2tleXdvcmQ+PGtleXdvcmQ+TUFMRTwva2V5d29yZD48a2V5d29yZD5NRURJQVRPUjwva2V5d29y

ZD48a2V5d29yZD5tZWRpYXRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+TUVUQUJPTElTTTwva2V5d29y

ZD48a2V5d29yZD5NaWRkbGUgQWdlPC9rZXl3b3JkPjxrZXl3b3JkPk15ZWxvcGVyb3hpZGFzZTwv

a2V5d29yZD48a2V5d29yZD5ORUNST1NJUzwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwv

a2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwv

a2V5d29yZD48a2V5d29yZD5QQ1I8L2tleXdvcmQ+PGtleXdvcmQ+UEVST1hJREFTRTwva2V5d29y

ZD48a2V5d29yZD5QT0xZTUVSQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltZXJhc2UgQ2hhaW4g

UmVhY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlFV

QU5USVRBVElWRTwva2V5d29yZD48a2V5d29yZD5SRUFDVElPTjwva2V5d29yZD48a2V5d29yZD5S

RVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFDVDwva2V5d29yZD48

a2V5d29yZD5yZXNwaXJhdG9yeSB0cmFjdCBpbmZlY3Rpb25zPC9rZXl3b3JkPjxrZXl3b3JkPlJF

U1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlNFUlVNPC9rZXl3b3JkPjxrZXl3b3JkPlNPTFVCTEU8

L2tleXdvcmQ+PGtleXdvcmQ+U1BVVFVNPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29y

ZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3

b3JkPnN1cHBvcnQsbm9uLXUucy5nb3YmYXBvczt0PC9rZXl3b3JkPjxrZXl3b3JkPlRSQUNUPC9r

ZXl3b3JkPjxrZXl3b3JkPlRVTU9SPC9rZXl3b3JkPjxrZXl3b3JkPlRVTU9SIE5FQ1JPU0lTIEZB

Q1RPUjwva2V5d29yZD48a2V5d29yZD5VTklURUQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEIFNU

QVRFUzwva2V5d29yZD48a2V5d29yZD5WSVJBTDwva2V5d29yZD48a2V5d29yZD52aXJ1cyBkaXNl

YXNlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAxPC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+Mi8yMDAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkFBUk9OMjAw

MTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [99] QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\09AARON2001'Aaron, Angel, et al. 2001 AARON2001 /id\00'\00 . TNF-α production from peripheral blood monocytes is also increased in COPD patients and has been implicated in the cachexia and skeletal muscle apoptosis found in some patients with severe disease. TNF-α is a potent activator of NF-κB and this may amplify the inflammatory response. Unfortunately anti-TNF therapies have not proved to be effective in COPD patients and may have serious adverse effects ADDIN EN.CITE <EndNote><Cite><Author>Rennard</Author><Year>2007</Year><RecNum>9852</RecNum><DisplayText>[100]</DisplayText><record><rec-number>9852</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478976">9852</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rennard,S.I.</author><author>Fogarty,C.</author><author>Kelsen,S.</author><author>Long,W.</author><author>Ramsdell,J.</author><author>Allison,J.</author><author>Mahler,D.</author><author>Saadeh,C.</author><author>Siler,T.</author><author>Snell,P.</author><author>Korenblat,P.</author><author>Smith,W.</author><author>Kaye,M.</author><author>Mandel,M.</author><author>Andrews,C.</author><author>Prabhu,R.</author><author>Donohoue,J.F.</author><author>Watt,R.</author><author>Hung,K.L..</author><author>Schlenker-Herceg,R.</author><author>Barnathan,E.S.</author><author>Murray,E.S.</author></authors></contributors><titles><title>The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease</title><secondary-title>Am J Respir Crit Care Med</secondary-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>926-934</pages><volume>175.</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>safety</keyword><keyword>EFFICACY</keyword><keyword>IN</keyword><keyword>CHRONIC</keyword><keyword>CHRONIC OBSTRUCTIVE</keyword><keyword>Chronic obstructive pulmonary disease</keyword><keyword>OBSTRUCTIVE</keyword><keyword>PULMONARY</keyword><keyword>DISEASE</keyword></keywords><dates><year>2007</year><pub-dates><date>2007</date></pub-dates></dates><label>RENNARD2007</label><urls></urls></record></Cite></EndNote>[100]. The reason for the failure of anti-TNF therapies in COPD is presumably because other proinflammatory cytokines drive the inflammatory process. IL-6, which has pleiotropic effects and amplifies inflammation is increased in the sputum and blood of patients with COPD. As discussed above, the Th17/ILC3 cytokines IL-17A and IL-22 are increased in the airways of COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaSBTdGVmYW5vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh

cj48UmVjTnVtPjEwNzkxPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3Nl08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTA3OTE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTM3ODQ3ODk5MSI+MTA3OTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkRpIFN0ZWZhbm8sQS48L2F1dGhvcj48YXV0aG9yPkNhcmFtb3JpLEcuPC9hdXRob3I+

PGF1dGhvcj5HbmVtbWksSS48L2F1dGhvcj48YXV0aG9yPkNvbnRvbGksTS48L2F1dGhvcj48YXV0

aG9yPlZpY2FyaSxDLjwvYXV0aG9yPjxhdXRob3I+Q2FwZWxsaSxBLjwvYXV0aG9yPjxhdXRob3I+

TWFnbm8sRi48L2F1dGhvcj48YXV0aG9yPkQmYXBvcztBbm5hLFMuRS48L2F1dGhvcj48YXV0aG9y

PlphbmluaSxBLjwvYXV0aG9yPjxhdXRob3I+QnJ1bixQLjwvYXV0aG9yPjxhdXRob3I+Q2Fzb2xh

cmksUC48L2F1dGhvcj48YXV0aG9yPkNodW5nLEsuRi48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQ

LkouPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5BZGNvY2ssSS48L2F1

dGhvcj48YXV0aG9yPkJhbGJpLEIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0

aXRsZXM+PHRpdGxlPlQgaGVscGVyIHR5cGUgMTctcmVsYXRlZCBjeXRva2luZSBleHByZXNzaW9u

IGlzIGluY3JlYXNlZCBpbiB0aGUgYnJvbmNoaWFsIG11Y29zYSBvZiBzdGFibGUgY2hyb25pYyBv

YnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZSBwYXRpZW50czwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5DbGluIEV4cCBJbW11bm9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkNsaW4gRXhwIEltbXVub2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MzE2LTMyNDwvcGFnZXM+PHZvbHVtZT4xNTc8L3ZvbHVtZT48bnVtYmVyPjI8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFDVElWQVRFRDwva2V5d29yZD48a2V5d29yZD5CSU9QU0lFUzwva2V5d29y

ZD48a2V5d29yZD5CSU9QU1k8L2tleXdvcmQ+PGtleXdvcmQ+YnJvbmNoaWFsPC9rZXl3b3JkPjxr

ZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hB

SU48L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9C

U1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5

IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5DT1BE

PC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwv

a2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVE9SPC9rZXl3

b3JkPjxrZXl3b3JkPkVORE9USEVMSUFMPC9rZXl3b3JkPjxrZXl3b3JkPmVuZG90aGVsaWFsIGNl

bGxzPC9rZXl3b3JkPjxrZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVT

U0lPTjwva2V5d29yZD48a2V5d29yZD5mdW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5ISUdIPC9r

ZXl3b3JkPjxrZXl3b3JkPklMLTIzPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlz

dHJ5PC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT1JFQUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPklO

PC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRp

b248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPklOVEVS

TEVVS0lOPC9rZXl3b3JkPjxrZXl3b3JkPklOVk9MVkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPkx1

bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFlNUEhPQ1lURTwva2V5d29yZD48a2V5d29yZD5MeW1waG9j

eXRlczwva2V5d29yZD48a2V5d29yZD5tUk5BPC9rZXl3b3JkPjxrZXl3b3JkPk1VQ09TQTwva2V5

d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVSUzwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48

a2V5d29yZD5QT0xZTUVSQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltZXJhc2UgQ2hhaW4gUmVh

Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlFVQU5U

SVRBVElWRTwva2V5d29yZD48a2V5d29yZD5SRUFDVElPTjwva2V5d29yZD48a2V5d29yZD5yZWNl

cHRvcjwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFUE9SVDwv

a2V5d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBw

b3J0PC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklD

PC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29yZD48a2V5d29yZD5TVUJKRUNUUzwva2V5

d29yZD48a2V5d29yZD5UPC9rZXl3b3JkPjxrZXl3b3JkPlQgbHltcGhvY3l0ZTwva2V5d29yZD48

a2V5d29yZD5UIExZTVBIT0NZVEVTPC9rZXl3b3JkPjxrZXl3b3JkPlQtbHltcGhvY3l0ZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+VFlQRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OC8yMDA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGxhYmVsPkRJU1RFRkFOTzIwMDlBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRl

PjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaSBTdGVmYW5vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVh

cj48UmVjTnVtPjEwNzkxPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3Nl08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTA3OTE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTM3ODQ3ODk5MSI+MTA3OTE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkRpIFN0ZWZhbm8sQS48L2F1dGhvcj48YXV0aG9yPkNhcmFtb3JpLEcuPC9hdXRob3I+

PGF1dGhvcj5HbmVtbWksSS48L2F1dGhvcj48YXV0aG9yPkNvbnRvbGksTS48L2F1dGhvcj48YXV0

aG9yPlZpY2FyaSxDLjwvYXV0aG9yPjxhdXRob3I+Q2FwZWxsaSxBLjwvYXV0aG9yPjxhdXRob3I+

TWFnbm8sRi48L2F1dGhvcj48YXV0aG9yPkQmYXBvcztBbm5hLFMuRS48L2F1dGhvcj48YXV0aG9y

PlphbmluaSxBLjwvYXV0aG9yPjxhdXRob3I+QnJ1bixQLjwvYXV0aG9yPjxhdXRob3I+Q2Fzb2xh

cmksUC48L2F1dGhvcj48YXV0aG9yPkNodW5nLEsuRi48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQ

LkouPC9hdXRob3I+PGF1dGhvcj5QYXBpLEEuPC9hdXRob3I+PGF1dGhvcj5BZGNvY2ssSS48L2F1

dGhvcj48YXV0aG9yPkJhbGJpLEIuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0

aXRsZXM+PHRpdGxlPlQgaGVscGVyIHR5cGUgMTctcmVsYXRlZCBjeXRva2luZSBleHByZXNzaW9u

IGlzIGluY3JlYXNlZCBpbiB0aGUgYnJvbmNoaWFsIG11Y29zYSBvZiBzdGFibGUgY2hyb25pYyBv

YnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZSBwYXRpZW50czwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5DbGluIEV4cCBJbW11bm9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2Rp

Y2FsPjxmdWxsLXRpdGxlPkNsaW4gRXhwIEltbXVub2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+MzE2LTMyNDwvcGFnZXM+PHZvbHVtZT4xNTc8L3ZvbHVtZT48bnVtYmVyPjI8L251

bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdv

cmRzPjxrZXl3b3JkPkFDVElWQVRFRDwva2V5d29yZD48a2V5d29yZD5CSU9QU0lFUzwva2V5d29y

ZD48a2V5d29yZD5CSU9QU1k8L2tleXdvcmQ+PGtleXdvcmQ+YnJvbmNoaWFsPC9rZXl3b3JkPjxr

ZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hB

SU48L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9C

U1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5

IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5DT1BE

PC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FPC9rZXl3b3JkPjxrZXl3b3JkPkNZVE9LSU5FUzwv

a2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVE9SPC9rZXl3

b3JkPjxrZXl3b3JkPkVORE9USEVMSUFMPC9rZXl3b3JkPjxrZXl3b3JkPmVuZG90aGVsaWFsIGNl

bGxzPC9rZXl3b3JkPjxrZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVT

U0lPTjwva2V5d29yZD48a2V5d29yZD5mdW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5ISUdIPC9r

ZXl3b3JkPjxrZXl3b3JkPklMLTIzPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVub2hpc3RvY2hlbWlz

dHJ5PC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT1JFQUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPklO

PC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRp

b248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPklOVEVS

TEVVS0lOPC9rZXl3b3JkPjxrZXl3b3JkPklOVk9MVkVNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPkx1

bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFlNUEhPQ1lURTwva2V5d29yZD48a2V5d29yZD5MeW1waG9j

eXRlczwva2V5d29yZD48a2V5d29yZD5tUk5BPC9rZXl3b3JkPjxrZXl3b3JkPk1VQ09TQTwva2V5

d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+TlVNQkVSUzwva2V5d29yZD48

a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48

a2V5d29yZD5QT0xZTUVSQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlBvbHltZXJhc2UgQ2hhaW4gUmVh

Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlFVQU5U

SVRBVElWRTwva2V5d29yZD48a2V5d29yZD5SRUFDVElPTjwva2V5d29yZD48a2V5d29yZD5yZWNl

cHRvcjwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPlJFUE9SVDwv

a2V5d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBw

b3J0PC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklD

PC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29yZD48a2V5d29yZD5TVUJKRUNUUzwva2V5

d29yZD48a2V5d29yZD5UPC9rZXl3b3JkPjxrZXl3b3JkPlQgbHltcGhvY3l0ZTwva2V5d29yZD48

a2V5d29yZD5UIExZTVBIT0NZVEVTPC9rZXl3b3JkPjxrZXl3b3JkPlQtbHltcGhvY3l0ZXM8L2tl

eXdvcmQ+PGtleXdvcmQ+VFlQRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OC8yMDA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGxhYmVsPkRJU1RFRkFOTzIwMDlBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRl

PjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [76]. The alarmins IL-33 and TSLP show increased expression in epithelial cells of COPD patients and may orchestrate ILCs within the airway PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YaWE8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

dW0+MTIyNjU8L1JlY051bT48RGlzcGxheVRleHQ+WzEwMSwgMTAyXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjI2NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxNDI4NDI2OTA3Ij4xMjI2NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+WGlhLCBKLjwvYXV0aG9yPjxhdXRob3I+WmhhbywgSi48L2F1dGhvcj48YXV0aG9yPlNo

YW5nLCBKLjwvYXV0aG9yPjxhdXRob3I+TGksIE0uPC9hdXRob3I+PGF1dGhvcj5aZW5nLCBaLjwv

YXV0aG9yPjxhdXRob3I+WmhhbywgSi48L2F1dGhvcj48YXV0aG9yPldhbmcsIEouPC9hdXRob3I+

PGF1dGhvcj5YdSwgWS48L2F1dGhvcj48YXV0aG9yPlhpZSwgSi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IGFu

ZCBDcml0aWNhbCBDYXJlIE1lZGljaW5lLCBUb25namkgSG9zcGl0YWwsIFRvbmdqaSBNZWRpY2Fs

IENvbGxlZ2UsIEh1YXpob25nIFVuaXZlcnNpdHkgb2YgU2NpZW5jZSBhbmQgVGVjaG5vbG9neSwg

V3VoYW4sIENoaW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBhbmQgQ3JpdGljYWwg

Q2FyZSBNZWRpY2luZSwgVG9uZ2ppIEhvc3BpdGFsLCBUb25namkgTWVkaWNhbCBDb2xsZWdlLCBI

dWF6aG9uZyBVbml2ZXJzaXR5IG9mIFNjaWVuY2UgYW5kIFRlY2hub2xvZ3ksIFd1aGFuLCBDaGlu

YSB4aWVqamdnQGhvdG1haWwuY29tLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluY3Jl

YXNlZCBJTC0zMyBleHByZXNzaW9uIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBQaHlzaW9sIEx1bmcgQ2VsbCBNb2wg

UGh5c2lvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiBw

aHlzaW9sb2d5LiBMdW5nIGNlbGx1bGFyIGFuZCBtb2xlY3VsYXIgcGh5c2lvbG9neTwvYWx0LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGh5c2lvbCBMdW5nIENl

bGwgTW9sIFBoeXNpb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5MNjE5LTI3PC9w

YWdlcz48dm9sdW1lPjMwODwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUv

MDEvMTg8L2VkaXRpb24+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5B

cHIgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwNDAtMDYwNTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yNTU5NTY0ODwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjExNTIvYWpwbHVuZy4wMDMwNS4yMDE0PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5sbTwvcmVtb3RlLWRhdGFiYXNl

LXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPllpbmc8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNOdW0+MTA2MTU8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNjE1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0

aW1lc3RhbXA9IjEzNzg0Nzg5ODgiPjEwNjE1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5ZaW5nLFMuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7Q29ubm9yLEIuPC9hdXRo

b3I+PGF1dGhvcj5SYXRvZmYsSi48L2F1dGhvcj48YXV0aG9yPk1lbmcsUS48L2F1dGhvcj48YXV0

aG9yPkZhbmcsQy48L2F1dGhvcj48YXV0aG9yPkNvdXNpbnMsRC48L2F1dGhvcj48YXV0aG9yPlpo

YW5nLEcuPC9hdXRob3I+PGF1dGhvcj5HdSxTLjwvYXV0aG9yPjxhdXRob3I+R2FvLFouPC9hdXRo

b3I+PGF1dGhvcj5TaGFtamksQi48L2F1dGhvcj48YXV0aG9yPkVkd2FyZHMsTS5KLjwvYXV0aG9y

PjxhdXRob3I+TGVlLFQuSC48L2F1dGhvcj48YXV0aG9yPkNvcnJpZ2FuLEMuSi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXhwcmVzc2lvbiBhbmQgY2Vs

bHVsYXIgcHJvdmVuYW5jZSBvZiB0aHltaWMgc3Ryb21hbCBseW1waG9wb2lldGluIGFuZCBjaGVt

b2tpbmVzIGluIHBhdGllbnRzIHdpdGggc2V2ZXJlIGFzdGhtYSBhbmQgY2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEltbXVub2wu

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBJbW11

bm9sLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI3OTAtMjc5ODwvcGFnZXM+PHZv

bHVtZT4xODE8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBp

biBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDQ1VNVUxBVElPTjwv

a2V5d29yZD48a2V5d29yZD5BREFNIFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPkFEQU0xMSBw

cm90ZWluLGh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tl

eXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkJpb3N5bnRoZXNpczwva2V5

d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFS

PC9rZXl3b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUiBMQVZBR0U8L2tleXdvcmQ+PGtleXdv

cmQ+YnJvbmNob2FsdmVvbGFyIGxhdmFnZSBmbHVpZDwva2V5d29yZD48a2V5d29yZD5DQ0wxIHBy

b3RlaW4saHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+Q0NMMTcgcHJvdGVpbixodW1hbjwva2V5d29y

ZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNFTExVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1va2luZSBDQ0wxPC9rZXl3b3JkPjxrZXl3

b3JkPkNoZW1va2luZSBDQ0wxNzwva2V5d29yZD48a2V5d29yZD5DaGVtb2tpbmUgQ1hDTDEwPC9r

ZXl3b3JkPjxrZXl3b3JkPkNoZW1va2luZSBDWENMMTE8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbW9r

aW5lczwva2V5d29yZD48a2V5d29yZD5DaGVtb3RheGlzLExldWtvY3l0ZTwva2V5d29yZD48a2V5

d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdv

cmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29y

ZD48a2V5d29yZD5DT01QQVJBVElWRTwva2V5d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVk

eTwva2V5d29yZD48a2V5d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRS

T0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5DWENMMTAgcHJvdGVp

bixodW1hbjwva2V5d29yZD48a2V5d29yZD5DWENMMTEgcHJvdGVpbixodW1hbjwva2V5d29yZD48

a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORVM8L2tleXdvcmQ+PGtl

eXdvcmQ+RElGRkVSRU5USUFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+

PGtleXdvcmQ+RUxJU0E8L2tleXdvcmQ+PGtleXdvcmQ+RU5DT0RJTkc8L2tleXdvcmQ+PGtleXdv

cmQ+RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

RkxVSUQ8L2tleXdvcmQ+PGtleXdvcmQ+R0VORVRJQ1M8L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5T

PC9rZXl3b3JkPjxrZXl3b3JkPkhZQlJJRElaQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v

aGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5

d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JbiBTaXR1IEh5YnJpZGl6YXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORkxVWDwva2V5d29yZD48a2V5

d29yZD5MQVZBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TEFWQUdFIEZMVUlEPC9rZXl3b3JkPjxrZXl3

b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+TUVUQUJPTElTTTwva2V5d29yZD48a2V5d29yZD5N

aWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5tUk5BPC9rZXl3b3JkPjxrZXl3b3JkPk1VQ09T

QTwva2V5d29yZD48a2V5d29yZD5tdWNvc2FsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJFUlM8L2tl

eXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSE9MT0dZPC9r

ZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29y

ZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydDwva2V5

d29yZD48a2V5d29yZD5SZXNwaXJhdG9yeSBNdWNvc2E8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPlNFTEVDVElWRTwva2V5d29yZD48a2V5d29yZD5TRVZFUkU8

L2tleXdvcmQ+PGtleXdvcmQ+c2V2ZXJpdHkgb2YgaWxsbmVzcyBpbmRleDwva2V5d29yZD48a2V5

d29yZD5TSVRVPC9rZXl3b3JkPjxrZXl3b3JkPlN0cm9tYWwgQ2VsbHM8L2tleXdvcmQ+PGtleXdv

cmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJK

RUNUUzwva2V5d29yZD48a2V5d29yZD5UPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29y

ZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3JkPjxrZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48a2V5

d29yZD50LWx5bXBob2N5dGUgc3Vic2V0czwva2V5d29yZD48a2V5d29yZD50aDEgY2VsbHM8L2tl

eXdvcmQ+PGtleXdvcmQ+VGgyPC9rZXl3b3JkPjxrZXl3b3JkPnRoMiBjZWxsczwva2V5d29yZD48

a2V5d29yZD50aHltaWMgc3Ryb21hbCBseW1waG9wb2lldGluPC9rZXl3b3JkPjxrZXl3b3JkPlRo

eW11cyBHbGFuZDwva2V5d29yZD48a2V5d29yZD5UdW1vciBTdXBwcmVzc29yIFByb3RlaW5zPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT44LzE1LzIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+WUlORzIwMDg8L2xh

YmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YaWE8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

dW0+MTIyNjU8L1JlY051bT48RGlzcGxheVRleHQ+WzEwMSwgMTAyXTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjI2NTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxNDI4NDI2OTA3Ij4xMjI2NTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+WGlhLCBKLjwvYXV0aG9yPjxhdXRob3I+WmhhbywgSi48L2F1dGhvcj48YXV0aG9yPlNo

YW5nLCBKLjwvYXV0aG9yPjxhdXRob3I+TGksIE0uPC9hdXRob3I+PGF1dGhvcj5aZW5nLCBaLjwv

YXV0aG9yPjxhdXRob3I+WmhhbywgSi48L2F1dGhvcj48YXV0aG9yPldhbmcsIEouPC9hdXRob3I+

PGF1dGhvcj5YdSwgWS48L2F1dGhvcj48YXV0aG9yPlhpZSwgSi48L2F1dGhvcj48L2F1dGhvcnM+

PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIFJlc3BpcmF0b3J5IGFu

ZCBDcml0aWNhbCBDYXJlIE1lZGljaW5lLCBUb25namkgSG9zcGl0YWwsIFRvbmdqaSBNZWRpY2Fs

IENvbGxlZ2UsIEh1YXpob25nIFVuaXZlcnNpdHkgb2YgU2NpZW5jZSBhbmQgVGVjaG5vbG9neSwg

V3VoYW4sIENoaW5hLiYjeEQ7RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBhbmQgQ3JpdGljYWwg

Q2FyZSBNZWRpY2luZSwgVG9uZ2ppIEhvc3BpdGFsLCBUb25namkgTWVkaWNhbCBDb2xsZWdlLCBI

dWF6aG9uZyBVbml2ZXJzaXR5IG9mIFNjaWVuY2UgYW5kIFRlY2hub2xvZ3ksIFd1aGFuLCBDaGlu

YSB4aWVqamdnQGhvdG1haWwuY29tLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluY3Jl

YXNlZCBJTC0zMyBleHByZXNzaW9uIGluIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBQaHlzaW9sIEx1bmcgQ2VsbCBNb2wg

UGh5c2lvbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiBw

aHlzaW9sb2d5LiBMdW5nIGNlbGx1bGFyIGFuZCBtb2xlY3VsYXIgcGh5c2lvbG9neTwvYWx0LXRp

dGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUGh5c2lvbCBMdW5nIENl

bGwgTW9sIFBoeXNpb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5MNjE5LTI3PC9w

YWdlcz48dm9sdW1lPjMwODwvdm9sdW1lPjxudW1iZXI+NzwvbnVtYmVyPjxlZGl0aW9uPjIwMTUv

MDEvMTg8L2VkaXRpb24+PGRhdGVzPjx5ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5B

cHIgMTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjEwNDAtMDYwNTwvaXNibj48YWNj

ZXNzaW9uLW51bT4yNTU5NTY0ODwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGVsZWN0cm9u

aWMtcmVzb3VyY2UtbnVtPjEwLjExNTIvYWpwbHVuZy4wMDMwNS4yMDE0PC9lbGVjdHJvbmljLXJl

c291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5sbTwvcmVtb3RlLWRhdGFiYXNl

LXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48

QXV0aG9yPllpbmc8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNOdW0+MTA2MTU8L1JlY051

bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNjE1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0

aW1lc3RhbXA9IjEzNzg0Nzg5ODgiPjEwNjE1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5ZaW5nLFMuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7Q29ubm9yLEIuPC9hdXRo

b3I+PGF1dGhvcj5SYXRvZmYsSi48L2F1dGhvcj48YXV0aG9yPk1lbmcsUS48L2F1dGhvcj48YXV0

aG9yPkZhbmcsQy48L2F1dGhvcj48YXV0aG9yPkNvdXNpbnMsRC48L2F1dGhvcj48YXV0aG9yPlpo

YW5nLEcuPC9hdXRob3I+PGF1dGhvcj5HdSxTLjwvYXV0aG9yPjxhdXRob3I+R2FvLFouPC9hdXRo

b3I+PGF1dGhvcj5TaGFtamksQi48L2F1dGhvcj48YXV0aG9yPkVkd2FyZHMsTS5KLjwvYXV0aG9y

PjxhdXRob3I+TGVlLFQuSC48L2F1dGhvcj48YXV0aG9yPkNvcnJpZ2FuLEMuSi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+RXhwcmVzc2lvbiBhbmQgY2Vs

bHVsYXIgcHJvdmVuYW5jZSBvZiB0aHltaWMgc3Ryb21hbCBseW1waG9wb2lldGluIGFuZCBjaGVt

b2tpbmVzIGluIHBhdGllbnRzIHdpdGggc2V2ZXJlIGFzdGhtYSBhbmQgY2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIEltbXVub2wu

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBJbW11

bm9sLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI3OTAtMjc5ODwvcGFnZXM+PHZv

bHVtZT4xODE8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBp

biBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDQ1VNVUxBVElPTjwv

a2V5d29yZD48a2V5d29yZD5BREFNIFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPkFEQU0xMSBw

cm90ZWluLGh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkFEVUxUPC9rZXl3b3JkPjxrZXl3b3JkPkFn

ZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tl

eXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3JkPkJpb3N5bnRoZXNpczwva2V5

d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFS

PC9rZXl3b3JkPjxrZXl3b3JkPkJST05DSE9BTFZFT0xBUiBMQVZBR0U8L2tleXdvcmQ+PGtleXdv

cmQ+YnJvbmNob2FsdmVvbGFyIGxhdmFnZSBmbHVpZDwva2V5d29yZD48a2V5d29yZD5DQ0wxIHBy

b3RlaW4saHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+Q0NMMTcgcHJvdGVpbixodW1hbjwva2V5d29y

ZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3Jk

PkNFTExVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1va2luZSBDQ0wxPC9rZXl3b3JkPjxrZXl3

b3JkPkNoZW1va2luZSBDQ0wxNzwva2V5d29yZD48a2V5d29yZD5DaGVtb2tpbmUgQ1hDTDEwPC9r

ZXl3b3JkPjxrZXl3b3JkPkNoZW1va2luZSBDWENMMTE8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbW9r

aW5lczwva2V5d29yZD48a2V5d29yZD5DaGVtb3RheGlzLExldWtvY3l0ZTwva2V5d29yZD48a2V5

d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdv

cmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29y

ZD48a2V5d29yZD5DT01QQVJBVElWRTwva2V5d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVk

eTwva2V5d29yZD48a2V5d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRS

T0w8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5DWENMMTAgcHJvdGVp

bixodW1hbjwva2V5d29yZD48a2V5d29yZD5DWENMMTEgcHJvdGVpbixodW1hbjwva2V5d29yZD48

a2V5d29yZD5DWVRPS0lORTwva2V5d29yZD48a2V5d29yZD5DWVRPS0lORVM8L2tleXdvcmQ+PGtl

eXdvcmQ+RElGRkVSRU5USUFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+

PGtleXdvcmQ+RUxJU0E8L2tleXdvcmQ+PGtleXdvcmQ+RU5DT0RJTkc8L2tleXdvcmQ+PGtleXdv

cmQ+RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+

RkxVSUQ8L2tleXdvcmQ+PGtleXdvcmQ+R0VORVRJQ1M8L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5T

PC9rZXl3b3JkPjxrZXl3b3JkPkhZQlJJRElaQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5v

aGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PTE9HWTwva2V5d29yZD48a2V5

d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JbiBTaXR1IEh5YnJpZGl6YXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORkxVWDwva2V5d29yZD48a2V5

d29yZD5MQVZBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TEFWQUdFIEZMVUlEPC9rZXl3b3JkPjxrZXl3

b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+TUVUQUJPTElTTTwva2V5d29yZD48a2V5d29yZD5N

aWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5tUk5BPC9rZXl3b3JkPjxrZXl3b3JkPk1VQ09T

QTwva2V5d29yZD48a2V5d29yZD5tdWNvc2FsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJFUlM8L2tl

eXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSE9MT0dZPC9r

ZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdv

cmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vhc2UsQ2hyb25pYyBPYnN0cnVjdGl2ZTwva2V5d29y

ZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+

PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UmVzZWFyY2ggU3VwcG9ydDwva2V5

d29yZD48a2V5d29yZD5SZXNwaXJhdG9yeSBNdWNvc2E8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPlNFTEVDVElWRTwva2V5d29yZD48a2V5d29yZD5TRVZFUkU8

L2tleXdvcmQ+PGtleXdvcmQ+c2V2ZXJpdHkgb2YgaWxsbmVzcyBpbmRleDwva2V5d29yZD48a2V5

d29yZD5TSVRVPC9rZXl3b3JkPjxrZXl3b3JkPlN0cm9tYWwgQ2VsbHM8L2tleXdvcmQ+PGtleXdv

cmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5TVUJK

RUNUUzwva2V5d29yZD48a2V5d29yZD5UPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29y

ZD48a2V5d29yZD5UIENFTExTPC9rZXl3b3JkPjxrZXl3b3JkPlQtQ0VMTDwva2V5d29yZD48a2V5

d29yZD50LWx5bXBob2N5dGUgc3Vic2V0czwva2V5d29yZD48a2V5d29yZD50aDEgY2VsbHM8L2tl

eXdvcmQ+PGtleXdvcmQ+VGgyPC9rZXl3b3JkPjxrZXl3b3JkPnRoMiBjZWxsczwva2V5d29yZD48

a2V5d29yZD50aHltaWMgc3Ryb21hbCBseW1waG9wb2lldGluPC9rZXl3b3JkPjxrZXl3b3JkPlRo

eW11cyBHbGFuZDwva2V5d29yZD48a2V5d29yZD5UdW1vciBTdXBwcmVzc29yIFByb3RlaW5zPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDg8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT44LzE1LzIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+WUlORzIwMDg8L2xh

YmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [101, 102].ChemokinesChemokines play a critical role in attracting inflammatory cells from the circulation into the lungs in asthma and COPD and act through G-protein coupled receptors that may be targeted by small molecule antagonists. CCL11 is selectively attractant to eosinophils via CCR3 and is expressed by epithelial cells of asthmatics, whereas CCL17 and CCL22 from dendritic cells attract Th2 cells via CCR4.CXCL8 concentrations are increased in induced sputum of COPD patients and increase further during exacerbations QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\09AARON2001'Aaron, Angel, et al. 2001 AARON2001 /id\00'\00 . CXCL8 secreted from macrophages, T-cells, epithelial cells and neutrophils is chemotactic for neutrophils via high affinity CXCR2, which are also activated by related CXC chemokines, such as CXCL1 and CXCL5. CXCL1 concentrations are markedly elevated in sputum and BAL fluid of COPD patients and this chemokine may be more important as a chemoattractant than CXCL8, acting via CXCR2, which are expressed predominantly on neutrophils and monocytes ADDIN EN.CITE <EndNote><Cite><Author>Traves</Author><Year>2002</Year><RecNum>7167</RecNum><DisplayText>[37]</DisplayText><record><rec-number>7167</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478931">7167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Traves,S.L.</author><author>Culpitt,S.</author><author>Russell,R.E.K.</author><author>Barnes,P.J.</author><author>Donnelly,L.E.</author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Elevated levels of the chemokines GRO-</style><style face="normal" font="Symbol" charset="2" size="100%">a</style><style face="normal" font="default" size="100%"> and MCP-1 in sputum samples from COPD patients</style></title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>590-595</pages><volume>57</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>BLOOD</keyword><keyword>CELL</keyword><keyword>chemokines</keyword><keyword>Chemotaxis</keyword><keyword>COPD</keyword><keyword>IL-8</keyword><keyword>IN</keyword><keyword>MCP-1</keyword><keyword>MONONUCLEAR</keyword><keyword>PATIENTS</keyword><keyword>PERIPHERAL</keyword><keyword>SPUTUM</keyword></keywords><dates><year>2002</year><pub-dates><date>2002</date></pub-dates></dates><label>TRAVES2002</label><urls></urls></record></Cite></EndNote>[37]. CXCL1 induces significantly more chemotaxis of monocytes of COPD patient compared to those of normal smokers and this may reflect increased turnover and recovery of CXCR2 in monocytes of COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmF2ZXM8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+ODc0NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMzhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjg3NDc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk1OCI+ODc0Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

VHJhdmVzLFMuTC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLFMuSi48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5Eb25uZWxseSxMLkUuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNwZWNpZmljIENYQyBidXQgbm90IENDIGNo

ZW1va2luZXMgY2F1c2UgZWxldmF0ZWQgbW9ub2N5dGUgbWlncmF0aW9uIGluIENPUEQ6IGEgcm9s

ZSBmb3IgQ1hDUjI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBMZXVrb2MuQmlvbC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIExldWtvYy5CaW9s

LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQ0MS00NTA8L3BhZ2VzPjx2b2x1bWU+

NzY8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxPVzwv

a2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29y

ZD48a2V5d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVEFHT05JU1Q8L2tleXdvcmQ+PGtleXdvcmQ+QU5UQUdPTklT

VFM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdvcmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29y

ZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSEFOR0VTPC9rZXl3b3JkPjxrZXl3b3JkPmNo

ZW1va2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hlbW90YXhpczwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNI

Uk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0lSQ1VMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5

d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5FTkhB

TkNFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RP

Ujwva2V5d29yZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5

PC9rZXl3b3JkPjxrZXl3b3JkPkhPU1Q8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORklMVFJBVElPTjwva2V5d29yZD48

a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3

b3JkPjxrZXl3b3JkPklORkxVWDwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbiA4PC9rZXl3

b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOLTg8L2tleXdvcmQ+PGtleXdvcmQ+SVJSRVZFUlNJQkxF

PC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtleXdvcmQ+TEVVS09DWVRFPC9rZXl3

b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdv

cmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5

d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRURJQVRFRDwva2V5d29yZD48a2V5d29yZD5N

SUdSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+TU9OT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+TW9u

b2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPk1PTk9OVUNMRUFSPC9rZXl3b3JkPjxrZXl3b3JkPk5V

TUJFUlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVQVElERTwva2V5d29yZD48a2V5d29yZD5QRVJJUEhF

UkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9URUlO

PC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwv

a2V5d29yZD48a2V5d29yZD5SZWNlcHRvciBleHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJl

Y2VwdG9yczwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UElSQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UE9OU0VTPC9rZXl3b3JkPjxrZXl3b3JkPnJpc2s8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5

d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3Jk

PjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdv

cmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRVM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMjAvMjAwNDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5UUkFWRVMyMDA0PC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmF2ZXM8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+ODc0NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMzhdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjg3NDc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk1OCI+ODc0Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

VHJhdmVzLFMuTC48L2F1dGhvcj48YXV0aG9yPlNtaXRoLFMuSi48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5Eb25uZWxseSxMLkUuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNwZWNpZmljIENYQyBidXQgbm90IENDIGNo

ZW1va2luZXMgY2F1c2UgZWxldmF0ZWQgbW9ub2N5dGUgbWlncmF0aW9uIGluIENPUEQ6IGEgcm9s

ZSBmb3IgQ1hDUjI8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+SiBMZXVrb2MuQmlvbC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5KIExldWtvYy5CaW9s

LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjQ0MS00NTA8L3BhZ2VzPjx2b2x1bWU+

NzY8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QUlSRkxPVzwv

a2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29y

ZD48a2V5d29yZD5BTFZFT0xBUjwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdl

PC9rZXl3b3JkPjxrZXl3b3JkPkFOVEFHT05JU1Q8L2tleXdvcmQ+PGtleXdvcmQ+QU5UQUdPTklT

VFM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTQVk8L2tleXdvcmQ+PGtleXdvcmQ+QkxPT0Q8L2tleXdv

cmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29y

ZD5DRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DSEFOR0VTPC9rZXl3b3JkPjxrZXl3b3JkPmNo

ZW1va2luZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hlbW90YXhpczwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNI

Uk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0lSQ1VMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5

d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5FTkhB

TkNFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RP

Ujwva2V5d29yZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5

PC9rZXl3b3JkPjxrZXl3b3JkPkhPU1Q8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORklMVFJBVElPTjwva2V5d29yZD48

a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3

b3JkPjxrZXl3b3JkPklORkxVWDwva2V5d29yZD48a2V5d29yZD5JbnRlcmxldWtpbiA4PC9rZXl3

b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOLTg8L2tleXdvcmQ+PGtleXdvcmQ+SVJSRVZFUlNJQkxF

PC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtleXdvcmQ+TEVVS09DWVRFPC9rZXl3

b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdv

cmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5

d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRURJQVRFRDwva2V5d29yZD48a2V5d29yZD5N

SUdSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+TU9OT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+TW9u

b2N5dGVzPC9rZXl3b3JkPjxrZXl3b3JkPk1PTk9OVUNMRUFSPC9rZXl3b3JkPjxrZXl3b3JkPk5V

TUJFUlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVQVElERTwva2V5d29yZD48a2V5d29yZD5QRVJJUEhF

UkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9URUlO

PC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwv

a2V5d29yZD48a2V5d29yZD5SZWNlcHRvciBleHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPlJl

Y2VwdG9yczwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UElSQVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdvcmQ+UkVT

UE9OU0VTPC9rZXl3b3JkPjxrZXl3b3JkPnJpc2s8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5

d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3Jk

PjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdv

cmQ+VEhFUkFQSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+

VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRVM8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0

ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjUvMjAvMjAwNDwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5UUkFWRVMyMDA0PC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [38]. CXCR2 antagonists reduce sputum neutrophils in COPD patients, but provide relatively little clinical benefit ADDIN EN.CITE <EndNote><Cite><Author>Rennard</Author><Year>2015</Year><RecNum>12268</RecNum><DisplayText>[103]</DisplayText><record><rec-number>12268</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1428599684">12268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rennard, S. I.</author><author>Dale, D. C.</author><author>Donohue, J. F.</author><author>Kanniess, F.</author><author>Magnussen, H.</author><author>Sutherland, E. R.</author><author>Watz, H.</author><author>Lu, S.</author><author>Stryszak, P.</author><author>Rosenberg, E.</author><author>Staudinger, H.</author></authors></contributors><auth-address>University of Nebraska Medical Center, Pulmonary and Critical Care Medicine , 985885 Nebraska Medical Center , Omaha, United States , 68198-5885 , (402) 559-7313 , (402) 559-4878 ; srennard@unmc.edu.</auth-address><titles><title>CXCR2 antagonist MK-7123- a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease</title><secondary-title>Am J Respir Crit Care Med</secondary-title><alt-title>American journal of respiratory and critical care medicine</alt-title></titles><periodical><full-title>Am J Respir Crit Care Med</full-title></periodical><pages>1001-11</pages><volume>191</volume><edition>2015/02/20</edition><dates><year>2015</year><pub-dates><date>Feb 19</date></pub-dates></dates><isbn>1073-449x</isbn><accession-num>25695403</accession-num><urls></urls><electronic-resource-num>10.1164/rccm.201405-0992OC</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[103]. CCL2 is increased in COPD sputum and BAL fluid and plays a role in monocyte chemotaxis via activation of CCR2 ADDIN EN.CITE <EndNote><Cite><Author>Traves</Author><Year>2002</Year><RecNum>7167</RecNum><DisplayText>[37]</DisplayText><record><rec-number>7167</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478931">7167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Traves,S.L.</author><author>Culpitt,S.</author><author>Russell,R.E.K.</author><author>Barnes,P.J.</author><author>Donnelly,L.E.</author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Elevated levels of the chemokines GRO-</style><style face="normal" font="Symbol" charset="2" size="100%">a</style><style face="normal" font="default" size="100%"> and MCP-1 in sputum samples from COPD patients</style></title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>590-595</pages><volume>57</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>BLOOD</keyword><keyword>CELL</keyword><keyword>chemokines</keyword><keyword>Chemotaxis</keyword><keyword>COPD</keyword><keyword>IL-8</keyword><keyword>IN</keyword><keyword>MCP-1</keyword><keyword>MONONUCLEAR</keyword><keyword>PATIENTS</keyword><keyword>PERIPHERAL</keyword><keyword>SPUTUM</keyword></keywords><dates><year>2002</year><pub-dates><date>2002</date></pub-dates></dates><label>TRAVES2002</label><urls></urls></record></Cite></EndNote>[37]. CCL5 is also expressed in airways of COPD patients during exacerbations and activates CCR5 on T-cells and CCR3 on eosinophils, which may account for the increased eosinophils and T cells in the wall of large airways that have been reported during exacerbations of chronic bronchitis. CXCR3 are up-regulated on Tc1 and Th1 cells of COPD patients with increased expression of their ligands CXCL9, CXCL10 and CXCL11 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3N0YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT45OTY5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3OF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+OTk2OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTc4Ij45OTY5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

b3N0YSxDLjwvYXV0aG9yPjxhdXRob3I+UnVmaW5vLFIuPC9hdXRob3I+PGF1dGhvcj5UcmF2ZXMs

Uy5MLjwvYXV0aG9yPjxhdXRob3I+TGFwYSBFIFNpbHZhIEpSPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DWENSMyBhbmQgQ0NSNSBjaGVtb2tpbmVzIGlu

IHRoZSBpbmR1Y2VkIHNwdXR1bSBmcm9tIHBhdGllbnRzIHdpdGggQ09QRDwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5DaGVzdC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5DaGVzdC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNi0zMzwv

cGFnZXM+PHZvbHVtZT4xMzM8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdv

cmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbW9raW5lczwva2V5d29yZD48a2V5d29yZD5D

T05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09S

UkVMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09VTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZF

UkVOVElBTDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVMSVNB

PC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tl

eXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxr

ZXl3b3JkPklORFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxr

ZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxZ

TVBIT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+THltcGhvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29y

ZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5OQVRJ

T05BTDwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJF

UlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlJFR1VM

QVRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9rZXl3b3JkPjxrZXl3b3JkPlNN

QUxMPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48

a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVh

cj48cHViLWRhdGVzPjxkYXRlPjIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+

Q09TVEEyMDA3PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3N0YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

Y051bT45OTY5PC9SZWNOdW0+PERpc3BsYXlUZXh0Pls3OF08L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+OTk2OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc4OTc4Ij45OTY5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJu

YWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5D

b3N0YSxDLjwvYXV0aG9yPjxhdXRob3I+UnVmaW5vLFIuPC9hdXRob3I+PGF1dGhvcj5UcmF2ZXMs

Uy5MLjwvYXV0aG9yPjxhdXRob3I+TGFwYSBFIFNpbHZhIEpSPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5DWENSMyBhbmQgQ0NSNSBjaGVtb2tpbmVzIGlu

IHRoZSBpbmR1Y2VkIHNwdXR1bSBmcm9tIHBhdGllbnRzIHdpdGggQ09QRDwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5DaGVzdC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5DaGVzdC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4yNi0zMzwv

cGFnZXM+PHZvbHVtZT4xMzM8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5BaXJ3YXkgb2JzdHJ1Y3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48

a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdv

cmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Y2hlbW9raW5lczwva2V5d29yZD48a2V5d29yZD5D

T05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q09S

UkVMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Q09VTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkRJRkZF

UkVOVElBTDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkVMSVNB

PC9rZXl3b3JkPjxrZXl3b3JkPkVYUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tl

eXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxr

ZXl3b3JkPklORFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxr

ZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPkxZ

TVBIT0NZVEU8L2tleXdvcmQ+PGtleXdvcmQ+THltcGhvY3l0ZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29y

ZD5NRVRIT0Q8L2tleXdvcmQ+PGtleXdvcmQ+TWV0aG9kczwva2V5d29yZD48a2V5d29yZD5OQVRJ

T05BTDwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPk5VTUJF

UlM8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9n

ZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlJFR1VM

QVRJTkc8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9rZXl3b3JkPjxrZXl3b3JkPlNN

QUxMPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlQgQ0VMTDwva2V5d29yZD48

a2V5d29yZD5ULUNFTEw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVh

cj48cHViLWRhdGVzPjxkYXRlPjIwMDg8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+

Q09TVEEyMDA3PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [78]. CXCR3 ligands induce increased chemotaxis of monocytes and lymphocytes from COPD patients with may reflect increased CXCR3 expression in COPD ADDIN EN.CITE <EndNote><Cite><Author>Costa</Author><Year>2016</Year><RecNum>12719</RecNum><DisplayText>[104]</DisplayText><record><rec-number>12719</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1458037840">12719</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Costa, C.</author><author>Traves, S. L.</author><author>Tudhope, S. J.</author><author>Fenwick, P. S.</author><author>Belchamber, K. B.</author><author>Russell, R. E.</author><author>Barnes, P. J.</author><author>Donnelly, L. E.</author></authors></contributors><auth-address>Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK.&#xD;Chest Clinic, King Edward King VII Hospital, Windsor, UK.&#xD;Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK l.donnelly@imperial.ac.uk.</auth-address><titles><title>Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD</title><secondary-title>Eur Respir J</secondary-title><alt-title>The European respiratory journal</alt-title></titles><periodical><full-title>Eur Respir J</full-title></periodical><pages>1093-1102</pages><volume>47</volume><number>4</number><edition>2016/03/12</edition><dates><year>2016</year><pub-dates><date>Mar 10</date></pub-dates></dates><isbn>0903-1936</isbn><accession-num>26965295</accession-num><urls></urls><electronic-resource-num>10.1183/13993003.01642-2015</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[104].InflammasomeInflammasomes are multi-protein signalling complexes that regulate the expression of the proinflammatory cytokines IL-1α, IL-1β and IL-18 in response to external and endogenous danger signals, by releasing them from precursors via caspase-1 generation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051

bT4xMjc3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTA1LCAxMDZdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyNzc3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0NTk5MzEzMjMiPjEyNzc3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5KbywgRS4gSy48L2F1dGhvcj48YXV0aG9yPktpbSwgSi4gSy48L2F1dGhvcj48YXV0aG9y

PlNoaW4sIEQuIE0uPC9hdXRob3I+PGF1dGhvcj5TYXNha2F3YSwgQy48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1pY3JvYmlvbG9n

eSwgQ2h1bmduYW0gTmF0aW9uYWwgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIERhZWpl

b24gMzAxLTc0NywgU291dGggS29yZWEuJiN4RDtJbmZlY3Rpb24gU2lnbmFsaW5nIE5ldHdvcmsg

UmVzZWFyY2ggQ2VudGVyLCBDaHVuZ25hbSBOYXRpb25hbCBVbml2ZXJzaXR5IFNjaG9vbCBvZiBN

ZWRpY2luZSwgRGFlamVvbiAzMDEtNzQ3LCBTb3V0aCBLb3JlYS4mI3hEO01lZGljYWwgTXljb2xv

Z3kgUmVzZWFyY2ggQ2VudGVyLCBDaGliYSBVbml2ZXJzaXR5LCBDaGliYSAyNjAtODY3MywgSmFw

YW4uJiN4RDtOaXBwb24gSW5zdGl0dXRlIGZvciBCaW9sb2dpY2FsIFNjaWVuY2UsIFRva3lvIDE5

OC0wMDI0LCBKYXBhbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgbWVj

aGFuaXNtcyByZWd1bGF0aW5nIE5MUlAzIGluZmxhbW1hc29tZSBhY3RpdmF0aW9uPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkNlbGwgTW9sIEltbXVub2w8L3NlY29uZGFyeS10aXRsZT48YWx0LXRp

dGxlPkNlbGx1bGFyICZhbXA7IG1vbGVjdWxhciBpbW11bm9sb2d5PC9hbHQtdGl0bGU+PC90aXRs

ZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2VsbCBNb2wgSW1tdW5vbDwvZnVsbC10aXRsZT48

YWJici0xPkNlbGx1bGFyICZhbXA7IG1vbGVjdWxhciBpbW11bm9sb2d5PC9hYmJyLTE+PC9wZXJp

b2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZWxsIE1vbCBJbW11bm9sPC9mdWxs

LXRpdGxlPjxhYmJyLTE+Q2VsbHVsYXIgJmFtcDsgbW9sZWN1bGFyIGltbXVub2xvZ3k8L2FiYnIt

MT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4xNDgtNTk8L3BhZ2VzPjx2b2x1bWU+MTM8L3ZvbHVt

ZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE1LzExLzEwPC9lZGl0aW9uPjxkYXRlcz48

eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTY3Mi03NjgxPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NTQ5ODAwPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0Nzg2NjM0PC9jdXN0b20yPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L2NtaS4yMDE1Ljk1PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXBy

b3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkxlZTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051bT4xMjg5OTwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTI4OTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQ3NTU5MzMzMCI+MTI4OTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkxlZSwgUy48L2F1dGhvcj48YXV0aG9yPlN1aCwgRy4gWS48L2F1dGhvcj48YXV0aG9y

PlJ5dGVyLCBTLiBXLjwvYXV0aG9yPjxhdXRob3I+Q2hvaSwgQS4gTS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xIERlcGFydG1lbnQgb2YgQ3JpdGljYWwg

Q2FyZSBNZWRpY2luZSwgU2Ftc3VuZyBNZWRpY2FsIENlbnRlciwgU3VuZ2t5dW5rd2FuIFVuaXZl

cnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTZW91bCwgUmVwdWJsaWMgb2YgS29yZWEuJiN4RDsy

IEpvYW4gYW5kIFNhbmZvcmQgSS4gV2VpbGwgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgTmV3IFlv

cmstUHJlc2J5dGVyaWFuIEhvc3BpdGFsLCBOZXcgWW9yaywgTmV3IFlvcms7IGFuZC4mI3hEOzMg

RGl2aXNpb24gb2YgUHVsbW9uYXJ5IGFuZCBDcml0aWNhbCBDYXJlIE1lZGljaW5lLCBXZWlsbCBD

b3JuZWxsIE1lZGljYWwgQ2VudGVyLCBOZXcgWW9yaywgTmV3IFlvcmsuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+UmVndWxhdGlvbiBhbmQgRnVuY3Rpb24gb2YgdGhlIE51Y2xlb3RpZGUg

QmluZGluZyBEb21haW4gTGV1Y2luZS1SaWNoIFJlcGVhdC1Db250YWluaW5nIFJlY2VwdG9yLCBQ

eXJpbiBEb21haW4tQ29udGFpbmluZy0zIEluZmxhbW1hc29tZSBpbiBMdW5nIERpc2Vhc2U8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ2VsbCBNb2wgQmlvbDwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiByZXNwaXJhdG9yeSBjZWxsIGFu

ZCBtb2xlY3VsYXIgYmlvbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPkFtIEogUmVzcGlyIENlbGwgTW9sIEJpb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4xNTEtNjA8L3BhZ2VzPjx2b2x1bWU+NTQ8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJl

cj48ZWRpdGlvbj4yMDE1LzA5LzMwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxz

PC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJvdGVpbnMvZ2VuZXRpY3MvaW1tdW5vbG9neS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWFzb21lcy9n

ZW5ldGljcy9pbW11bm9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbiBNZWRpYXRvcnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5MdW5nL2ltbXVub2xv

Z3kvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmcgRGlzZWFzZXMv

Z2VuZXRpY3MvaW1tdW5vbG9neS8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5T

aWduYWwgVHJhbnNkdWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hc29tZXM8L2tleXdv

cmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnB1bG1vbmFyeSBkaXNl

YXNlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA0NC0xNTQ5PC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI2NDE4MTQ0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48

Y3VzdG9tMj5QTUM0ODIxMDQ1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MTY1L3JjbWIuMjAxNS0wMjMxVFI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0

YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVu

ZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051

bT4xMjc3NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTA1LCAxMDZdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyNzc3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0NTk5MzEzMjMiPjEyNzc3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5KbywgRS4gSy48L2F1dGhvcj48YXV0aG9yPktpbSwgSi4gSy48L2F1dGhvcj48YXV0aG9y

PlNoaW4sIEQuIE0uPC9hdXRob3I+PGF1dGhvcj5TYXNha2F3YSwgQy48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1pY3JvYmlvbG9n

eSwgQ2h1bmduYW0gTmF0aW9uYWwgVW5pdmVyc2l0eSBTY2hvb2wgb2YgTWVkaWNpbmUsIERhZWpl

b24gMzAxLTc0NywgU291dGggS29yZWEuJiN4RDtJbmZlY3Rpb24gU2lnbmFsaW5nIE5ldHdvcmsg

UmVzZWFyY2ggQ2VudGVyLCBDaHVuZ25hbSBOYXRpb25hbCBVbml2ZXJzaXR5IFNjaG9vbCBvZiBN

ZWRpY2luZSwgRGFlamVvbiAzMDEtNzQ3LCBTb3V0aCBLb3JlYS4mI3hEO01lZGljYWwgTXljb2xv

Z3kgUmVzZWFyY2ggQ2VudGVyLCBDaGliYSBVbml2ZXJzaXR5LCBDaGliYSAyNjAtODY3MywgSmFw

YW4uJiN4RDtOaXBwb24gSW5zdGl0dXRlIGZvciBCaW9sb2dpY2FsIFNjaWVuY2UsIFRva3lvIDE5

OC0wMDI0LCBKYXBhbi48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5Nb2xlY3VsYXIgbWVj

aGFuaXNtcyByZWd1bGF0aW5nIE5MUlAzIGluZmxhbW1hc29tZSBhY3RpdmF0aW9uPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkNlbGwgTW9sIEltbXVub2w8L3NlY29uZGFyeS10aXRsZT48YWx0LXRp

dGxlPkNlbGx1bGFyICZhbXA7IG1vbGVjdWxhciBpbW11bm9sb2d5PC9hbHQtdGl0bGU+PC90aXRs

ZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2VsbCBNb2wgSW1tdW5vbDwvZnVsbC10aXRsZT48

YWJici0xPkNlbGx1bGFyICZhbXA7IG1vbGVjdWxhciBpbW11bm9sb2d5PC9hYmJyLTE+PC9wZXJp

b2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5DZWxsIE1vbCBJbW11bm9sPC9mdWxs

LXRpdGxlPjxhYmJyLTE+Q2VsbHVsYXIgJmFtcDsgbW9sZWN1bGFyIGltbXVub2xvZ3k8L2FiYnIt

MT48L2FsdC1wZXJpb2RpY2FsPjxwYWdlcz4xNDgtNTk8L3BhZ2VzPjx2b2x1bWU+MTM8L3ZvbHVt

ZT48bnVtYmVyPjI8L251bWJlcj48ZWRpdGlvbj4yMDE1LzExLzEwPC9lZGl0aW9uPjxkYXRlcz48

eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyPC9kYXRlPjwvcHViLWRhdGVzPjwv

ZGF0ZXM+PGlzYm4+MTY3Mi03NjgxPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2NTQ5ODAwPC9hY2Nl

c3Npb24tbnVtPjx1cmxzPjwvdXJscz48Y3VzdG9tMj5QTUM0Nzg2NjM0PC9jdXN0b20yPjxlbGVj

dHJvbmljLXJlc291cmNlLW51bT4xMC4xMDM4L2NtaS4yMDE1Ljk1PC9lbGVjdHJvbmljLXJlc291

cmNlLW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXBy

b3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0

aG9yPkxlZTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051bT4xMjg5OTwvUmVjTnVtPjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTI4OTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQ3NTU5MzMzMCI+MTI4OTk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkxlZSwgUy48L2F1dGhvcj48YXV0aG9yPlN1aCwgRy4gWS48L2F1dGhvcj48YXV0aG9y

PlJ5dGVyLCBTLiBXLjwvYXV0aG9yPjxhdXRob3I+Q2hvaSwgQS4gTS48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz4xIERlcGFydG1lbnQgb2YgQ3JpdGljYWwg

Q2FyZSBNZWRpY2luZSwgU2Ftc3VuZyBNZWRpY2FsIENlbnRlciwgU3VuZ2t5dW5rd2FuIFVuaXZl

cnNpdHkgU2Nob29sIG9mIE1lZGljaW5lLCBTZW91bCwgUmVwdWJsaWMgb2YgS29yZWEuJiN4RDsy

IEpvYW4gYW5kIFNhbmZvcmQgSS4gV2VpbGwgRGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgTmV3IFlv

cmstUHJlc2J5dGVyaWFuIEhvc3BpdGFsLCBOZXcgWW9yaywgTmV3IFlvcms7IGFuZC4mI3hEOzMg

RGl2aXNpb24gb2YgUHVsbW9uYXJ5IGFuZCBDcml0aWNhbCBDYXJlIE1lZGljaW5lLCBXZWlsbCBD

b3JuZWxsIE1lZGljYWwgQ2VudGVyLCBOZXcgWW9yaywgTmV3IFlvcmsuPC9hdXRoLWFkZHJlc3M+

PHRpdGxlcz48dGl0bGU+UmVndWxhdGlvbiBhbmQgRnVuY3Rpb24gb2YgdGhlIE51Y2xlb3RpZGUg

QmluZGluZyBEb21haW4gTGV1Y2luZS1SaWNoIFJlcGVhdC1Db250YWluaW5nIFJlY2VwdG9yLCBQ

eXJpbiBEb21haW4tQ29udGFpbmluZy0zIEluZmxhbW1hc29tZSBpbiBMdW5nIERpc2Vhc2U8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ2VsbCBNb2wgQmlvbDwvc2Vjb25kYXJ5

LXRpdGxlPjxhbHQtdGl0bGU+QW1lcmljYW4gam91cm5hbCBvZiByZXNwaXJhdG9yeSBjZWxsIGFu

ZCBtb2xlY3VsYXIgYmlvbG9neTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPkFtIEogUmVzcGlyIENlbGwgTW9sIEJpb2w8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz4xNTEtNjA8L3BhZ2VzPjx2b2x1bWU+NTQ8L3ZvbHVtZT48bnVtYmVyPjI8L251bWJl

cj48ZWRpdGlvbj4yMDE1LzA5LzMwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BbmltYWxz

PC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJvdGVpbnMvZ2VuZXRpY3MvaW1tdW5vbG9neS8q

bWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbjwv

a2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWFzb21lcy9n

ZW5ldGljcy9pbW11bm9sb2d5LyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkluZmxhbW1h

dGlvbiBNZWRpYXRvcnMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5MdW5nL2ltbXVub2xv

Z3kvKm1ldGFib2xpc20vcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmcgRGlzZWFzZXMv

Z2VuZXRpY3MvaW1tdW5vbG9neS8qbWV0YWJvbGlzbS9wYXRob2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+TWl0b2Nob25kcmlhL2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5T

aWduYWwgVHJhbnNkdWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hc29tZXM8L2tleXdv

cmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPnB1bG1vbmFyeSBkaXNl

YXNlczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE2PC95ZWFyPjxwdWItZGF0

ZXM+PGRhdGU+RmViPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA0NC0xNTQ5PC9p

c2JuPjxhY2Nlc3Npb24tbnVtPjI2NDE4MTQ0PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48

Y3VzdG9tMj5QTUM0ODIxMDQ1PC9jdXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4x

MTY1L3JjbWIuMjAxNS0wMjMxVFI8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0

YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVu

ZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [105, 106]. Most attention has focused on NLRP3 Inflammasomes, which may play a role in several inflammatory lung diseases, including asthma and COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

dW0+MTI3Nzg8L1JlY051bT48RGlzcGxheVRleHQ+WzEwN108L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTI3Nzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTQ1OTkzMTQzMSI+MTI3Nzg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PktpbSwgUi4gWS48L2F1dGhvcj48YXV0aG9yPlBpbmtlcnRvbiwgSi4gVy48L2F1dGhvcj48YXV0

aG9yPkdpYnNvbiwgUC4gRy48L2F1dGhvcj48YXV0aG9yPkNvb3BlciwgTS4gQS48L2F1dGhvcj48

YXV0aG9yPkhvcnZhdCwgSi4gQy48L2F1dGhvcj48YXV0aG9yPkhhbnNicm8sIFAuIE0uPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UHJpb3JpdHkgUmVzZWFy

Y2ggQ2VudHJlIGZvciBBc3RobWEgYW5kIFJlc3BpcmF0b3J5IERpc2Vhc2VzLCBIdW50ZXIgTWVk

aWNhbCBSZXNlYXJjaCBJbnN0aXR1dGUgYW5kIFRoZSBVbml2ZXJzaXR5IG9mIE5ld2Nhc3RsZSwg

TmV3Y2FzdGxlLCBOZXcgU291dGggV2FsZXMsIEF1c3RyYWxpYS4mI3hEO0RpdmlzaW9uIG9mIENo

ZW1pc3RyeSBhbmQgU3RydWN0dXJhbCBCaW9sb2d5LCBJbnN0aXR1dGUgZm9yIE1vbGVjdWxhciBC

aW9zY2llbmNlLCBUaGUgVW5pdmVyc2l0eSBvZiBRdWVlbnNsYW5kLCBCcmlzYmFuZSwgUXVlZW5z

bGFuZCwgQXVzdHJhbGlhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluZmxhbW1hc29t

ZXMgaW4gQ09QRCBhbmQgbmV1dHJvcGhpbGljIGFzdGhtYTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5UaG9yYXg8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRob3JheDwvYWx0LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L2Fs

dC1wZXJpb2RpY2FsPjxwYWdlcz4xMTk5LTIwMTwvcGFnZXM+PHZvbHVtZT43MDwvdm9sdW1lPjxu

dW1iZXI+MTI8L251bWJlcj48ZWRpdGlvbj4yMDE1LzEwLzI0PC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5Bc3RobWEvZ2VuZXRpY3MvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5DYXJyaWVyIFByb3RlaW5zL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FzcGFzZSAx

L3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzL3BoeXNpb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uIFByb2ZpbGluZzwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWFzb21lcy8qcGh5c2lvbG9neTwva2V5d29y

ZD48a2V5d29yZD5JbnRlcmxldWtpbi0xYmV0YS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXRyb3BoaWxzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vh

c2UsIENocm9uaWMgT2JzdHJ1Y3RpdmUvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5TbW9raW5nL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdv

cmQ+PGtleXdvcmQ+Q09QRCBFeGFjZXJiYXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQgQVUg

TWVjaGFuaXNtczwva2V5d29yZD48a2V5d29yZD5Jbm5hdGUgSW1tdW5pdHk8L2tleXdvcmQ+PGtl

eXdvcmQ+UmVzcGlyYXRvcnkgSW5mZWN0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5EZWM8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMDQwLTYzNzY8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY0OTM5OTA8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTM2L3Ro

b3JheGpubC0yMDE0LTIwNjczNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRh

YmFzZS1wcm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5n

PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaW08L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

dW0+MTI3Nzg8L1JlY051bT48RGlzcGxheVRleHQ+WzEwN108L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+

PHJlYy1udW1iZXI+MTI3Nzg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTQ1OTkzMTQzMSI+MTI3Nzg8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PktpbSwgUi4gWS48L2F1dGhvcj48YXV0aG9yPlBpbmtlcnRvbiwgSi4gVy48L2F1dGhvcj48YXV0

aG9yPkdpYnNvbiwgUC4gRy48L2F1dGhvcj48YXV0aG9yPkNvb3BlciwgTS4gQS48L2F1dGhvcj48

YXV0aG9yPkhvcnZhdCwgSi4gQy48L2F1dGhvcj48YXV0aG9yPkhhbnNicm8sIFAuIE0uPC9hdXRo

b3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+UHJpb3JpdHkgUmVzZWFy

Y2ggQ2VudHJlIGZvciBBc3RobWEgYW5kIFJlc3BpcmF0b3J5IERpc2Vhc2VzLCBIdW50ZXIgTWVk

aWNhbCBSZXNlYXJjaCBJbnN0aXR1dGUgYW5kIFRoZSBVbml2ZXJzaXR5IG9mIE5ld2Nhc3RsZSwg

TmV3Y2FzdGxlLCBOZXcgU291dGggV2FsZXMsIEF1c3RyYWxpYS4mI3hEO0RpdmlzaW9uIG9mIENo

ZW1pc3RyeSBhbmQgU3RydWN0dXJhbCBCaW9sb2d5LCBJbnN0aXR1dGUgZm9yIE1vbGVjdWxhciBC

aW9zY2llbmNlLCBUaGUgVW5pdmVyc2l0eSBvZiBRdWVlbnNsYW5kLCBCcmlzYmFuZSwgUXVlZW5z

bGFuZCwgQXVzdHJhbGlhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkluZmxhbW1hc29t

ZXMgaW4gQ09QRCBhbmQgbmV1dHJvcGhpbGljIGFzdGhtYTwvdGl0bGU+PHNlY29uZGFyeS10aXRs

ZT5UaG9yYXg8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPlRob3JheDwvYWx0LXRpdGxlPjwv

dGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L3Blcmlv

ZGljYWw+PGFsdC1wZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L2Fs

dC1wZXJpb2RpY2FsPjxwYWdlcz4xMTk5LTIwMTwvcGFnZXM+PHZvbHVtZT43MDwvdm9sdW1lPjxu

dW1iZXI+MTI8L251bWJlcj48ZWRpdGlvbj4yMDE1LzEwLzI0PC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5Bc3RobWEvZ2VuZXRpY3MvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5DYXJyaWVyIFByb3RlaW5zL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FzcGFzZSAx

L3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b2tpbmVzL3BoeXNpb2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uIFByb2ZpbGluZzwva2V5d29yZD48a2V5d29yZD5I

dW1hbnM8L2tleXdvcmQ+PGtleXdvcmQ+SW5mbGFtbWFzb21lcy8qcGh5c2lvbG9neTwva2V5d29y

ZD48a2V5d29yZD5JbnRlcmxldWtpbi0xYmV0YS9waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk5ldXRyb3BoaWxzL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHVsbW9uYXJ5IERpc2Vh

c2UsIENocm9uaWMgT2JzdHJ1Y3RpdmUvKnBoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29y

ZD5TbW9raW5nL3BoeXNpb3BhdGhvbG9neTwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdv

cmQ+PGtleXdvcmQ+Q09QRCBFeGFjZXJiYXRpb25zPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQgQVUg

TWVjaGFuaXNtczwva2V5d29yZD48a2V5d29yZD5Jbm5hdGUgSW1tdW5pdHk8L2tleXdvcmQ+PGtl

eXdvcmQ+UmVzcGlyYXRvcnkgSW5mZWN0aW9uPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5

ZWFyPjIwMTU8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT5EZWM8L2RhdGU+PC9wdWItZGF0ZXM+PC9k

YXRlcz48aXNibj4wMDQwLTYzNzY8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjY0OTM5OTA8L2FjY2Vz

c2lvbi1udW0+PHVybHM+PC91cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTM2L3Ro

b3JheGpubC0yMDE0LTIwNjczNjwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRh

YmFzZS1wcm92aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5n

PC9sYW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [107]. The role of NLRP3 inflammasomes in asthma is uncertain, with conflicting results in animal models, but recent studies have shown that NLRP3 may play a role in Th2 cell differentiation, independently of caspase-1 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcnVjaGFyZDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT4xMjkzNjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTA4XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjkzNjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxNDgyNTA4NTU2Ij4xMjkzNjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+QnJ1Y2hhcmQsIE0uPC9hdXRob3I+PGF1dGhvcj5SZWJlLCBDLjwvYXV0aG9yPjxhdXRo

b3I+RGVyYW5nZXJlLCBWLjwvYXV0aG9yPjxhdXRob3I+VG9nYmUsIEQuPC9hdXRob3I+PGF1dGhv

cj5SeWZmZWwsIEIuPC9hdXRob3I+PGF1dGhvcj5Cb2lkb3QsIFIuPC9hdXRob3I+PGF1dGhvcj5I

dW1ibGluLCBFLjwvYXV0aG9yPjxhdXRob3I+SGFtbWFuLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2hh

bG1pbiwgRi48L2F1dGhvcj48YXV0aG9yPkJlcmdlciwgSC48L2F1dGhvcj48YXV0aG9yPkNoZXZy

aWF1eCwgQS48L2F1dGhvcj48YXV0aG9yPkxpbWFnbmUsIEUuPC9hdXRob3I+PGF1dGhvcj5BcGV0

b2gsIEwuPC9hdXRob3I+PGF1dGhvcj5WZWdyYW4sIEYuPC9hdXRob3I+PGF1dGhvcj5HaGlyaW5n

aGVsbGksIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

MV0gSW5zZXJtLCBVODY2LCBEaWpvbiwgRnJhbmNlLiBbMl0gRmFjdWx0ZSBkZSBNZWRlY2luZSwg

VW5pdmVyc2l0ZSBkZSBCb3VyZ29nbmUsIERpam9uLCBGcmFuY2UuJiN4RDsxXSBJbnNlcm0sIFU4

NjYsIERpam9uLCBGcmFuY2UuIFsyXSBGYWN1bHRlIGRlIE1lZGVjaW5lLCBVbml2ZXJzaXRlIGRl

IEJvdXJnb2duZSwgRGlqb24sIEZyYW5jZS4gWzNdIENlbnRyZSBHZW9yZ2VzIEZyYW5jb2lzIExl

Y2xlcmMsIERpam9uLCBGcmFuY2UuJiN4RDtBcnRpbW11bmUsIE9ybGVhbnMsIEZyYW5jZS4mI3hE

O0xhYm9yYXRvcnkgb2YgRXhwZXJpbWVudGFsIGFuZCBNb2xlY3VsYXIgSW1tdW5vbG9neSBhbmQg

TmV1cm9nZW5ldGljcywgVU1SIDczNTUgQ05SUy1Vbml2ZXJzaXR5IG9mIE9ybGVhbnMsIE9ybGVh

bnMsIEZyYW5jZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgcmVjZXB0b3IgTkxS

UDMgaXMgYSB0cmFuc2NyaXB0aW9uYWwgcmVndWxhdG9yIG9mIFRIMiBkaWZmZXJlbnRpYXRpb248

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IEltbXVub2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPk5hdHVyZSBpbW11bm9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmF0IEltbXVub2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5OYXR1cmUgaW1tdW5v

bG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0

IEltbXVub2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5OYXR1cmUgaW1tdW5vbG9neTwvYWJici0xPjwv

YWx0LXBlcmlvZGljYWw+PHBhZ2VzPjg1OS03MDwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxu

dW1iZXI+ODwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDYvMjM8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hL2dlbmV0aWNzL2ltbXVub2xv

Z3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2VzdGVybjwva2V5d29y

ZD48a2V5d29yZD5DRDQtUG9zaXRpdmUgVC1MeW1waG9jeXRlcy9pbW11bm9sb2d5L21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+Q2FycmllciBQcm90ZWlucy9nZW5ldGljcy8qaW1tdW5vbG9n

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGlmZmVyZW50aWF0aW9uL2dlbmV0

aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBQcm9m

aWxpbmc8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uIFJlZ3VsYXRpb24sIE5lb3Bs

YXN0aWMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXNvbWVzL2dlbmV0aWNz

L2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbnRlcmZlcm9uIFJlZ3Vs

YXRvcnkgRmFjdG9ycy9nZW5ldGljcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+SW50ZXJsZXVraW4tNC9nZW5ldGljcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+TklIIDNUMyBD

ZWxsczwva2V5d29yZD48a2V5d29yZD5OTFIgRmFtaWx5LCBQeXJpbiBEb21haW4tQ29udGFpbmlu

ZyAzIFByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+TmVvcGxhc21zLCBFeHBlcmltZW50YWwvZ2Vu

ZXRpY3MvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk9saWdvbnVjbGVv

dGlkZSBBcnJheSBTZXF1ZW5jZSBBbmFseXNpczwva2V5d29yZD48a2V5d29yZD5Qcm9tb3RlciBS

ZWdpb25zLCBHZW5ldGljL2dlbmV0aWNzL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJv

dGVpbiBCaW5kaW5nL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmV2ZXJzZSBUcmFuc2Ny

aXB0YXNlIFBvbHltZXJhc2UgQ2hhaW4gUmVhY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFs

IFRyYW5zZHVjdGlvbi9nZW5ldGljcy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRoMiBD

ZWxscy8qaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRyYW5zLUFjdGl2

YXRvcnMvZ2VuZXRpY3MvKmltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyOS0yOTA4PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MDk4

OTk3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAzOC9uaS4zMjAyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNl

LXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xh

bmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcnVjaGFyZDwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

PFJlY051bT4xMjkzNjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTA4XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjkzNjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxNDgyNTA4NTU2Ij4xMjkzNjwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+QnJ1Y2hhcmQsIE0uPC9hdXRob3I+PGF1dGhvcj5SZWJlLCBDLjwvYXV0aG9yPjxhdXRo

b3I+RGVyYW5nZXJlLCBWLjwvYXV0aG9yPjxhdXRob3I+VG9nYmUsIEQuPC9hdXRob3I+PGF1dGhv

cj5SeWZmZWwsIEIuPC9hdXRob3I+PGF1dGhvcj5Cb2lkb3QsIFIuPC9hdXRob3I+PGF1dGhvcj5I

dW1ibGluLCBFLjwvYXV0aG9yPjxhdXRob3I+SGFtbWFuLCBBLjwvYXV0aG9yPjxhdXRob3I+Q2hh

bG1pbiwgRi48L2F1dGhvcj48YXV0aG9yPkJlcmdlciwgSC48L2F1dGhvcj48YXV0aG9yPkNoZXZy

aWF1eCwgQS48L2F1dGhvcj48YXV0aG9yPkxpbWFnbmUsIEUuPC9hdXRob3I+PGF1dGhvcj5BcGV0

b2gsIEwuPC9hdXRob3I+PGF1dGhvcj5WZWdyYW4sIEYuPC9hdXRob3I+PGF1dGhvcj5HaGlyaW5n

aGVsbGksIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

MV0gSW5zZXJtLCBVODY2LCBEaWpvbiwgRnJhbmNlLiBbMl0gRmFjdWx0ZSBkZSBNZWRlY2luZSwg

VW5pdmVyc2l0ZSBkZSBCb3VyZ29nbmUsIERpam9uLCBGcmFuY2UuJiN4RDsxXSBJbnNlcm0sIFU4

NjYsIERpam9uLCBGcmFuY2UuIFsyXSBGYWN1bHRlIGRlIE1lZGVjaW5lLCBVbml2ZXJzaXRlIGRl

IEJvdXJnb2duZSwgRGlqb24sIEZyYW5jZS4gWzNdIENlbnRyZSBHZW9yZ2VzIEZyYW5jb2lzIExl

Y2xlcmMsIERpam9uLCBGcmFuY2UuJiN4RDtBcnRpbW11bmUsIE9ybGVhbnMsIEZyYW5jZS4mI3hE

O0xhYm9yYXRvcnkgb2YgRXhwZXJpbWVudGFsIGFuZCBNb2xlY3VsYXIgSW1tdW5vbG9neSBhbmQg

TmV1cm9nZW5ldGljcywgVU1SIDczNTUgQ05SUy1Vbml2ZXJzaXR5IG9mIE9ybGVhbnMsIE9ybGVh

bnMsIEZyYW5jZS48L2F1dGgtYWRkcmVzcz48dGl0bGVzPjx0aXRsZT5UaGUgcmVjZXB0b3IgTkxS

UDMgaXMgYSB0cmFuc2NyaXB0aW9uYWwgcmVndWxhdG9yIG9mIFRIMiBkaWZmZXJlbnRpYXRpb248

L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0IEltbXVub2w8L3NlY29uZGFyeS10aXRsZT48YWx0

LXRpdGxlPk5hdHVyZSBpbW11bm9sb2d5PC9hbHQtdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+

PGZ1bGwtdGl0bGU+TmF0IEltbXVub2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5OYXR1cmUgaW1tdW5v

bG9neTwvYWJici0xPjwvcGVyaW9kaWNhbD48YWx0LXBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+TmF0

IEltbXVub2w8L2Z1bGwtdGl0bGU+PGFiYnItMT5OYXR1cmUgaW1tdW5vbG9neTwvYWJici0xPjwv

YWx0LXBlcmlvZGljYWw+PHBhZ2VzPjg1OS03MDwvcGFnZXM+PHZvbHVtZT4xNjwvdm9sdW1lPjxu

dW1iZXI+ODwvbnVtYmVyPjxlZGl0aW9uPjIwMTUvMDYvMjM8L2VkaXRpb24+PGtleXdvcmRzPjxr

ZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hL2dlbmV0aWNzL2ltbXVub2xv

Z3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5CbG90dGluZywgV2VzdGVybjwva2V5d29y

ZD48a2V5d29yZD5DRDQtUG9zaXRpdmUgVC1MeW1waG9jeXRlcy9pbW11bm9sb2d5L21ldGFib2xp

c208L2tleXdvcmQ+PGtleXdvcmQ+Q2FycmllciBQcm90ZWlucy9nZW5ldGljcy8qaW1tdW5vbG9n

eS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgRGlmZmVyZW50aWF0aW9uL2dlbmV0

aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNlbGwgTGluZSwgVHVtb3I8L2tleXdv

cmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbiBQcm9m

aWxpbmc8L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uIFJlZ3VsYXRpb24sIE5lb3Bs

YXN0aWMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5JbmZsYW1tYXNvbWVzL2dlbmV0aWNz

L2ltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5JbnRlcmZlcm9uIFJlZ3Vs

YXRvcnkgRmFjdG9ycy9nZW5ldGljcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdvcmQ+PGtl

eXdvcmQ+SW50ZXJsZXVraW4tNC9nZW5ldGljcy9pbW11bm9sb2d5L21ldGFib2xpc208L2tleXdv

cmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBJbmJyZWQgQzU3Qkw8L2tl

eXdvcmQ+PGtleXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+TklIIDNUMyBD

ZWxsczwva2V5d29yZD48a2V5d29yZD5OTFIgRmFtaWx5LCBQeXJpbiBEb21haW4tQ29udGFpbmlu

ZyAzIFByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+TmVvcGxhc21zLCBFeHBlcmltZW50YWwvZ2Vu

ZXRpY3MvaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk9saWdvbnVjbGVv

dGlkZSBBcnJheSBTZXF1ZW5jZSBBbmFseXNpczwva2V5d29yZD48a2V5d29yZD5Qcm9tb3RlciBS

ZWdpb25zLCBHZW5ldGljL2dlbmV0aWNzL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UHJv

dGVpbiBCaW5kaW5nL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UmV2ZXJzZSBUcmFuc2Ny

aXB0YXNlIFBvbHltZXJhc2UgQ2hhaW4gUmVhY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+U2lnbmFs

IFRyYW5zZHVjdGlvbi9nZW5ldGljcy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlRoMiBD

ZWxscy8qaW1tdW5vbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlRyYW5zLUFjdGl2

YXRvcnMvZ2VuZXRpY3MvKmltbXVub2xvZ3kvbWV0YWJvbGlzbTwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXVnPC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTUyOS0yOTA4PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI2MDk4

OTk3PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAzOC9uaS4zMjAyPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48cmVtb3RlLWRhdGFiYXNl

LXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPjxsYW5ndWFnZT5lbmc8L2xh

bmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [108]. It is possible that NLRP3 inflammasomes play a role in acute exacerbations of asthma, where there is an increase in oxidative stress.The adapter protein ASC is an important component of the NLRP3 inflammasome, which recruits pro-caspase-1 to the protein complex and is increased in lungs of COPD patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFua2xpbjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

PFJlY051bT4xMjc4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTA5XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjc4MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxNDU5OTQyNTY2Ij4xMjc4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+RnJhbmtsaW4sIEIuIFMuPC9hdXRob3I+PGF1dGhvcj5Cb3NzYWxsZXIsIEwuPC9hdXRo

b3I+PGF1dGhvcj5EZSBOYXJkbywgRC48L2F1dGhvcj48YXV0aG9yPlJhdHRlciwgSi4gTS48L2F1

dGhvcj48YXV0aG9yPlN0dXR6LCBBLjwvYXV0aG9yPjxhdXRob3I+RW5nZWxzLCBHLjwvYXV0aG9y

PjxhdXRob3I+QnJlbmtlciwgQy48L2F1dGhvcj48YXV0aG9yPk5vcmRob2ZmLCBNLjwvYXV0aG9y

PjxhdXRob3I+TWlyYW5kb2xhLCBTLiBSLjwvYXV0aG9yPjxhdXRob3I+QWwtQW1vdWRpLCBBLjwv

YXV0aG9yPjxhdXRob3I+TWFuZ2FuLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+WmltbWVyLCBTLjwv

YXV0aG9yPjxhdXRob3I+TW9ua3MsIEIuIEcuPC9hdXRob3I+PGF1dGhvcj5Gcmlja2UsIE0uPC9h

dXRob3I+PGF1dGhvcj5TY2htaWR0LCBSLiBFLjwvYXV0aG9yPjxhdXRob3I+RXNwZXZpaywgVC48

L2F1dGhvcj48YXV0aG9yPkpvbmVzLCBCLjwvYXV0aG9yPjxhdXRob3I+SmFybmlja2ksIEEuIEcu

PC9hdXRob3I+PGF1dGhvcj5IYW5zYnJvLCBQLiBNLjwvYXV0aG9yPjxhdXRob3I+QnVzdG8sIFAu

PC9hdXRob3I+PGF1dGhvcj5NYXJzaGFrLVJvdGhzdGVpbiwgQS48L2F1dGhvcj48YXV0aG9yPkhv

cm5lbWFubiwgUy48L2F1dGhvcj48YXV0aG9yPkFndXp6aSwgQS48L2F1dGhvcj48YXV0aG9yPkth

c3Rlbm11bGxlciwgVy48L2F1dGhvcj48YXV0aG9yPkxhdHosIEUuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXRlIG9mIElubmF0ZSBJbW11bml0

eSwgVW5pdmVyc2l0eSBIb3NwaXRhbHMsIFVuaXZlcnNpdHkgb2YgQm9ubiwgQm9ubiwgR2VybWFu

eS4mI3hEOzFdIERlcGFydG1lbnQgb2YgSW1tdW5vbG9neSBhbmQgUmhldW1hdG9sb2d5LCBIYW5u

b3ZlciBNZWRpY2FsIFNjaG9vbCwgSGFubm92ZXIsIEdlcm1hbnkuIFsyXSBEZXBhcnRtZW50IG9m

IEluZmVjdGlvdXMgRGlzZWFzZXMgYW5kIEltbXVub2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWFzc2Fj

aHVzZXR0cyBNZWRpY2FsIFNjaG9vbCwgV29yY2VzdGVyLCBNYXNzYWNodXNldHRzLCBVU0EuJiN4

RDtHZXJtYW4gQ2VudGVyIGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcywgQm9ubiwgR2Vy

bWFueS4mI3hEOzFdIEluc3RpdHV0ZSBvZiBJbm5hdGUgSW1tdW5pdHksIFVuaXZlcnNpdHkgSG9z

cGl0YWxzLCBVbml2ZXJzaXR5IG9mIEJvbm4sIEJvbm4sIEdlcm1hbnkuIFsyXSBHZXJtYW4gQ2Vu

dGVyIGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcywgQm9ubiwgR2VybWFueS4mI3hEO0Rl

cGFydG1lbnQgb2YgTWVkaWNpbmUvQ2FyZGlvbG9neSwgVW5pdmVyc2l0eSBIb3NwaXRhbHMsIFVu

aXZlcnNpdHkgb2YgQm9ubiwgQm9ubiwgR2VybWFueS4mI3hEOzFdIEluc3RpdHV0ZSBvZiBJbm5h

dGUgSW1tdW5pdHksIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBVbml2ZXJzaXR5IG9mIEJvbm4sIEJv

bm4sIEdlcm1hbnkuIFsyXSBEZXBhcnRtZW50IG9mIEluZmVjdGlvdXMgRGlzZWFzZXMgYW5kIElt

bXVub2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWFzc2FjaHVzZXR0cyBNZWRpY2FsIFNjaG9vbCwgV29y

Y2VzdGVyLCBNYXNzYWNodXNldHRzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEltbXVub2xvZ3kg

YW5kIFJoZXVtYXRvbG9neSwgSGFubm92ZXIgTWVkaWNhbCBTY2hvb2wsIEhhbm5vdmVyLCBHZXJt

YW55LiYjeEQ7Q2VudGVyIG9mIE1vbGVjdWxhciBJbmZsYW1tYXRpb24gUmVzZWFyY2gsIERlcGFy

dG1lbnQgb2YgQ2FuY2VyIFJlc2VhcmNoIGFuZCBNb2xlY3VsYXIgTWVkaWNpbmUsIE5vcndlZ2lh

biBVbml2ZXJzaXR5IG9mIFNjaWVuY2UgYW5kIFRlY2hub2xvZ3ksIFRyb25kaGVpbSwgTm9yd2F5

LiYjeEQ7Q2VudHJlIGZvciBBc3RobWEgYW5kIFJlc3BpcmF0b3J5IERpc2Vhc2UsIFRoZSBVbml2

ZXJzaXR5IG9mIE5ld2Nhc3RsZSwgTmV3Y2FzdGxlLCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50

IG9mIEluZmVjdGlvdXMgRGlzZWFzZXMgYW5kIEltbXVub2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWFz

c2FjaHVzZXR0cyBNZWRpY2FsIFNjaG9vbCwgV29yY2VzdGVyLCBNYXNzYWNodXNldHRzLCBVU0Eu

JiN4RDtVbml2ZXJzaXR5IEhvc3BpdGFsIFp1cmljaCwgSW5zdGl0dXRlIG9mIE5ldXJvcGF0aG9s

b2d5LCBadXJpY2gsIFN3aXR6ZXJsYW5kLiYjeEQ7SW5zdGl0dXRlIG9mIE1vbGVjdWxhciBNZWRp

Y2luZSBhbmQgRXhwZXJpbWVudGFsIEltbXVub2xvZ3ksIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBV

bml2ZXJzaXR5IG9mIEJvbm4sIEJvbm4sIEdlcm1hbnkuJiN4RDsxXSBJbnN0aXR1dGUgb2YgSW5u

YXRlIEltbXVuaXR5LCBVbml2ZXJzaXR5IEhvc3BpdGFscywgVW5pdmVyc2l0eSBvZiBCb25uLCBC

b25uLCBHZXJtYW55LiBbMl0gRGVwYXJ0bWVudCBvZiBJbmZlY3Rpb3VzIERpc2Vhc2VzIGFuZCBJ

bW11bm9sb2d5LCBVbml2ZXJzaXR5IG9mIE1hc3NhY2h1c2V0dHMgTWVkaWNhbCBTY2hvb2wsIFdv

cmNlc3RlciwgTWFzc2FjaHVzZXR0cywgVVNBLiBbM10gR2VybWFuIENlbnRlciBmb3IgTmV1cm9k

ZWdlbmVyYXRpdmUgRGlzZWFzZXMsIEJvbm4sIEdlcm1hbnkuIFs0XSBDZW50ZXIgb2YgTW9sZWN1

bGFyIEluZmxhbW1hdGlvbiBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDYW5jZXIgUmVzZWFyY2gg

YW5kIE1vbGVjdWxhciBNZWRpY2luZSwgTm9yd2VnaWFuIFVuaXZlcnNpdHkgb2YgU2NpZW5jZSBh

bmQgVGVjaG5vbG9neSwgVHJvbmRoZWltLCBOb3J3YXkuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+VGhlIGFkYXB0b3IgQVNDIGhhcyBleHRyYWNlbGx1bGFyIGFuZCAmYXBvcztwcmlvbm9p

ZCZhcG9zOyBhY3Rpdml0aWVzIHRoYXQgcHJvcGFnYXRlIGluZmxhbW1hdGlvbjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5OYXQgSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+TmF0

dXJlIGltbXVub2xvZ3k8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OYXQgSW1tdW5vbDwvZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSBpbW11bm9sb2d5PC9hYmJy

LTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQgSW1tdW5vbDwv

ZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSBpbW11bm9sb2d5PC9hYmJyLTE+PC9hbHQtcGVyaW9k

aWNhbD48cGFnZXM+NzI3LTM3PC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj44PC9u

dW1iZXI+PGVkaXRpb24+MjAxNC8wNi8yNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW1p

bm8gQWNpZCBDaGxvcm9tZXRoeWwgS2V0b25lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzL2ltbXVub2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QXBvcHRvc2lzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFwb3B0

b3NpcyBSZWd1bGF0b3J5IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPkF1dG9hbnRpYm9kaWVz

L2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXV0b2ltbXVuZSBEaXNlYXNlcy9pbW11bm9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJvdGVpbnMvZ2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+Q2FzcGFzZSAxL2dlbmV0aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkNhc3Bhc2UgSW5oaWJpdG9ycy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBD

b21tdW5pY2F0aW9uL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b3NrZWxldGFsIFBy

b3RlaW5zL2dlbmV0aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5JbmZsYW1tYXNvbWVzL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

SW5mbGFtbWF0aW9uLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkludGVybGV1a2luLTFi

ZXRhLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkx5c29zb21lcy9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5N

aWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBCQUxCIEM8L2tleXdvcmQ+PGtleXdv

cmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9r

ZXl3b3JkPjxrZXl3b3JkPlBoYWdvY3l0b3Npcy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlByaW9ucy9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+UHNldWRvbW9uYXMgSW5mZWN0aW9u

cy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBzZXVkb21vbmFzIGFlcnVnaW5vc2EvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2ltbXVub2xvZ3k8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjktMjkwODwvaXNibj48

YWNjZXNzaW9uLW51bT4yNDk1MjUwNTwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNDExNjY3NjwvY3VzdG9tMj48Y3VzdG9tNj5OSUhNUzU5MjEyOTwvY3VzdG9tNj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9uaS4yOTEzPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3Zp

ZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFua2xpbjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

PFJlY051bT4xMjc4MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTA5XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMjc4MDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxNDU5OTQyNTY2Ij4xMjc4MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+RnJhbmtsaW4sIEIuIFMuPC9hdXRob3I+PGF1dGhvcj5Cb3NzYWxsZXIsIEwuPC9hdXRo

b3I+PGF1dGhvcj5EZSBOYXJkbywgRC48L2F1dGhvcj48YXV0aG9yPlJhdHRlciwgSi4gTS48L2F1

dGhvcj48YXV0aG9yPlN0dXR6LCBBLjwvYXV0aG9yPjxhdXRob3I+RW5nZWxzLCBHLjwvYXV0aG9y

PjxhdXRob3I+QnJlbmtlciwgQy48L2F1dGhvcj48YXV0aG9yPk5vcmRob2ZmLCBNLjwvYXV0aG9y

PjxhdXRob3I+TWlyYW5kb2xhLCBTLiBSLjwvYXV0aG9yPjxhdXRob3I+QWwtQW1vdWRpLCBBLjwv

YXV0aG9yPjxhdXRob3I+TWFuZ2FuLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+WmltbWVyLCBTLjwv

YXV0aG9yPjxhdXRob3I+TW9ua3MsIEIuIEcuPC9hdXRob3I+PGF1dGhvcj5Gcmlja2UsIE0uPC9h

dXRob3I+PGF1dGhvcj5TY2htaWR0LCBSLiBFLjwvYXV0aG9yPjxhdXRob3I+RXNwZXZpaywgVC48

L2F1dGhvcj48YXV0aG9yPkpvbmVzLCBCLjwvYXV0aG9yPjxhdXRob3I+SmFybmlja2ksIEEuIEcu

PC9hdXRob3I+PGF1dGhvcj5IYW5zYnJvLCBQLiBNLjwvYXV0aG9yPjxhdXRob3I+QnVzdG8sIFAu

PC9hdXRob3I+PGF1dGhvcj5NYXJzaGFrLVJvdGhzdGVpbiwgQS48L2F1dGhvcj48YXV0aG9yPkhv

cm5lbWFubiwgUy48L2F1dGhvcj48YXV0aG9yPkFndXp6aSwgQS48L2F1dGhvcj48YXV0aG9yPkth

c3Rlbm11bGxlciwgVy48L2F1dGhvcj48YXV0aG9yPkxhdHosIEUuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SW5zdGl0dXRlIG9mIElubmF0ZSBJbW11bml0

eSwgVW5pdmVyc2l0eSBIb3NwaXRhbHMsIFVuaXZlcnNpdHkgb2YgQm9ubiwgQm9ubiwgR2VybWFu

eS4mI3hEOzFdIERlcGFydG1lbnQgb2YgSW1tdW5vbG9neSBhbmQgUmhldW1hdG9sb2d5LCBIYW5u

b3ZlciBNZWRpY2FsIFNjaG9vbCwgSGFubm92ZXIsIEdlcm1hbnkuIFsyXSBEZXBhcnRtZW50IG9m

IEluZmVjdGlvdXMgRGlzZWFzZXMgYW5kIEltbXVub2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWFzc2Fj

aHVzZXR0cyBNZWRpY2FsIFNjaG9vbCwgV29yY2VzdGVyLCBNYXNzYWNodXNldHRzLCBVU0EuJiN4

RDtHZXJtYW4gQ2VudGVyIGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcywgQm9ubiwgR2Vy

bWFueS4mI3hEOzFdIEluc3RpdHV0ZSBvZiBJbm5hdGUgSW1tdW5pdHksIFVuaXZlcnNpdHkgSG9z

cGl0YWxzLCBVbml2ZXJzaXR5IG9mIEJvbm4sIEJvbm4sIEdlcm1hbnkuIFsyXSBHZXJtYW4gQ2Vu

dGVyIGZvciBOZXVyb2RlZ2VuZXJhdGl2ZSBEaXNlYXNlcywgQm9ubiwgR2VybWFueS4mI3hEO0Rl

cGFydG1lbnQgb2YgTWVkaWNpbmUvQ2FyZGlvbG9neSwgVW5pdmVyc2l0eSBIb3NwaXRhbHMsIFVu

aXZlcnNpdHkgb2YgQm9ubiwgQm9ubiwgR2VybWFueS4mI3hEOzFdIEluc3RpdHV0ZSBvZiBJbm5h

dGUgSW1tdW5pdHksIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBVbml2ZXJzaXR5IG9mIEJvbm4sIEJv

bm4sIEdlcm1hbnkuIFsyXSBEZXBhcnRtZW50IG9mIEluZmVjdGlvdXMgRGlzZWFzZXMgYW5kIElt

bXVub2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWFzc2FjaHVzZXR0cyBNZWRpY2FsIFNjaG9vbCwgV29y

Y2VzdGVyLCBNYXNzYWNodXNldHRzLCBVU0EuJiN4RDtEZXBhcnRtZW50IG9mIEltbXVub2xvZ3kg

YW5kIFJoZXVtYXRvbG9neSwgSGFubm92ZXIgTWVkaWNhbCBTY2hvb2wsIEhhbm5vdmVyLCBHZXJt

YW55LiYjeEQ7Q2VudGVyIG9mIE1vbGVjdWxhciBJbmZsYW1tYXRpb24gUmVzZWFyY2gsIERlcGFy

dG1lbnQgb2YgQ2FuY2VyIFJlc2VhcmNoIGFuZCBNb2xlY3VsYXIgTWVkaWNpbmUsIE5vcndlZ2lh

biBVbml2ZXJzaXR5IG9mIFNjaWVuY2UgYW5kIFRlY2hub2xvZ3ksIFRyb25kaGVpbSwgTm9yd2F5

LiYjeEQ7Q2VudHJlIGZvciBBc3RobWEgYW5kIFJlc3BpcmF0b3J5IERpc2Vhc2UsIFRoZSBVbml2

ZXJzaXR5IG9mIE5ld2Nhc3RsZSwgTmV3Y2FzdGxlLCBBdXN0cmFsaWEuJiN4RDtEZXBhcnRtZW50

IG9mIEluZmVjdGlvdXMgRGlzZWFzZXMgYW5kIEltbXVub2xvZ3ksIFVuaXZlcnNpdHkgb2YgTWFz

c2FjaHVzZXR0cyBNZWRpY2FsIFNjaG9vbCwgV29yY2VzdGVyLCBNYXNzYWNodXNldHRzLCBVU0Eu

JiN4RDtVbml2ZXJzaXR5IEhvc3BpdGFsIFp1cmljaCwgSW5zdGl0dXRlIG9mIE5ldXJvcGF0aG9s

b2d5LCBadXJpY2gsIFN3aXR6ZXJsYW5kLiYjeEQ7SW5zdGl0dXRlIG9mIE1vbGVjdWxhciBNZWRp

Y2luZSBhbmQgRXhwZXJpbWVudGFsIEltbXVub2xvZ3ksIFVuaXZlcnNpdHkgSG9zcGl0YWxzLCBV

bml2ZXJzaXR5IG9mIEJvbm4sIEJvbm4sIEdlcm1hbnkuJiN4RDsxXSBJbnN0aXR1dGUgb2YgSW5u

YXRlIEltbXVuaXR5LCBVbml2ZXJzaXR5IEhvc3BpdGFscywgVW5pdmVyc2l0eSBvZiBCb25uLCBC

b25uLCBHZXJtYW55LiBbMl0gRGVwYXJ0bWVudCBvZiBJbmZlY3Rpb3VzIERpc2Vhc2VzIGFuZCBJ

bW11bm9sb2d5LCBVbml2ZXJzaXR5IG9mIE1hc3NhY2h1c2V0dHMgTWVkaWNhbCBTY2hvb2wsIFdv

cmNlc3RlciwgTWFzc2FjaHVzZXR0cywgVVNBLiBbM10gR2VybWFuIENlbnRlciBmb3IgTmV1cm9k

ZWdlbmVyYXRpdmUgRGlzZWFzZXMsIEJvbm4sIEdlcm1hbnkuIFs0XSBDZW50ZXIgb2YgTW9sZWN1

bGFyIEluZmxhbW1hdGlvbiBSZXNlYXJjaCwgRGVwYXJ0bWVudCBvZiBDYW5jZXIgUmVzZWFyY2gg

YW5kIE1vbGVjdWxhciBNZWRpY2luZSwgTm9yd2VnaWFuIFVuaXZlcnNpdHkgb2YgU2NpZW5jZSBh

bmQgVGVjaG5vbG9neSwgVHJvbmRoZWltLCBOb3J3YXkuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48

dGl0bGU+VGhlIGFkYXB0b3IgQVNDIGhhcyBleHRyYWNlbGx1bGFyIGFuZCAmYXBvcztwcmlvbm9p

ZCZhcG9zOyBhY3Rpdml0aWVzIHRoYXQgcHJvcGFnYXRlIGluZmxhbW1hdGlvbjwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5OYXQgSW1tdW5vbDwvc2Vjb25kYXJ5LXRpdGxlPjxhbHQtdGl0bGU+TmF0

dXJlIGltbXVub2xvZ3k8L2FsdC10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRs

ZT5OYXQgSW1tdW5vbDwvZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSBpbW11bm9sb2d5PC9hYmJy

LTE+PC9wZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5OYXQgSW1tdW5vbDwv

ZnVsbC10aXRsZT48YWJici0xPk5hdHVyZSBpbW11bm9sb2d5PC9hYmJyLTE+PC9hbHQtcGVyaW9k

aWNhbD48cGFnZXM+NzI3LTM3PC9wYWdlcz48dm9sdW1lPjE1PC92b2x1bWU+PG51bWJlcj44PC9u

dW1iZXI+PGVkaXRpb24+MjAxNC8wNi8yNDwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW1p

bm8gQWNpZCBDaGxvcm9tZXRoeWwgS2V0b25lcy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdv

cmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5BbnRpYm9kaWVzL2ltbXVub2xvZ3k8L2tleXdv

cmQ+PGtleXdvcmQ+QXBvcHRvc2lzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkFwb3B0

b3NpcyBSZWd1bGF0b3J5IFByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPkF1dG9hbnRpYm9kaWVz

L2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+QXV0b2ltbXVuZSBEaXNlYXNlcy9pbW11bm9s

b2d5PC9rZXl3b3JkPjxrZXl3b3JkPkNhcnJpZXIgUHJvdGVpbnMvZ2VuZXRpY3M8L2tleXdvcmQ+

PGtleXdvcmQ+Q2FzcGFzZSAxL2dlbmV0aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkNhc3Bhc2UgSW5oaWJpdG9ycy9waGFybWFjb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2VsbCBD

b21tdW5pY2F0aW9uL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q3l0b3NrZWxldGFsIFBy

b3RlaW5zL2dlbmV0aWNzLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwva2V5

d29yZD48a2V5d29yZD5JbmZsYW1tYXNvbWVzL2ltbXVub2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

SW5mbGFtbWF0aW9uLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkludGVybGV1a2luLTFi

ZXRhLyppbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkx5c29zb21lcy9wYXRob2xvZ3k8L2tl

eXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXMvaW1tdW5vbG9neTwva2V5d29yZD48a2V5d29yZD5N

aWNlPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEluYnJlZCBCQUxCIEM8L2tleXdvcmQ+PGtleXdv

cmQ+TWljZSwgSW5icmVkIEM1N0JMPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2UsIEtub2Nrb3V0PC9r

ZXl3b3JkPjxrZXl3b3JkPlBoYWdvY3l0b3Npcy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlByaW9ucy9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+UHNldWRvbW9uYXMgSW5mZWN0aW9u

cy9pbW11bm9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBzZXVkb21vbmFzIGFlcnVnaW5vc2EvaW1t

dW5vbG9neTwva2V5d29yZD48a2V5d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uL2ltbXVub2xvZ3k8

L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxNDwveWVhcj48cHViLWRhdGVzPjxk

YXRlPkF1ZzwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjE1MjktMjkwODwvaXNibj48

YWNjZXNzaW9uLW51bT4yNDk1MjUwNTwvYWNjZXNzaW9uLW51bT48dXJscz48L3VybHM+PGN1c3Rv

bTI+UE1DNDExNjY3NjwvY3VzdG9tMj48Y3VzdG9tNj5OSUhNUzU5MjEyOTwvY3VzdG9tNj48ZWxl

Y3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAzOC9uaS4yOTEzPC9lbGVjdHJvbmljLXJlc291cmNl

LW51bT48cmVtb3RlLWRhdGFiYXNlLXByb3ZpZGVyPk5MTTwvcmVtb3RlLWRhdGFiYXNlLXByb3Zp

ZGVyPjxsYW5ndWFnZT5lbmc8L2xhbmd1YWdlPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [109]. ASC accumulation is associated with the formation of extracellular “specks” which perpetuate the generation of IL-1β outside the cell. However in patients with stable COPD there is no increase in NLRP3 inflammasomes, except in patients with severe disease, possibly as a result of the inflammasome inhibitory molecules NALP7 and IL-37 ADDIN EN.CITE <EndNote><Cite><Author>Di Stefano</Author><Year>2014</Year><RecNum>11866</RecNum><DisplayText>[110]</DisplayText><record><rec-number>11866</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1391418781">11866</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Di Stefano, A.</author><author>Caramori, G.</author><author>Barczyk, A.</author><author>Vicari, C.</author><author>Brun, P.</author><author>Zanini, A.</author><author>Cappello, F.</author><author>Garofano, E.</author><author>Padovani, A.</author><author>Contoli, M.</author><author>Casolari, P.</author><author>Durham, A. L.</author><author>Chung, K. F.</author><author>Barnes, P. J.</author><author>Papi, A.</author><author>Adcock, I.</author><author>Balbi, B.</author></authors></contributors><auth-address>Divisione di Pneumologia e Laboratorio di Citoimmunopatologia dell&apos;Apparato Cardio Respiratorio, Fondazione Salvatore Maugeri, IRCCS, Veruno (NO) e Tradate, , Pavia, Italy.</auth-address><titles><title>Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD</title><secondary-title>Thorax</secondary-title><alt-title>Thorax</alt-title></titles><periodical><full-title>Thorax</full-title></periodical><alt-periodical><full-title>Thorax</full-title></alt-periodical><pages>516-524</pages><volume>69</volume><edition>2014/01/17</edition><dates><year>2014</year><pub-dates><date>Jan 15</date></pub-dates></dates><isbn>0040-6376</isbn><accession-num>24430176</accession-num><urls></urls><electronic-resource-num>10.1136/thoraxjnl-2012-203062</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[110]. The minimal role of the inflammasome in COPD is underlined by the lack of benefit with an IL-1β blocking antibody (canakinumab) in stable COPD ADDIN EN.CITE <EndNote><Cite><Author>Rogliani</Author><Year>2015</Year><RecNum>12271</RecNum><DisplayText>[111]</DisplayText><record><rec-number>12271</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1429014143">12271</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rogliani, P.</author><author>Calzetta, L.</author><author>Ora, J.</author><author>Matera, M. G.</author></authors></contributors><auth-address>Department of System Medicine, University of Rome &quot;Tor Vergata&quot;, Rome, Italy. Electronic address: paola.rogliani@uniroma2.it.&#xD;Department of System Medicine, University of Rome &quot;Tor Vergata&quot;, Rome, Italy.&#xD;Department of Experimental Medicine, Second University of Naples, Naples, Italy.</auth-address><titles><title>Canakinumab for the treatment of chronic obstructive pulmonary disease</title><secondary-title>Pulm Pharmacol Ther</secondary-title><alt-title>Pulmonary pharmacology &amp; therapeutics</alt-title></titles><periodical><full-title>Pulm Pharmacol Ther</full-title></periodical><pages>15-27</pages><volume>31</volume><edition>2015/02/11</edition><dates><year>2015</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1094-5539</isbn><accession-num>25660162</accession-num><urls></urls><electronic-resource-num>10.1016/j.pupt.2015.01.005</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[111]. As in asthma, is more likely that NLRP3 inflammasome activation is linked to acute exacerbations, where pathogens, oxidative stress and ATP, all of which activate NLRP3 inflammasome are increased. Oxidative stressIncreased oxidative stress is an important driving mechanism in asthma and COPD, with increased ROS exposure due to cigarette smoking and air pollution as well as endogenously from activated inflammatory cells such as macrophages, neutrophils and eosinophils. This may be exacerbated by reduced antioxidants in the diet or endogenously. In asthma there is evidence for increased oxidative stress demonstrated by the increased concentrations of 8-isoprostane (a product of oxidized arachidonic acid) in exhaled breath condensates and increased ethane (a product of lipid peroxidation) in the expired air of asthmatic patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb250dXNjaGk8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFy

PjxSZWNOdW0+NjQ5ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTEyLCAxMTNdPC9EaXNwbGF5VGV4

dD48cmVjb3JkPjxyZWMtbnVtYmVyPjY0OTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRp

bWVzdGFtcD0iMTM3ODQ3ODkyMSI+NjQ5ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+TW9udHVzY2hpLFAuPC9hdXRob3I+PGF1dGhvcj5DaWFiYXR0b25pLEcuPC9hdXRo

b3I+PGF1dGhvcj5Db3JyYWRpLE0uPC9hdXRob3I+PGF1dGhvcj5OaWdodGluZ2FsZSxKLkEuPC9h

dXRob3I+PGF1dGhvcj5Db2xsaW5zLEouVi48L2F1dGhvcj48YXV0aG9yPktoYXJpdG9ub3YsUy5B

LjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PHRpdGxlcz48dGl0bGU+SW5jcmVhc2VkIDgtSXNvcHJvc3RhbmUsIGEgIG1hcmtlciBv

ZiBveGlkYXRpdmUgc3RyZXNzLCBpbiBleGhhbGVkIGNvbmRlbnNhdGVzIG9mIGFzdGhtYXRpYyBw

YXRpZW50czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVk

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0gSiBS

ZXNwaXIgQ3JpdCBDYXJlIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNi0y

MjA8L3BhZ2VzPjx2b2x1bWU+MTYwPC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5JbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPk5FVzwva2V5d29yZD48a2V5d29yZD5P

WElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwva2V5d29yZD48a2V5

d29yZD5zdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1h

PC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5leGhhbGVkPC9r

ZXl3b3JkPjxrZXl3b3JkPmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

MTk5OTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5NT05UVVNDSEkxOTk5PC9sYWJl

bD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+UGFyZWRpPC9BdXRo

b3I+PFllYXI+MjAwMDwvWWVhcj48UmVjTnVtPjcxMDk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjcxMDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0

cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3ODkz

MSI+NzEwOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGFyZWRpLFAu

PC9hdXRob3I+PGF1dGhvcj5LaGFyaXRvbm92LFMuQS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQ

LkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkVsZXZh

dGlvbiBvZiBleGhhbGVkIGV0aGFuZSBjb25jZW50cmF0aW9uIGluIGFzdGhtYTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1l

ZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE0NTAtMTQ1NDwvcGFnZXM+PHZvbHVt

ZT4xNjI8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkVMRVZBVElPTjwva2V5d29y

ZD48a2V5d29yZD5leGhhbGVkPC9rZXl3b3JkPjxrZXl3b3JkPmV0aGFuZTwva2V5d29yZD48a2V5

d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3Jk

PkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5MaXBpZCBQZXJveGlkYXRpb248L2tleXdvcmQ+PGtl

eXdvcmQ+T1hJREFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3M8L2tleXdv

cmQ+PGtleXdvcmQ+c3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPkFJUjwva2V5d29yZD48a2V5d29y

ZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwva2V5d29yZD48a2V5d29yZD5h

c3RobWF0aWM8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+QUdF

PC9rZXl3b3JkPjxrZXl3b3JkPjE1PC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtl

eXdvcmQ+TklUUklDPC9rZXl3b3JkPjxrZXl3b3JkPm5pdHJpYyBveGlkZTwva2V5d29yZD48a2V5

d29yZD5PWElERTwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29yZD5DaGVtaWx1

bWluZXNjZW5jZTwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+RkxPVzwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5zdGVy

b2lkPC9rZXl3b3JkPjxrZXl3b3JkPk48L2tleXdvcmQ+PGtleXdvcmQ+MTI8L2tleXdvcmQ+PGtl

eXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdv

cmQ+Q09SUkVMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdv

cmQ+cmVzaWR1YWwgdm9sdW1lPC9rZXl3b3JkPjxrZXl3b3JkPlZPTFVNRTwva2V5d29yZD48a2V5

d29yZD50b3RhbCBsdW5nIGNhcGFjaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+

PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdv

cmQ+QWlyd2F5IG9ic3RydWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSU9OPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4x

MC8xLzIwMDA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+UEFSRURJMjAwMEI8L2xh

YmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb250dXNjaGk8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFy

PjxSZWNOdW0+NjQ5ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTEyLCAxMTNdPC9EaXNwbGF5VGV4

dD48cmVjb3JkPjxyZWMtbnVtYmVyPjY0OTg8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRp

bWVzdGFtcD0iMTM3ODQ3ODkyMSI+NjQ5ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+TW9udHVzY2hpLFAuPC9hdXRob3I+PGF1dGhvcj5DaWFiYXR0b25pLEcuPC9hdXRo

b3I+PGF1dGhvcj5Db3JyYWRpLE0uPC9hdXRob3I+PGF1dGhvcj5OaWdodGluZ2FsZSxKLkEuPC9h

dXRob3I+PGF1dGhvcj5Db2xsaW5zLEouVi48L2F1dGhvcj48YXV0aG9yPktoYXJpdG9ub3YsUy5B

LjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmli

dXRvcnM+PHRpdGxlcz48dGl0bGU+SW5jcmVhc2VkIDgtSXNvcHJvc3RhbmUsIGEgIG1hcmtlciBv

ZiBveGlkYXRpdmUgc3RyZXNzLCBpbiBleGhhbGVkIGNvbmRlbnNhdGVzIG9mIGFzdGhtYXRpYyBw

YXRpZW50czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVk

PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0gSiBS

ZXNwaXIgQ3JpdCBDYXJlIE1lZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIxNi0y

MjA8L3BhZ2VzPjx2b2x1bWU+MTYwPC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5JbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPk5FVzwva2V5d29yZD48a2V5d29yZD5P

WElEQVRJVkU8L2tleXdvcmQ+PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwva2V5d29yZD48a2V5

d29yZD5zdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1h

PC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5leGhhbGVkPC9r

ZXl3b3JkPjxrZXl3b3JkPmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4xOTk5PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

MTk5OTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5NT05UVVNDSEkxOTk5PC9sYWJl

bD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+UGFyZWRpPC9BdXRo

b3I+PFllYXI+MjAwMDwvWWVhcj48UmVjTnVtPjcxMDk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjcxMDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0

cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3ODkz

MSI+NzEwOTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGlj

bGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGFyZWRpLFAu

PC9hdXRob3I+PGF1dGhvcj5LaGFyaXRvbm92LFMuQS48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQ

LkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkVsZXZh

dGlvbiBvZiBleGhhbGVkIGV0aGFuZSBjb25jZW50cmF0aW9uIGluIGFzdGhtYTwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9zZWNvbmRhcnktdGl0bGU+

PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1l

ZDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE0NTAtMTQ1NDwvcGFnZXM+PHZvbHVt

ZT4xNjI8L3ZvbHVtZT48bnVtYmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBG

aWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkVMRVZBVElPTjwva2V5d29y

ZD48a2V5d29yZD5leGhhbGVkPC9rZXl3b3JkPjxrZXl3b3JkPmV0aGFuZTwva2V5d29yZD48a2V5

d29yZD5DT05DRU5UUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3Jk

PkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5MaXBpZCBQZXJveGlkYXRpb248L2tleXdvcmQ+PGtl

eXdvcmQ+T1hJREFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3M8L2tleXdv

cmQ+PGtleXdvcmQ+c3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPkFJUjwva2V5d29yZD48a2V5d29y

ZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPnBhdGhvZ2VuZXNpczwva2V5d29yZD48a2V5d29yZD5h

c3RobWF0aWM8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+QUdF

PC9rZXl3b3JkPjxrZXl3b3JkPjE1PC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtl

eXdvcmQ+TklUUklDPC9rZXl3b3JkPjxrZXl3b3JkPm5pdHJpYyBveGlkZTwva2V5d29yZD48a2V5

d29yZD5PWElERTwva2V5d29yZD48a2V5d29yZD5OTzwva2V5d29yZD48a2V5d29yZD5DaGVtaWx1

bWluZXNjZW5jZTwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+RkxPVzwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5zdGVy

b2lkPC9rZXl3b3JkPjxrZXl3b3JkPk48L2tleXdvcmQ+PGtleXdvcmQ+MTI8L2tleXdvcmQ+PGtl

eXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdv

cmQ+Q09SUkVMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdv

cmQ+cmVzaWR1YWwgdm9sdW1lPC9rZXl3b3JkPjxrZXl3b3JkPlZPTFVNRTwva2V5d29yZD48a2V5

d29yZD50b3RhbCBsdW5nIGNhcGFjaXR5PC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+

PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdv

cmQ+QWlyd2F5IG9ic3RydWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSU9OPC9rZXl3

b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4x

MC8xLzIwMDA8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+UEFSRURJMjAwMEI8L2xh

YmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [112, 113]. Increased oxidative stress is related to disease severity, may amplify the inflammatory response, and may reduce responsiveness to corticosteroids. This is seen in smoking asthmatic patients, who have neutrophilic inflammation in their airways and reduce steroid responsiveness PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb2xvc2E8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE2NjQ8L1JlY051bT48RGlzcGxheVRleHQ+WzExNF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE2NjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwNSI+MTE2NjQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBvbG9zYSxSLjwvYXV0aG9yPjxhdXRob3I+VGhvbXNvbixOLkMuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNtb2tpbmcgYW5kIGFzdGhtYTogZGFu

Z2Vyb3VzIGxpYWlzb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ci5SZXNwaXIuSi48L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIuUmVzcGly

LkouPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFEVkVSU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+YWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48

a2V5d29yZD5BTFRFUkVEPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29y

ZD5jZXNzYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRFPC9rZXl3b3JkPjxrZXl3b3Jk

PmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPmNsaW5pY2FsIHRyaWFsczwva2V5d29yZD48a2V5

d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lEPC9rZXl3b3JkPjxr

ZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RTPC9rZXl3b3JkPjxrZXl3b3Jk

PkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5mdW5j

dGlvbjwva2V5d29yZD48a2V5d29yZD5mdXR1cmU8L2tleXdvcmQ+PGtleXdvcmQ+SU1QUk9WRUQ8

L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5JTlRFUkFDVDwva2V5

d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+

PGtleXdvcmQ+TUFOQUdJTkc8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FQ0hBTklTTVM8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3Jk

PlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBIRU5PVFlQRTwva2V5d29yZD48a2V5d29yZD5Q

T1BVTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5Q

UkVWQUxFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPlJBVEU8L2tleXdvcmQ+PGtleXdvcmQ+UkFURVM8

L2tleXdvcmQ+PGtleXdvcmQ+UkVDRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3

b3JkPjxrZXl3b3JkPlJldmlldzwva2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3

b3JkPlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+c21va2luZyBjZXNzYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+U1RSQVRFR0lFUzwva2V5d29yZD48a2V5d29yZD5TWU1QVE9NUzwva2V5d29yZD48

a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD5USEVSQVBJRVM8L2tleXdvcmQ+

PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtl

eXdvcmQ+VFJJQUw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPjgvMTYvMjAxMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJl

bD5QT0xPU0EyMDEyPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Qb2xvc2E8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE2NjQ8L1JlY051bT48RGlzcGxheVRleHQ+WzExNF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE2NjQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwNSI+MTE2NjQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBvbG9zYSxSLjwvYXV0aG9yPjxhdXRob3I+VGhvbXNvbixOLkMuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlNtb2tpbmcgYW5kIGFzdGhtYTogZGFu

Z2Vyb3VzIGxpYWlzb25zPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ci5SZXNwaXIuSi48L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIuUmVzcGly

LkouPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl

PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFEVkVSU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+YWR2ZXJzZSBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48

a2V5d29yZD5BTFRFUkVEPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29y

ZD5jZXNzYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJFVFRFPC9rZXl3b3JkPjxrZXl3b3Jk

PmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPmNsaW5pY2FsIHRyaWFsczwva2V5d29yZD48a2V5

d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lEPC9rZXl3b3JkPjxr

ZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RTPC9rZXl3b3JkPjxrZXl3b3Jk

PkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5mdW5j

dGlvbjwva2V5d29yZD48a2V5d29yZD5mdXR1cmU8L2tleXdvcmQ+PGtleXdvcmQ+SU1QUk9WRUQ8

L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5JTlRFUkFDVDwva2V5

d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+

PGtleXdvcmQ+TUFOQUdJTkc8L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FQ0hBTklTTVM8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3Jk

PlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBIRU5PVFlQRTwva2V5d29yZD48a2V5d29yZD5Q

T1BVTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5Q

UkVWQUxFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPlJBVEU8L2tleXdvcmQ+PGtleXdvcmQ+UkFURVM8

L2tleXdvcmQ+PGtleXdvcmQ+UkVDRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3

b3JkPjxrZXl3b3JkPlJldmlldzwva2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3b3JkPjxrZXl3

b3JkPlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+c21va2luZyBjZXNzYXRpb248L2tleXdvcmQ+

PGtleXdvcmQ+U1RSQVRFR0lFUzwva2V5d29yZD48a2V5d29yZD5TWU1QVE9NUzwva2V5d29yZD48

a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD5USEVSQVBJRVM8L2tleXdvcmQ+

PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtl

eXdvcmQ+VFJJQUw8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48

cHViLWRhdGVzPjxkYXRlPjgvMTYvMjAxMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJl

bD5QT0xPU0EyMDEyPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90

ZT4A

ADDIN EN.CITE.DATA [114].Oxidative stress is a key driving mechanism in COPD ADDIN EN.CITE <EndNote><Cite><Author>Kirkham</Author><Year>2013</Year><RecNum>11727</RecNum><DisplayText>[115]</DisplayText><record><rec-number>11727</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378479006">11727</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kirkham,P.A.</author><author>Barnes,P.J.</author></authors></contributors><titles><title>Oxidative stress in COPD</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>266-273</pages><volume>144</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>OXIDATIVE</keyword><keyword>Oxidative Stress</keyword><keyword>stress</keyword><keyword>IN</keyword><keyword>COPD</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>KIRKHAM2013</label><urls></urls></record></Cite></EndNote>[115]. Cigarette smoking is a major risk factor for COPD, but even in ex-smokers oxidative stress remains high due to endogenous production from activated inflammatory cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb250dXNjaGk8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFy

PjxSZWNOdW0+NzA5MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTE2XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj43MDkwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5MzAiPjcwOTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPk1vbnR1c2NoaSxQLjwvYXV0aG9yPjxhdXRob3I+Q29sbGlucyxKLlYuPC9hdXRob3I+PGF1

dGhvcj5DaWFiYXR0b25pLEcuPC9hdXRob3I+PGF1dGhvcj5MYXp6ZXJpLE4uPC9hdXRob3I+PGF1

dGhvcj5Db3JyYWRpLE0uPC9hdXRob3I+PGF1dGhvcj5LaGFyaXRvbm92LFMuQS48L2F1dGhvcj48

YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUi

PkV4aGFsZWQgOC1pc29wcm9zdGFuZSBhcyBhbjwvc3R5bGU+PHN0eWxlIGZhY2U9Iml0YWxpYyIg

Zm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+IGluIHZpdm88L3N0eWxlPjxzdHlsZSBmYWNlPSJu

b3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPiBiaW9tYXJrZXIgb2YgbHVuZyBveGlk

YXRpdmUgc3RyZXNzIGluIHBhdGllbnRzIHdpdGggQ09QRCBhbmQgaGVhbHRoeSBzbW9rZXJzPC9z

dHlsZT48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZDwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUmVz

cGlyIENyaXQgQ2FyZSBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTc1LTEx

Nzc8L3BhZ2VzPjx2b2x1bWU+MTYyPC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PHJlcHJpbnQt

ZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5l

eGhhbGVkPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOIFZJVk88L2tl

eXdvcmQ+PGtleXdvcmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+

PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdv

cmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5IRUFMVEhZPC9rZXl3b3JkPjxrZXl3b3JkPlNDSE9PTDwva2V5d29yZD48a2V5d29yZD5N

RURJQ0lORTwva2V5d29yZD48a2V5d29yZD5OQVRJT05BTDwva2V5d29yZD48a2V5d29yZD5IRUFS

VDwva2V5d29yZD48a2V5d29yZD5sb25kb248L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3

b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3

b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9r

ZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPklOIFZJVFJPPC9rZXl3b3JkPjxrZXl3b3JkPlNZU1RFTUlDPC9rZXl3b3Jk

PjxrZXl3b3JkPkxVTkdTPC9rZXl3b3JkPjxrZXl3b3JkPkNPTkNFTlRSQVRJT048L2tleXdvcmQ+

PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5TRUNSRVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPlNFQ1JFVElPTjwva2V5d29yZD48a2V5d29y

ZD5BUkFDSElET05JQzwva2V5d29yZD48a2V5d29yZD5BcmFjaGlkb25pYyBhY2lkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFDSUQ8L2tleXdvcmQ+PGtleXdvcmQ+QUNVVEU8L2tleXdvcmQ+PGtleXdvcmQ+

RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1BFQ0lG

SUM8L2tleXdvcmQ+PGtleXdvcmQ+RU5aWU1FPC9rZXl3b3JkPjxrZXl3b3JkPjEyPC9rZXl3b3Jk

PjxrZXl3b3JkPjE1PC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29y

ZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5QUk9EVUNUSU9OPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDAwPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPk1PTlRVU0NISTIwMDBBPC9sYWJlbD48dXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb250dXNjaGk8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFy

PjxSZWNOdW0+NzA5MDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTE2XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj43MDkwPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5MzAiPjcwOTA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPk1vbnR1c2NoaSxQLjwvYXV0aG9yPjxhdXRob3I+Q29sbGlucyxKLlYuPC9hdXRob3I+PGF1

dGhvcj5DaWFiYXR0b25pLEcuPC9hdXRob3I+PGF1dGhvcj5MYXp6ZXJpLE4uPC9hdXRob3I+PGF1

dGhvcj5Db3JyYWRpLE0uPC9hdXRob3I+PGF1dGhvcj5LaGFyaXRvbm92LFMuQS48L2F1dGhvcj48

YXV0aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRs

ZXM+PHRpdGxlPjxzdHlsZSBmYWNlPSJub3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUi

PkV4aGFsZWQgOC1pc29wcm9zdGFuZSBhcyBhbjwvc3R5bGU+PHN0eWxlIGZhY2U9Iml0YWxpYyIg

Zm9udD0iZGVmYXVsdCIgc2l6ZT0iMTAwJSI+IGluIHZpdm88L3N0eWxlPjxzdHlsZSBmYWNlPSJu

b3JtYWwiIGZvbnQ9ImRlZmF1bHQiIHNpemU9IjEwMCUiPiBiaW9tYXJrZXIgb2YgbHVuZyBveGlk

YXRpdmUgc3RyZXNzIGluIHBhdGllbnRzIHdpdGggQ09QRCBhbmQgaGVhbHRoeSBzbW9rZXJzPC9z

dHlsZT48L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIgQ3JpdCBDYXJlIE1lZDwv

c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUmVz

cGlyIENyaXQgQ2FyZSBNZWQ8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xMTc1LTEx

Nzc8L3BhZ2VzPjx2b2x1bWU+MTYyPC92b2x1bWU+PG51bWJlcj4zPC9udW1iZXI+PHJlcHJpbnQt

ZWRpdGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5l

eGhhbGVkPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOIFZJVk88L2tl

eXdvcmQ+PGtleXdvcmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5PWElEQVRJVkU8L2tleXdvcmQ+

PGtleXdvcmQ+T3hpZGF0aXZlIFN0cmVzczwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdv

cmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5

d29yZD5IRUFMVEhZPC9rZXl3b3JkPjxrZXl3b3JkPlNDSE9PTDwva2V5d29yZD48a2V5d29yZD5N

RURJQ0lORTwva2V5d29yZD48a2V5d29yZD5OQVRJT05BTDwva2V5d29yZD48a2V5d29yZD5IRUFS

VDwva2V5d29yZD48a2V5d29yZD5sb25kb248L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3

b3JkPjxrZXl3b3JkPnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3

b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9r

ZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3

b3JkPjxrZXl3b3JkPklOIFZJVFJPPC9rZXl3b3JkPjxrZXl3b3JkPlNZU1RFTUlDPC9rZXl3b3Jk

PjxrZXl3b3JkPkxVTkdTPC9rZXl3b3JkPjxrZXl3b3JkPkNPTkNFTlRSQVRJT048L2tleXdvcmQ+

PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29y

ZD5TRUNSRVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPlNFQ1JFVElPTjwva2V5d29yZD48a2V5d29y

ZD5BUkFDSElET05JQzwva2V5d29yZD48a2V5d29yZD5BcmFjaGlkb25pYyBhY2lkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFDSUQ8L2tleXdvcmQ+PGtleXdvcmQ+QUNVVEU8L2tleXdvcmQ+PGtleXdvcmQ+

RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPlNNT0tJTkc8L2tleXdvcmQ+PGtleXdvcmQ+U1BFQ0lG

SUM8L2tleXdvcmQ+PGtleXdvcmQ+RU5aWU1FPC9rZXl3b3JkPjxrZXl3b3JkPjEyPC9rZXl3b3Jk

PjxrZXl3b3JkPjE1PC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29y

ZD5JTkNSRUFTRTwva2V5d29yZD48a2V5d29yZD5QUk9EVUNUSU9OPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMDA8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4yMDAwPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPk1PTlRVU0NISTIwMDBBPC9sYWJlbD48dXJscz48L3Vy

bHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [116]. There is also a reduced expression of antioxidants in COPD. Most antioxidants are regulated by the transcription factor nuclear erythroid-2 related factor-2 (Nrf2), which is activated by oxidative stress. However in COPD lungs and cells Nrf2 is not appropriately activated despite high levels of oxidative stress in the lungs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWxob3RyYTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4xMDI3NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTE3XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDI3NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTgzIj4xMDI3Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+TWFsaG90cmEsRC48L2F1dGhvcj48YXV0aG9yPlRoaW1tdWxhcHBhLFIuPC9hdXRob3I+

PGF1dGhvcj5OYXZhcy1BY2llbixBLjwvYXV0aG9yPjxhdXRob3I+U2FuZGZvcmQsQS48L2F1dGhv

cj48YXV0aG9yPkVsbGlvdHQsTS48L2F1dGhvcj48YXV0aG9yPlNpbmdoLEEuPC9hdXRob3I+PGF1

dGhvcj5DaGVuLEwuPC9hdXRob3I+PGF1dGhvcj5aaHVhbmcsWC48L2F1dGhvcj48YXV0aG9yPkhv

Z2csSi48L2F1dGhvcj48YXV0aG9yPlBhcmUsUC48L2F1dGhvcj48YXV0aG9yPlR1ZGVyLFIuTS48

L2F1dGhvcj48YXV0aG9yPkJpc3dhbCxTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48dGl0bGVzPjx0aXRsZT5EZWNsaW5lIGluIE5SRjIgcmVndWxhdGVkIGFudGlveGlkYW50cyBp

biBDT1BEIGx1bmdzIGR1ZSB0byBsb3NzIG9mIGl0cyBwb3NpdGl2ZSByZWd1bGF0b3IgREotMTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUmVzcGlyIENy

aXQgQ2FyZSBNZWQuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTkyLTYwNDwvcGFn

ZXM+PHZvbHVtZT4xNzg8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRPUjwva2V5d29yZD48a2V5d29y

ZD5hbnRpb3hpZGFudDwva2V5d29yZD48a2V5d29yZD5BbnRpb3hpZGFudHM8L2tleXdvcmQ+PGtl

eXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5D

RUxMUzwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJF

VFRFIFNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+REFNQUdF

PC9rZXl3b3JkPjxrZXl3b3JkPkRFQ0xJTkU8L2tleXdvcmQ+PGtleXdvcmQ+REVDUkVBU0VEPC9r

ZXl3b3JkPjxrZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RTPC9rZXl3b3Jk

PjxrZXl3b3JkPkVQSVRIRUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpdGhlbGlhbCBjZWxsczwv

a2V5d29yZD48a2V5d29yZD5FWFBPU1VSRTwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GSUJST0JMQVNUUzwva2V5

d29yZD48a2V5d29yZD5HbHV0YXRoaW9uZTwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29y

ZD48a2V5d29yZD5JTVBBSVJFRDwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29y

ZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5EVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PklOSElCSVQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3JkPklO

SElCSVRTPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+

PGtleXdvcmQ+TUlDRTwva2V5d29yZD48a2V5d29yZD5NSUxEPC9rZXl3b3JkPjxrZXl3b3JkPk1P

TEVDVUxBUjwva2V5d29yZD48a2V5d29yZD5tUk5BPC9rZXl3b3JkPjxrZXl3b3JkPk5PVkVMPC9r

ZXl3b3JkPjxrZXl3b3JkPk5yZjI8L2tleXdvcmQ+PGtleXdvcmQ+T1hJREFUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9nZW5lc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBFUklQSEVSQUw8

L2tleXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURUQ8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVHVUxBVE9SUzwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5

d29yZD48a2V5d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48

a2V5d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3Jk

PlNUUkFURUdJRVM8L2tleXdvcmQ+PGtleXdvcmQ+c3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPlRI

RVJBUElFUzwva2V5d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NV

RTwva2V5d29yZD48a2V5d29yZD5USVNTVUVTPC9rZXl3b3JkPjxrZXl3b3JkPlRSQU5TQ1JJUFRJ

T048L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjYvMTIvMjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5NQUxIT1RS

QTIwMDhBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWxob3RyYTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

PFJlY051bT4xMDI3NjwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTE3XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDI3NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTgzIj4xMDI3Njwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+TWFsaG90cmEsRC48L2F1dGhvcj48YXV0aG9yPlRoaW1tdWxhcHBhLFIuPC9hdXRob3I+

PGF1dGhvcj5OYXZhcy1BY2llbixBLjwvYXV0aG9yPjxhdXRob3I+U2FuZGZvcmQsQS48L2F1dGhv

cj48YXV0aG9yPkVsbGlvdHQsTS48L2F1dGhvcj48YXV0aG9yPlNpbmdoLEEuPC9hdXRob3I+PGF1

dGhvcj5DaGVuLEwuPC9hdXRob3I+PGF1dGhvcj5aaHVhbmcsWC48L2F1dGhvcj48YXV0aG9yPkhv

Z2csSi48L2F1dGhvcj48YXV0aG9yPlBhcmUsUC48L2F1dGhvcj48YXV0aG9yPlR1ZGVyLFIuTS48

L2F1dGhvcj48YXV0aG9yPkJpc3dhbCxTLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9y

cz48dGl0bGVzPjx0aXRsZT5EZWNsaW5lIGluIE5SRjIgcmVndWxhdGVkIGFudGlveGlkYW50cyBp

biBDT1BEIGx1bmdzIGR1ZSB0byBsb3NzIG9mIGl0cyBwb3NpdGl2ZSByZWd1bGF0b3IgREotMTwv

dGl0bGU+PHNlY29uZGFyeS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkLjwvc2Vjb25k

YXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUmVzcGlyIENy

aXQgQ2FyZSBNZWQuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTkyLTYwNDwvcGFn

ZXM+PHZvbHVtZT4xNzg8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFDVElWQVRPUjwva2V5d29yZD48a2V5d29y

ZD5hbnRpb3hpZGFudDwva2V5d29yZD48a2V5d29yZD5BbnRpb3hpZGFudHM8L2tleXdvcmQ+PGtl

eXdvcmQ+QVNTRVNTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5D

RUxMUzwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEU8L2tleXdvcmQ+PGtleXdvcmQ+Q0lHQVJF

VFRFIFNNT0tFPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+REFNQUdF

PC9rZXl3b3JkPjxrZXl3b3JkPkRFQ0xJTkU8L2tleXdvcmQ+PGtleXdvcmQ+REVDUkVBU0VEPC9r

ZXl3b3JkPjxrZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RTPC9rZXl3b3Jk

PjxrZXl3b3JkPkVQSVRIRUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpdGhlbGlhbCBjZWxsczwv

a2V5d29yZD48a2V5d29yZD5FWFBPU1VSRTwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GSUJST0JMQVNUUzwva2V5

d29yZD48a2V5d29yZD5HbHV0YXRoaW9uZTwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29y

ZD48a2V5d29yZD5JTVBBSVJFRDwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29y

ZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5EVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PklOSElCSVQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3JkPklO

SElCSVRTPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tl

eXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+

PGtleXdvcmQ+TUlDRTwva2V5d29yZD48a2V5d29yZD5NSUxEPC9rZXl3b3JkPjxrZXl3b3JkPk1P

TEVDVUxBUjwva2V5d29yZD48a2V5d29yZD5tUk5BPC9rZXl3b3JkPjxrZXl3b3JkPk5PVkVMPC9r

ZXl3b3JkPjxrZXl3b3JkPk5yZjI8L2tleXdvcmQ+PGtleXdvcmQ+T1hJREFUSVZFPC9rZXl3b3Jk

PjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9nZW5lc2lz

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBFUklQSEVSQUw8

L2tleXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5SRUdVTEFURUQ8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVHVUxBVE9SUzwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5

d29yZD48a2V5d29yZD5TRVZFUklUWTwva2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48

a2V5d29yZD5TTU9LRTwva2V5d29yZD48a2V5d29yZD5TTU9LSU5HPC9rZXl3b3JkPjxrZXl3b3Jk

PlNUUkFURUdJRVM8L2tleXdvcmQ+PGtleXdvcmQ+c3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPlRI

RVJBUElFUzwva2V5d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NV

RTwva2V5d29yZD48a2V5d29yZD5USVNTVUVTPC9rZXl3b3JkPjxrZXl3b3JkPlRSQU5TQ1JJUFRJ

T048L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjYvMTIvMjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5NQUxIT1RS

QTIwMDhBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [117] QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\0CMALHOTRA20113Malhotra, Thimmulappa, et al. 2011 MALHOTRA2011 /id\003\00 and this may be related to increased acetylation due to decreased histone deacetylase-2 (HDAC2) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJjYWRvPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMjg3PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMThdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjExMjg3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5OTkiPjExMjg3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5NZXJjYWRvLE4uPC9hdXRob3I+PGF1dGhvcj5UaGltbXVsYXBwYSxSLjwvYXV0aG9yPjxh

dXRob3I+VGhvbWFzLEMuTS48L2F1dGhvcj48YXV0aG9yPkZlbndpY2ssUC5TLjwvYXV0aG9yPjxh

dXRob3I+Q2hhbmEsSy5LLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9yPjxh

dXRob3I+Qmlzd2FsLFMuPC9hdXRob3I+PGF1dGhvcj5JdG8sSy48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkRlY3JlYXNlZCBoaXN0b25lIGRlYWNldHlsYXNlIDIgaW1wYWlycyBOcmYyIGFjdGl2YXRpb24g

Ynkgb3hpZGF0aXZlIHN0cmVzczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CaW9jaGVtLkJpb3Bo

eXMuUmVzLkNvbW11bi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5CaW9jaGVtLkJpb3BoeXMuUmVzLkNvbW11bi48L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz4yOTItMjk4PC9wYWdlcz48dm9sdW1lPjQwNjwvdm9sdW1lPjxyZXByaW50LWVk

aXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+Mjwv

a2V5d29yZD48a2V5d29yZD5hY2V0eWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWSVRJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJVFk8

L2tleXdvcmQ+PGtleXdvcmQ+QUNVVEU8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3Jk

PjxrZXl3b3JkPkFOVEk8L2tleXdvcmQ+PGtleXdvcmQ+YW50aW94aWRhbnQ8L2tleXdvcmQ+PGtl

eXdvcmQ+YnJvbmNoaWFsPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VsbCBMaW5lPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExV

TEFSPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBP

QlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFy

eSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURSBTTU9LRTwva2V5d29yZD48a2V5

d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PkRFQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5ERUZFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJ

U0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RE9XTi1SRUdVTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FUElUSEVMSUFMPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkU8

L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkVT

PC9rZXl3b3JkPjxrZXl3b3JkPkhFQUxUSFk8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tleXdv

cmQ+PGtleXdvcmQ+SElHSDwva2V5d29yZD48a2V5d29yZD5oaXN0b25lPC9rZXl3b3JkPjxrZXl3

b3JkPkhpc3RvbmUgRGVhY2V0eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SGlzdG9uZSBEZWFjZXR5

bGFzZSAyPC9rZXl3b3JkPjxrZXl3b3JkPkhPLTE8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm9nZW4g

cGVyb3hpZGU8L2tleXdvcmQ+PGtleXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48

L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklWTzwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5

d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3

b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3

b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPk1VTFRJUExFPC9rZXl3b3JkPjxrZXl3b3JkPk5B

VElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPk5yZjI8L2tleXdv

cmQ+PGtleXdvcmQ+TlVDTEVBUjwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5veGlkYW50PC9rZXl3b3JkPjxrZXl3b3JkPk9YSURBVElWRTwva2V5d29yZD48

a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3

b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBTdGFiaWxpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlJFRFVDRUQ8L2tl

eXdvcmQ+PGtleXdvcmQ+Uk5BPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSBJbnRlcmZlcmVuY2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5d29yZD48a2V5d29yZD5TRU5TSVRJVklUWTwva2V5d29y

ZD48a2V5d29yZD5TVElNVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdvcmQ+

PGtleXdvcmQ+dHJpY2hvc3RhdGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+Vk9MVU5URUVSUzwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

Mi8xMi8yMDExPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPk1FUkNBRE8yMDExQTwv

bGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJjYWRvPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

UmVjTnVtPjExMjg3PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMThdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjExMjg3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5OTkiPjExMjg3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5NZXJjYWRvLE4uPC9hdXRob3I+PGF1dGhvcj5UaGltbXVsYXBwYSxSLjwvYXV0aG9yPjxh

dXRob3I+VGhvbWFzLEMuTS48L2F1dGhvcj48YXV0aG9yPkZlbndpY2ssUC5TLjwvYXV0aG9yPjxh

dXRob3I+Q2hhbmEsSy5LLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9yPjxh

dXRob3I+Qmlzd2FsLFMuPC9hdXRob3I+PGF1dGhvcj5JdG8sSy48L2F1dGhvcj48YXV0aG9yPkJh

cm5lcyxQLkouPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxl

PkRlY3JlYXNlZCBoaXN0b25lIGRlYWNldHlsYXNlIDIgaW1wYWlycyBOcmYyIGFjdGl2YXRpb24g

Ynkgb3hpZGF0aXZlIHN0cmVzczwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5CaW9jaGVtLkJpb3Bo

eXMuUmVzLkNvbW11bi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVs

bC10aXRsZT5CaW9jaGVtLkJpb3BoeXMuUmVzLkNvbW11bi48L2Z1bGwtdGl0bGU+PC9wZXJpb2Rp

Y2FsPjxwYWdlcz4yOTItMjk4PC9wYWdlcz48dm9sdW1lPjQwNjwvdm9sdW1lPjxyZXByaW50LWVk

aXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+Mjwv

a2V5d29yZD48a2V5d29yZD5hY2V0eWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWSVRJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJVFk8

L2tleXdvcmQ+PGtleXdvcmQ+QUNVVEU8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3Jk

PjxrZXl3b3JkPkFOVEk8L2tleXdvcmQ+PGtleXdvcmQ+YW50aW94aWRhbnQ8L2tleXdvcmQ+PGtl

eXdvcmQ+YnJvbmNoaWFsPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+

Q2VsbCBMaW5lPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExV

TEFSPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBP

QlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFy

eSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURSBTTU9LRTwva2V5d29yZD48a2V5

d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PkRFQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5ERUZFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJ

U0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RE9XTi1SRUdVTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3Jk

PkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FUElUSEVMSUFMPC9rZXl3b3JkPjxrZXl3b3JkPkVY

UFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+RkFDVE9SPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkU8

L2tleXdvcmQ+PGtleXdvcmQ+R2VuZSBFeHByZXNzaW9uPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkVT

PC9rZXl3b3JkPjxrZXl3b3JkPkhFQUxUSFk8L2tleXdvcmQ+PGtleXdvcmQ+SEVBUlQ8L2tleXdv

cmQ+PGtleXdvcmQ+SElHSDwva2V5d29yZD48a2V5d29yZD5oaXN0b25lPC9rZXl3b3JkPjxrZXl3

b3JkPkhpc3RvbmUgRGVhY2V0eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SGlzdG9uZSBEZWFjZXR5

bGFzZSAyPC9rZXl3b3JkPjxrZXl3b3JkPkhPLTE8L2tleXdvcmQ+PGtleXdvcmQ+SHlkcm9nZW4g

cGVyb3hpZGU8L2tleXdvcmQ+PGtleXdvcmQ+SU1QQUlSRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU48

L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklWTzwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5

d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3

b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3

b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9waGFnZXM8L2tleXdvcmQ+PGtl

eXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPk1VTFRJUExFPC9rZXl3b3JkPjxrZXl3b3JkPk5B

VElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPk5yZjI8L2tleXdv

cmQ+PGtleXdvcmQ+TlVDTEVBUjwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29y

ZD48a2V5d29yZD5veGlkYW50PC9rZXl3b3JkPjxrZXl3b3JkPk9YSURBVElWRTwva2V5d29yZD48

a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3

b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UHJvdGVpbiBTdGFiaWxpdHk8

L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlJFRFVDRUQ8L2tl

eXdvcmQ+PGtleXdvcmQ+Uk5BPC9rZXl3b3JkPjxrZXl3b3JkPlJOQSBJbnRlcmZlcmVuY2U8L2tl

eXdvcmQ+PGtleXdvcmQ+Uk9MRTwva2V5d29yZD48a2V5d29yZD5TRU5TSVRJVklUWTwva2V5d29y

ZD48a2V5d29yZD5TVElNVUxBVElPTjwva2V5d29yZD48a2V5d29yZD5zdHJlc3M8L2tleXdvcmQ+

PGtleXdvcmQ+dHJpY2hvc3RhdGluIEE8L2tleXdvcmQ+PGtleXdvcmQ+Vk9MVU5URUVSUzwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

Mi8xMi8yMDExPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPk1FUkNBRE8yMDExQTwv

bGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [118]. ROS have wide-ranging effects and amplify the inflammatory response by activating activate NF-B. Oxidative stress may also impair the function of antiproteases such as 1-antitrypsin, and thereby accelerates the breakdown of elastin in lung parenchyma. Oxidative stress markedly reduces HDAC2 activity and expression, through activation of phosphoinositide-3-kinase (PI3K) ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2009</Year><RecNum>10508</RecNum><DisplayText>[119]</DisplayText><record><rec-number>10508</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478986">10508</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, P. J.</author></authors></contributors><auth-address>National Heart and Lung Institute, Imperial College, London SW3 6LY, United Kingdom. p.j.barnes@imperial.ac.uk</auth-address><titles><title>Role of HDAC2 in the pathophysiology of COPD</title><secondary-title>Annu Rev Physiol</secondary-title><alt-title>Annual review of physiology</alt-title></titles><periodical><full-title>Annu Rev Physiol</full-title></periodical><pages>451-64</pages><volume>71</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Adrenal Cortex Hormones/physiology</keyword><keyword>Histone Deacetylase 2</keyword><keyword>Histone Deacetylases/*physiology</keyword><keyword>Humans</keyword><keyword>Lung/enzymology</keyword><keyword>Macrophages, Alveolar/enzymology</keyword><keyword>Oxidative Stress/physiology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/*physiopathology</keyword><keyword>Repressor Proteins/*physiology</keyword></keywords><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><isbn>1545-1585 (Electronic)&#xD;0066-4278 (Linking)</isbn><accession-num>18817512</accession-num><label>BARNES2009D</label><urls><related-urls><url>;[119]. This amplifies inflammation further and also prevents corticosteroids from switching of activated inflammatory genes, resulting in the characteristic corticosteroid resistance of COPD inflammation. Through similar mechanisms oxidative stress reduces the expression and activity of sirtuin-1, a key repair molecule that is implicated in ageing. The reduction in sirtuin-1 in COPD lungs and cells may underlie the accelerated ageing response seen in COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWthbWFydTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xMDcxNTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTIwLCAxMjFdPC9EaXNwbGF5VGV4

dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNzE1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0

aW1lc3RhbXA9IjEzNzg0Nzg5OTAiPjEwNzE1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5OYWthbWFydSxZLjwvYXV0aG9yPjxhdXRob3I+VnVwcHVzZXR0eSxDLjwvYXV0

aG9yPjxhdXRob3I+V2FkYSxILjwvYXV0aG9yPjxhdXRob3I+TWlsbmUsSi5DLjwvYXV0aG9yPjxh

dXRob3I+SXRvLE0uPC9hdXRob3I+PGF1dGhvcj5Sb3NzaW9zLEMuPC9hdXRob3I+PGF1dGhvcj5F

bGxpb3QsTS48L2F1dGhvcj48YXV0aG9yPkhvZ2csSi48L2F1dGhvcj48YXV0aG9yPktoYXJpdG9u

b3YsUy48L2F1dGhvcj48YXV0aG9yPkdvdG8sSC48L2F1dGhvcj48YXV0aG9yPkJlbWlzLEouRS48

L2F1dGhvcj48YXV0aG9yPkVsbGlvdHQsUC48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9h

dXRob3I+PGF1dGhvcj5JdG8sSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+QSBwcm90ZWluIGRlYWNldHlsYXNlIFNJUlQxIGlzIGEgbmVnYXRpdmUgcmVn

dWxhdG9yIG9mIG1ldGFsbG9wcm90ZWluYXNlLTk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RkFT

RUIgSi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5G

QVNFQiBKLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI4MTAtMjgxOTwvcGFnZXM+

PHZvbHVtZT4yMzwvdm9sdW1lPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQt

ZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5B

Q1RJVkFUT1I8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5B

Q1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BUFBST0FDSEVTPC9rZXl3b3JkPjxrZXl3b3JkPkFT

U0FZPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdv

cmQ+PGtleXdvcmQ+Y2hyb21hdGluPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+

PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9i

c3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURTwv

a2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEUgU01PS0U8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwv

a2V5d29yZD48a2V5d29yZD5ERUNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5

d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5FTEVWQVRJT048L2tleXdv

cmQ+PGtleXdvcmQ+RU5aWU1FPC9rZXl3b3JkPjxrZXl3b3JkPkVYRVJDSVNFPC9rZXl3b3JkPjxr

ZXl3b3JkPkV4ZXJjaXNlIFRvbGVyYW5jZTwva2V5d29yZD48a2V5d29yZD5FWFBPU1VSRTwva2V5

d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkgyTzI8L2tleXdvcmQ+

PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vcHJlY2lwaXRhdGlvbjwva2V5

d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5

d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdvcmQ+TUFD

Uk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5N

QVRSSVg8L2tleXdvcmQ+PGtleXdvcmQ+TWF0cml4IE1ldGFsbG9wcm90ZWluYXNlIDk8L2tleXdv

cmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ0U8L2tleXdvcmQ+PGtl

eXdvcmQ+TU1QOTwva2V5d29yZD48a2V5d29yZD5NT0xFQ1VMQVI8L2tleXdvcmQ+PGtleXdvcmQ+

TU9MRUNVTEU8L2tleXdvcmQ+PGtleXdvcmQ+bmV1dHJvcGhpbGlhPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5PVkVMPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk9Y

SURBVElWRTwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+

UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5d29yZD48a2V5d29yZD5Q

UklNQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9O

QVJZPC9rZXl3b3JkPjxrZXl3b3JkPlBVVEFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlJFRFVDRUQ8

L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlJOQTwva2V5d29y

ZD48a2V5d29yZD5STkEgSW50ZXJmZXJlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlNFTEVDVElWRTwv

a2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29yZD48

a2V5d29yZD5TUFVUVU08L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29y

ZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD5U

SVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+VE9MRVJBTkNFPC9rZXl3b3JkPjxrZXl3b3JkPlRSRUFU

TUVOVDwva2V5d29yZD48a2V5d29yZD5VOTM3IENlbGxzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT40LzE3LzIwMDk8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+TkFLQU1BUlUyMDA5PC9sYWJlbD48dXJscz48L3VybHM+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWVyY2FkbzwvQXV0aG9yPjxZZWFyPjIwMTU8

L1llYXI+PFJlY051bT4xMTkwMDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5MDA8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1

ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM5MzAwNzkzOSI+MTE5MDA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1lcmNhZG8sIE4uPC9hdXRob3I+

PGF1dGhvcj5JdG8sIEsuPC9hdXRob3I+PGF1dGhvcj5CYXJuZXMsIFAuSi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWNjZWxlcmF0ZWQgYWdlaW5nIGlu

IGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U6IG5ldyBjb25jZXB0czwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5UaG9yYXg8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz40ODItNDg5PC9wYWdlcz48dm9sdW1lPjcwPC92b2x1bWU+PGRhdGVzPjx5ZWFyPjIwMTU8L3ll

YXI+PC9kYXRlcz48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWthbWFydTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+

PFJlY051bT4xMDcxNTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTIwLCAxMjFdPC9EaXNwbGF5VGV4

dD48cmVjb3JkPjxyZWMtbnVtYmVyPjEwNzE1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl

eSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0

aW1lc3RhbXA9IjEzNzg0Nzg5OTAiPjEwNzE1PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBl

IG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhv

cnM+PGF1dGhvcj5OYWthbWFydSxZLjwvYXV0aG9yPjxhdXRob3I+VnVwcHVzZXR0eSxDLjwvYXV0

aG9yPjxhdXRob3I+V2FkYSxILjwvYXV0aG9yPjxhdXRob3I+TWlsbmUsSi5DLjwvYXV0aG9yPjxh

dXRob3I+SXRvLE0uPC9hdXRob3I+PGF1dGhvcj5Sb3NzaW9zLEMuPC9hdXRob3I+PGF1dGhvcj5F

bGxpb3QsTS48L2F1dGhvcj48YXV0aG9yPkhvZ2csSi48L2F1dGhvcj48YXV0aG9yPktoYXJpdG9u

b3YsUy48L2F1dGhvcj48YXV0aG9yPkdvdG8sSC48L2F1dGhvcj48YXV0aG9yPkJlbWlzLEouRS48

L2F1dGhvcj48YXV0aG9yPkVsbGlvdHQsUC48L2F1dGhvcj48YXV0aG9yPkJhcm5lcyxQLkouPC9h

dXRob3I+PGF1dGhvcj5JdG8sSy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+QSBwcm90ZWluIGRlYWNldHlsYXNlIFNJUlQxIGlzIGEgbmVnYXRpdmUgcmVn

dWxhdG9yIG9mIG1ldGFsbG9wcm90ZWluYXNlLTk8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+RkFT

RUIgSi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5G

QVNFQiBKLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI4MTAtMjgxOTwvcGFnZXM+

PHZvbHVtZT4yMzwvdm9sdW1lPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQt

ZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZBVElPTjwva2V5d29yZD48a2V5d29yZD5B

Q1RJVkFUT1I8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5B

Q1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BUFBST0FDSEVTPC9rZXl3b3JkPjxrZXl3b3JkPkFT

U0FZPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdv

cmQ+PGtleXdvcmQ+Y2hyb21hdGluPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+

PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9i

c3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJR0FSRVRURTwv

a2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEUgU01PS0U8L2tleXdvcmQ+PGtleXdvcmQ+Q09QRDwv

a2V5d29yZD48a2V5d29yZD5ERUNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5

d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5FTEVWQVRJT048L2tleXdv

cmQ+PGtleXdvcmQ+RU5aWU1FPC9rZXl3b3JkPjxrZXl3b3JkPkVYRVJDSVNFPC9rZXl3b3JkPjxr

ZXl3b3JkPkV4ZXJjaXNlIFRvbGVyYW5jZTwva2V5d29yZD48a2V5d29yZD5FWFBPU1VSRTwva2V5

d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkgyTzI8L2tleXdvcmQ+

PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdvcmQ+SW1tdW5vcHJlY2lwaXRhdGlvbjwva2V5

d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRTwva2V5d29yZD48a2V5

d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxr

ZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TFVOR1M8L2tleXdvcmQ+PGtleXdvcmQ+TUFD

Uk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48a2V5d29yZD5N

QVRSSVg8L2tleXdvcmQ+PGtleXdvcmQ+TWF0cml4IE1ldGFsbG9wcm90ZWluYXNlIDk8L2tleXdv

cmQ+PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ0U8L2tleXdvcmQ+PGtl

eXdvcmQ+TU1QOTwva2V5d29yZD48a2V5d29yZD5NT0xFQ1VMQVI8L2tleXdvcmQ+PGtleXdvcmQ+

TU9MRUNVTEU8L2tleXdvcmQ+PGtleXdvcmQ+bmV1dHJvcGhpbGlhPC9rZXl3b3JkPjxrZXl3b3Jk

Pk5PVkVMPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk9Y

SURBVElWRTwva2V5d29yZD48a2V5d29yZD5wYXRob2dlbmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+

UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5d29yZD48a2V5d29yZD5Q

UklNQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9O

QVJZPC9rZXl3b3JkPjxrZXl3b3JkPlBVVEFUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlJFRFVDRUQ8

L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlJOQTwva2V5d29y

ZD48a2V5d29yZD5STkEgSW50ZXJmZXJlbmNlPC9rZXl3b3JkPjxrZXl3b3JkPlNFTEVDVElWRTwv

a2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29yZD48

a2V5d29yZD5TUFVUVU08L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29y

ZD5TVFVEWTwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48a2V5d29yZD5U

SVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+VE9MRVJBTkNFPC9rZXl3b3JkPjxrZXl3b3JkPlRSRUFU

TUVOVDwva2V5d29yZD48a2V5d29yZD5VOTM3IENlbGxzPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT40LzE3LzIwMDk8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+TkFLQU1BUlUyMDA5PC9sYWJlbD48dXJscz48L3VybHM+

PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+TWVyY2FkbzwvQXV0aG9yPjxZZWFyPjIwMTU8

L1llYXI+PFJlY051bT4xMTkwMDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE5MDA8L3Jl

Yy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1

ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM5MzAwNzkzOSI+MTE5MDA8L2tl

eT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVm

LXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1lcmNhZG8sIE4uPC9hdXRob3I+

PGF1dGhvcj5JdG8sIEsuPC9hdXRob3I+PGF1dGhvcj5CYXJuZXMsIFAuSi48L2F1dGhvcj48L2F1

dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWNjZWxlcmF0ZWQgYWdlaW5nIGlu

IGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U6IG5ldyBjb25jZXB0czwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5UaG9yYXg8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdl

cz40ODItNDg5PC9wYWdlcz48dm9sdW1lPjcwPC92b2x1bWU+PGRhdGVzPjx5ZWFyPjIwMTU8L3ll

YXI+PC9kYXRlcz48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [120, 121]. ProteasesProteases also participate in the inflammatory response in asthma and COPD through the breakdown of proteins. As discussed above, mast cell tryptase may play a role in the AHR of asthma ADDIN EN.CITE <EndNote><Cite><Author>Caughey</Author><Year>2016</Year><RecNum>12928</RecNum><DisplayText>[31]</DisplayText><record><rec-number>12928</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482418559">12928</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Caughey, G. H.</author></authors></contributors><auth-address>Cardiovascular Research Institute, School of Medicine, University of California at San Francisco, CA, United States; Department of Medicine, School of Medicine, University of California at San Francisco, CA, United States; Veterans Affairs Medical Center, San Francisco, CA, United States. Electronic address: George.Caughey@ucsf.edu.</auth-address><titles><title>Mast cell proteases as pharmacological targets</title><secondary-title>Eur J Pharmacol</secondary-title><alt-title>European journal of pharmacology</alt-title></titles><periodical><full-title>Eur J Pharmacol</full-title></periodical><pages>44-55</pages><volume>778</volume><edition>2015/05/11</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Mast Cells/drug effects/*enzymology</keyword><keyword>Molecular Targeted Therapy/*methods</keyword><keyword>Peptide Hydrolases/chemistry/*metabolism</keyword><keyword>Basophil</keyword><keyword>Carboxypeptidase A3</keyword><keyword>Cathepsin C</keyword><keyword>Cathepsin G</keyword><keyword>Cathepsin L</keyword><keyword>Chymase</keyword><keyword>Dipeptidylpeptidase I</keyword><keyword>Mast cell</keyword><keyword>Protease</keyword><keyword>Tryptase</keyword></keywords><dates><year>2016</year><pub-dates><date>May 05</date></pub-dates></dates><isbn>0014-2999</isbn><accession-num>25958181</accession-num><urls></urls><custom2>PMC4636979</custom2><custom6>NIHMS688969</custom6><electronic-resource-num>10.1016/j.ejphar.2015.04.045</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[31]. In COPD patients breakdown of elastin fibres by elastases plays an important role in the development of emphysema and to neutrophilic inflammation through the generation of chemotactic peptides, such as acetylated Pro-Gly-Pro (matrikines), which are potent neutrophil chemoattractants that activate CXCR2 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWdnYXI8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

ZWNOdW0+MTA3OTQ8L1JlY051bT48RGlzcGxheVRleHQ+WzEyMl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTA3OTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk5MSI+MTA3OTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkdhZ2dhcixBLjwvYXV0aG9yPjxhdXRob3I+SmFja3NvbixQLkwuPC9hdXRob3I+PGF1dGhv

cj5Ob2VyYWdlcixCLkQuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7UmVpbGx5LFAuSi48L2F1dGhv

cj48YXV0aG9yPk1jUXVhaWQsRC5CLjwvYXV0aG9yPjxhdXRob3I+Um93ZSxTLk0uPC9hdXRob3I+

PGF1dGhvcj5DbGFuY3ksSi5QLjwvYXV0aG9yPjxhdXRob3I+QmxhbG9jayxKLkUuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkEgbm92ZWwgcHJvdGVvbHl0

aWMgY2FzY2FkZSBnZW5lcmF0ZXMgYW4gZXh0cmFjZWxsdWxhciBtYXRyaXgtZGVyaXZlZCBjaGVt

b2F0dHJhY3RhbnQgaW4gY2hyb25pYyBuZXV0cm9waGlsaWMgaW5mbGFtbWF0aW9uPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkogSW1tdW5vbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5KIEltbXVub2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+NTY2Mi01NjY5PC9wYWdlcz48dm9sdW1lPjE4MDwvdm9sdW1lPjxudW1iZXI+ODwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPkFDVVRF

PC9rZXl3b3JkPjxrZXl3b3JkPkFETUlOSVNUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldB

WTwva2V5d29yZD48a2V5d29yZD5hbmFsb2dzICZhbXA7IGRlcml2YXRpdmVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkFOSU1BTDwva2V5d29yZD48a2V5d29yZD5BbmltYWwgbW9kZWw8L2tleXdvcmQ+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNG

PC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1vdGFjdGljIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hlbW90YXhpcyxMZXVrb2N5dGU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48

a2V5d29yZD5DaHJvbmljIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q09MTEFHRU48L2tleXdv

cmQ+PGtleXdvcmQ+Q09VTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkNPVVJTRTwva2V5d29yZD48a2V5

d29yZD5DWVNUSUMgRklCUk9TSVM8L2tleXdvcmQ+PGtleXdvcmQ+REVDTElORTwva2V5d29yZD48

a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3JkPjxrZXl3

b3JkPkVsYXN0aW48L2tleXdvcmQ+PGtleXdvcmQ+RU5ET1BFUFRJREFTRTwva2V5d29yZD48a2V5

d29yZD5FVklERU5DRTwva2V5d29yZD48a2V5d29yZD5FWCBWSVZPPC9rZXl3b3JkPjxrZXl3b3Jk

PkVYQUNFUkJBVElPTjwva2V5d29yZD48a2V5d29yZD5FWFRSQUNFTExVTEFSPC9rZXl3b3JkPjxr

ZXl3b3JkPmV4dHJhY2VsbHVsYXIgbWF0cml4PC9rZXl3b3JkPjxrZXl3b3JkPmV4dHJhY2VsbHVs

YXIgbWF0cml4IHByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPkZJQlJPU0lTPC9rZXl3b3JkPjxr

ZXl3b3JkPkdFTkVSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdv

cmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklERU5USUZJQ0FUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPmltbXVuaXR5PC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+PGtleXdv

cmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklWTzwva2V5d29yZD48a2V5d29yZD5pbmZsYW1t

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPklO

SElCSVRPUjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPklO

VEVSQUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSQUNUSU9OUzwva2V5d29yZD48a2V5d29y

ZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TUFUUklYPC9rZXl3b3JkPjxrZXl3b3JkPk1hdHJpeCBNZXRhbGxvcHJvdGVpbmFzZSA4PC9rZXl3

b3JkPjxrZXl3b3JkPk1hdHJpeCBNZXRhbGxvcHJvdGVpbmFzZSA5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1FVEFCT0xJU008L2tleXdvcmQ+PGtleXdvcmQ+TWV0YWxsb3Byb3RlYXNlczwva2V5d29yZD48

a2V5d29yZD5NSUNFPC9rZXl3b3JkPjxrZXl3b3JkPk1PREVMPC9rZXl3b3JkPjxrZXl3b3JkPk1P

REVMUzwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRy

b3BoaWwgYWN0aXZhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48

a2V5d29yZD5OT1ZFTDwva2V5d29yZD48a2V5d29yZD5PbGlnb3BlcHRpZGVzPC9rZXl3b3JkPjxr

ZXl3b3JkPlBBVEhXQVk8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdBWVM8L2tleXdvcmQ+PGtleXdv

cmQ+UEVQVElERTwva2V5d29yZD48a2V5d29yZD5wZXB0aWRlczwva2V5d29yZD48a2V5d29yZD5w

cm9saW5lPC9rZXl3b3JkPjxrZXl3b3JkPnByb2x5bCBvbGlnb3BlcHRpZGFzZTwva2V5d29yZD48

a2V5d29yZD5wcm9seWwtZ2x5Y3lsLXByb2xpbmU8L2tleXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwv

a2V5d29yZD48a2V5d29yZD5QUk9URUlOUzwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tl

eXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3

b3JkPjxrZXl3b3JkPlJlY2VwdG9ycyxJbnRlcmxldWtpbi04QTwva2V5d29yZD48a2V5d29yZD5S

ZWNlcHRvcnMsSW50ZXJsZXVraW4tOEI8L2tleXdvcmQ+PGtleXdvcmQ+UkVHVUxBVElORzwva2V5

d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0

PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVUSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPlNFQ1JFVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+U0VSSU5FPC9rZXl3b3Jk

PjxrZXl3b3JkPnNlcmluZSBlbmRvcGVwdGlkYXNlczwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJ

Qzwva2V5d29yZD48a2V5d29yZD5TUFVUVU08L2tleXdvcmQ+PGtleXdvcmQ+U1RSVUNUVVJBTDwv

a2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3Jk

PjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48

a2V5d29yZD5USEVSQVBJRVM8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5

d29yZD5VU0U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjQvMTUvMjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5H

QUdHQVIyMDA4PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWdnYXI8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS

ZWNOdW0+MTA3OTQ8L1JlY051bT48RGlzcGxheVRleHQ+WzEyMl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTA3OTQ8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk5MSI+MTA3OTQ8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkdhZ2dhcixBLjwvYXV0aG9yPjxhdXRob3I+SmFja3NvbixQLkwuPC9hdXRob3I+PGF1dGhv

cj5Ob2VyYWdlcixCLkQuPC9hdXRob3I+PGF1dGhvcj5PJmFwb3M7UmVpbGx5LFAuSi48L2F1dGhv

cj48YXV0aG9yPk1jUXVhaWQsRC5CLjwvYXV0aG9yPjxhdXRob3I+Um93ZSxTLk0uPC9hdXRob3I+

PGF1dGhvcj5DbGFuY3ksSi5QLjwvYXV0aG9yPjxhdXRob3I+QmxhbG9jayxKLkUuPC9hdXRob3I+

PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkEgbm92ZWwgcHJvdGVvbHl0

aWMgY2FzY2FkZSBnZW5lcmF0ZXMgYW4gZXh0cmFjZWxsdWxhciBtYXRyaXgtZGVyaXZlZCBjaGVt

b2F0dHJhY3RhbnQgaW4gY2hyb25pYyBuZXV0cm9waGlsaWMgaW5mbGFtbWF0aW9uPC90aXRsZT48

c2Vjb25kYXJ5LXRpdGxlPkogSW1tdW5vbC48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVy

aW9kaWNhbD48ZnVsbC10aXRsZT5KIEltbXVub2wuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48

cGFnZXM+NTY2Mi01NjY5PC9wYWdlcz48dm9sdW1lPjE4MDwvdm9sdW1lPjxudW1iZXI+ODwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPkFDVVRF

PC9rZXl3b3JkPjxrZXl3b3JkPkFETUlOSVNUUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldB

WTwva2V5d29yZD48a2V5d29yZD5hbmFsb2dzICZhbXA7IGRlcml2YXRpdmVzPC9rZXl3b3JkPjxr

ZXl3b3JkPkFOSU1BTDwva2V5d29yZD48a2V5d29yZD5BbmltYWwgbW9kZWw8L2tleXdvcmQ+PGtl

eXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNG

PC9rZXl3b3JkPjxrZXl3b3JkPkNoZW1vdGFjdGljIEZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+

Q2hlbW90YXhpcyxMZXVrb2N5dGU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48

a2V5d29yZD5DaHJvbmljIERpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q09MTEFHRU48L2tleXdv

cmQ+PGtleXdvcmQ+Q09VTlRTPC9rZXl3b3JkPjxrZXl3b3JkPkNPVVJTRTwva2V5d29yZD48a2V5

d29yZD5DWVNUSUMgRklCUk9TSVM8L2tleXdvcmQ+PGtleXdvcmQ+REVDTElORTwva2V5d29yZD48

a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3JkPjxrZXl3

b3JkPkVsYXN0aW48L2tleXdvcmQ+PGtleXdvcmQ+RU5ET1BFUFRJREFTRTwva2V5d29yZD48a2V5

d29yZD5FVklERU5DRTwva2V5d29yZD48a2V5d29yZD5FWCBWSVZPPC9rZXl3b3JkPjxrZXl3b3Jk

PkVYQUNFUkJBVElPTjwva2V5d29yZD48a2V5d29yZD5FWFRSQUNFTExVTEFSPC9rZXl3b3JkPjxr

ZXl3b3JkPmV4dHJhY2VsbHVsYXIgbWF0cml4PC9rZXl3b3JkPjxrZXl3b3JkPmV4dHJhY2VsbHVs

YXIgbWF0cml4IHByb3RlaW5zPC9rZXl3b3JkPjxrZXl3b3JkPkZJQlJPU0lTPC9rZXl3b3JkPjxr

ZXl3b3JkPkdFTkVSQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdv

cmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklERU5USUZJQ0FUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPmltbXVuaXR5PC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0xPR1k8L2tleXdvcmQ+PGtleXdv

cmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklWTzwva2V5d29yZD48a2V5d29yZD5pbmZsYW1t

YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3b3JkPklO

SElCSVRPUjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1JTPC9rZXl3b3JkPjxrZXl3b3JkPklO

VEVSQUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSQUNUSU9OUzwva2V5d29yZD48a2V5d29y

ZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+

TUFUUklYPC9rZXl3b3JkPjxrZXl3b3JkPk1hdHJpeCBNZXRhbGxvcHJvdGVpbmFzZSA4PC9rZXl3

b3JkPjxrZXl3b3JkPk1hdHJpeCBNZXRhbGxvcHJvdGVpbmFzZSA5PC9rZXl3b3JkPjxrZXl3b3Jk

Pk1FVEFCT0xJU008L2tleXdvcmQ+PGtleXdvcmQ+TWV0YWxsb3Byb3RlYXNlczwva2V5d29yZD48

a2V5d29yZD5NSUNFPC9rZXl3b3JkPjxrZXl3b3JkPk1PREVMPC9rZXl3b3JkPjxrZXl3b3JkPk1P

REVMUzwva2V5d29yZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRy

b3BoaWwgYWN0aXZhdGlvbjwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48

a2V5d29yZD5OT1ZFTDwva2V5d29yZD48a2V5d29yZD5PbGlnb3BlcHRpZGVzPC9rZXl3b3JkPjxr

ZXl3b3JkPlBBVEhXQVk8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdBWVM8L2tleXdvcmQ+PGtleXdv

cmQ+UEVQVElERTwva2V5d29yZD48a2V5d29yZD5wZXB0aWRlczwva2V5d29yZD48a2V5d29yZD5w

cm9saW5lPC9rZXl3b3JkPjxrZXl3b3JkPnByb2x5bCBvbGlnb3BlcHRpZGFzZTwva2V5d29yZD48

a2V5d29yZD5wcm9seWwtZ2x5Y3lsLXByb2xpbmU8L2tleXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwv

a2V5d29yZD48a2V5d29yZD5QUk9URUlOUzwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tl

eXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3

b3JkPjxrZXl3b3JkPlJlY2VwdG9ycyxJbnRlcmxldWtpbi04QTwva2V5d29yZD48a2V5d29yZD5S

ZWNlcHRvcnMsSW50ZXJsZXVraW4tOEI8L2tleXdvcmQ+PGtleXdvcmQ+UkVHVUxBVElORzwva2V5

d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SZXNlYXJjaCBTdXBwb3J0

PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVUSU9OPC9rZXl3

b3JkPjxrZXl3b3JkPlNFQ1JFVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+U0VSSU5FPC9rZXl3b3Jk

PjxrZXl3b3JkPnNlcmluZSBlbmRvcGVwdGlkYXNlczwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJ

Qzwva2V5d29yZD48a2V5d29yZD5TUFVUVU08L2tleXdvcmQ+PGtleXdvcmQ+U1RSVUNUVVJBTDwv

a2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3Jk

PjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5USEVSQVBFVVRJQzwva2V5d29yZD48

a2V5d29yZD5USEVSQVBJRVM8L2tleXdvcmQ+PGtleXdvcmQ+dGhlcmFweTwva2V5d29yZD48a2V5

d29yZD5VU0U8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwODwveWVhcj48cHVi

LWRhdGVzPjxkYXRlPjQvMTUvMjAwODwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5H

QUdHQVIyMDA4PC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [122]. This may be self-perpetuating as neutrophils release MMP-9, which in turn generates more matrikines PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051

bT4xMTQ4NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTIzXTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj4xMTQ4NDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc5MDAyIj4xMTQ4NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

WHUsWC48L2F1dGhvcj48YXV0aG9yPkphY2tzb24sUC5MLjwvYXV0aG9yPjxhdXRob3I+VGFubmVy

LFMuPC9hdXRob3I+PGF1dGhvcj5IYXJkaXNvbixNLlQuPC9hdXRob3I+PGF1dGhvcj5BYmR1bCxS

b2RhIE0uPC9hdXRob3I+PGF1dGhvcj5CbGFsb2NrLEouRS48L2F1dGhvcj48YXV0aG9yPkdhZ2dh

cixBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BIHNl

bGYtcHJvcGFnYXRpbmcgbWF0cml4IG1ldGFsbG9wcm90ZWFzZS05IChNTVAtOSkgZGVwZW5kZW50

IGN5Y2xlIG9mIGNocm9uaWMgbmV1dHJvcGhpbGljIGluZmxhbW1hdGlvbjwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5QTG9TLk9uZS48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5QTG9TLk9uZS48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5l

MTU3ODE8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50

LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZB

VEVEPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWQVRFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWSVRJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJ

VFk8L2tleXdvcmQ+PGtleXdvcmQ+QWxsZXJneTwva2V5d29yZD48a2V5d29yZD5hbmFsb2dzICZh

bXA7IGRlcml2YXRpdmVzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb3N5bnRoZXNpczwva2V5d29yZD48

a2V5d29yZD5CTE9DS0FERTwva2V5d29yZD48a2V5d29yZD5CTE9PRDwva2V5d29yZD48a2V5d29y

ZD5CUkVBS0RPV048L2tleXdvcmQ+PGtleXdvcmQ+Q0Y8L2tleXdvcmQ+PGtleXdvcmQ+Q2hlbW90

YWN0aWMgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3Jk

PkNocm9uaWMgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5

d29yZD5DT0xMQUdFTjwva2V5d29yZD48a2V5d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5

d29yZD5Dcml0aWNhbCBDYXJlPC9rZXl3b3JkPjxrZXl3b3JkPkRFQ1JFQVNFRDwva2V5d29yZD48

a2V5d29yZD5ERVBFTkRFTlQ8L2tleXdvcmQ+PGtleXdvcmQ+REVWRUxPUE1FTlQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5

d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

RVggVklWTzwva2V5d29yZD48a2V5d29yZD5GZWVkYmFjayxQaHlzaW9sb2dpY2FsPC9rZXl3b3Jk

PjxrZXl3b3JkPkdFTkVSQVRFRDwva2V5d29yZD48a2V5d29yZD5HRU5FUkFUSU9OPC9rZXl3b3Jk

PjxrZXl3b3JkPkdSQU5VTEU8L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdv

cmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklNUExJQ0FUSU9OUzwva2V5d29yZD48a2V5d29y

ZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5pbmZs

YW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3JkPklO

VEFDVDwva2V5d29yZD48a2V5d29yZD5JU09MQVRFRDwva2V5d29yZD48a2V5d29yZD5MZWFkPC9r

ZXl3b3JkPjxrZXl3b3JkPk1BUCBLaW5hc2UgU2lnbmFsaW5nIFN5c3RlbTwva2V5d29yZD48a2V5

d29yZD5NQVBLPC9rZXl3b3JkPjxrZXl3b3JkPk1hc3MgU3BlY3Ryb21ldHJ5PC9rZXl3b3JkPjxr

ZXl3b3JkPk1BVFJJWDwva2V5d29yZD48a2V5d29yZD5NYXRyaXggTWV0YWxsb3Byb3RlaW5hc2Ug

OTwva2V5d29yZD48a2V5d29yZD5NRURJQ0lORTwva2V5d29yZD48a2V5d29yZD5NRVRBQk9MSVNN

PC9rZXl3b3JkPjxrZXl3b3JkPk1NUDk8L2tleXdvcmQ+PGtleXdvcmQ+TU9SQklESVRZPC9rZXl3

b3JkPjxrZXl3b3JkPk1PUlRBTElUWTwva2V5d29yZD48a2V5d29yZD5OLUFDRVRZTDwva2V5d29y

ZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRyb3BoaWwgYWN0aXZh

dGlvbjwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5PbGln

b3BlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9HWTwva2V5d29yZD48a2V5d29yZD5Q

QVRIV0FZPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UE1O

PC9rZXl3b3JkPjxrZXl3b3JkPlBSSU1BUlk8L2tleXdvcmQ+PGtleXdvcmQ+cHJvbGluZTwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdv

cmQ+PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycyxJbnRlcmxl

dWtpbi04QTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsSW50ZXJsZXVraW4tOEI8L2tleXdv

cmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFRDwva2V5d29yZD48

a2V5d29yZD5TVElNVUxBVEVEPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5

d29yZD5VTklURUQgU1RBVEVTPC9rZXl3b3JkPjxrZXl3b3JkPldPUkxEV0lERTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MS8xMy8y

MDExPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlhVMjAxMTwvbGFiZWw+PHVybHM+

PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051

bT4xMTQ4NDwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTIzXTwvRGlzcGxheVRleHQ+PHJlY29yZD48

cmVjLW51bWJlcj4xMTQ4NDwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIg

ZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIx

Mzc4NDc5MDAyIj4xMTQ4NDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

WHUsWC48L2F1dGhvcj48YXV0aG9yPkphY2tzb24sUC5MLjwvYXV0aG9yPjxhdXRob3I+VGFubmVy

LFMuPC9hdXRob3I+PGF1dGhvcj5IYXJkaXNvbixNLlQuPC9hdXRob3I+PGF1dGhvcj5BYmR1bCxS

b2RhIE0uPC9hdXRob3I+PGF1dGhvcj5CbGFsb2NrLEouRS48L2F1dGhvcj48YXV0aG9yPkdhZ2dh

cixBLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BIHNl

bGYtcHJvcGFnYXRpbmcgbWF0cml4IG1ldGFsbG9wcm90ZWFzZS05IChNTVAtOSkgZGVwZW5kZW50

IGN5Y2xlIG9mIGNocm9uaWMgbmV1dHJvcGhpbGljIGluZmxhbW1hdGlvbjwvdGl0bGU+PHNlY29u

ZGFyeS10aXRsZT5QTG9TLk9uZS48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5QTG9TLk9uZS48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5l

MTU3ODE8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxudW1iZXI+MTwvbnVtYmVyPjxyZXByaW50

LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+

QUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZB

VEVEPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWQVRFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFU

SU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWSVRJRVM8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJ

VFk8L2tleXdvcmQ+PGtleXdvcmQ+QWxsZXJneTwva2V5d29yZD48a2V5d29yZD5hbmFsb2dzICZh

bXA7IGRlcml2YXRpdmVzPC9rZXl3b3JkPjxrZXl3b3JkPkJpb3N5bnRoZXNpczwva2V5d29yZD48

a2V5d29yZD5CTE9DS0FERTwva2V5d29yZD48a2V5d29yZD5CTE9PRDwva2V5d29yZD48a2V5d29y

ZD5CUkVBS0RPV048L2tleXdvcmQ+PGtleXdvcmQ+Q0Y8L2tleXdvcmQ+PGtleXdvcmQ+Q2hlbW90

YWN0aWMgRmFjdG9yczwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3Jk

PkNocm9uaWMgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5

d29yZD5DT0xMQUdFTjwva2V5d29yZD48a2V5d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5

d29yZD5Dcml0aWNhbCBDYXJlPC9rZXl3b3JkPjxrZXl3b3JkPkRFQ1JFQVNFRDwva2V5d29yZD48

a2V5d29yZD5ERVBFTkRFTlQ8L2tleXdvcmQ+PGtleXdvcmQ+REVWRUxPUE1FTlQ8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5

d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+

RVggVklWTzwva2V5d29yZD48a2V5d29yZD5GZWVkYmFjayxQaHlzaW9sb2dpY2FsPC9rZXl3b3Jk

PjxrZXl3b3JkPkdFTkVSQVRFRDwva2V5d29yZD48a2V5d29yZD5HRU5FUkFUSU9OPC9rZXl3b3Jk

PjxrZXl3b3JkPkdSQU5VTEU8L2tleXdvcmQ+PGtleXdvcmQ+aHVtYW48L2tleXdvcmQ+PGtleXdv

cmQ+SFVNQU5TPC9rZXl3b3JkPjxrZXl3b3JkPklNUExJQ0FUSU9OUzwva2V5d29yZD48a2V5d29y

ZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5pbmZs

YW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVE9SPC9rZXl3b3JkPjxrZXl3b3JkPklO

VEFDVDwva2V5d29yZD48a2V5d29yZD5JU09MQVRFRDwva2V5d29yZD48a2V5d29yZD5MZWFkPC9r

ZXl3b3JkPjxrZXl3b3JkPk1BUCBLaW5hc2UgU2lnbmFsaW5nIFN5c3RlbTwva2V5d29yZD48a2V5

d29yZD5NQVBLPC9rZXl3b3JkPjxrZXl3b3JkPk1hc3MgU3BlY3Ryb21ldHJ5PC9rZXl3b3JkPjxr

ZXl3b3JkPk1BVFJJWDwva2V5d29yZD48a2V5d29yZD5NYXRyaXggTWV0YWxsb3Byb3RlaW5hc2Ug

OTwva2V5d29yZD48a2V5d29yZD5NRURJQ0lORTwva2V5d29yZD48a2V5d29yZD5NRVRBQk9MSVNN

PC9rZXl3b3JkPjxrZXl3b3JkPk1NUDk8L2tleXdvcmQ+PGtleXdvcmQ+TU9SQklESVRZPC9rZXl3

b3JkPjxrZXl3b3JkPk1PUlRBTElUWTwva2V5d29yZD48a2V5d29yZD5OLUFDRVRZTDwva2V5d29y

ZD48a2V5d29yZD5uZXV0cm9waGlsPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRyb3BoaWwgYWN0aXZh

dGlvbjwva2V5d29yZD48a2V5d29yZD5OZXV0cm9waGlsczwva2V5d29yZD48a2V5d29yZD5PbGln

b3BlcHRpZGVzPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9HWTwva2V5d29yZD48a2V5d29yZD5Q

QVRIV0FZPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UE1O

PC9rZXl3b3JkPjxrZXl3b3JkPlBSSU1BUlk8L2tleXdvcmQ+PGtleXdvcmQ+cHJvbGluZTwva2V5

d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8L2tleXdv

cmQ+PGtleXdvcmQ+UmVjZXB0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycyxJbnRlcmxl

dWtpbi04QTwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsSW50ZXJsZXVraW4tOEI8L2tleXdv

cmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFRDwva2V5d29yZD48

a2V5d29yZD5TVElNVUxBVEVEPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5

d29yZD5VTklURUQgU1RBVEVTPC9rZXl3b3JkPjxrZXl3b3JkPldPUkxEV0lERTwva2V5d29yZD48

L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDExPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MS8xMy8y

MDExPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlhVMjAxMTwvbGFiZWw+PHVybHM+

PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [123]. Human neutrophil elastase (HNE) not only has elastolytic activity but is also a potent stimulant of mucus secretion in the airways, mediated via epithelial growth factor receptors (EGFR) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWtleWFtYTwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT4xMDE5ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTI0XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDE5ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTgyIj4xMDE5ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+VGFrZXlhbWEsSy48L2F1dGhvcj48YXV0aG9yPkZhaHksSi5WLjwvYXV0aG9yPjxhdXRo

b3I+TmFkZWwsSi5BLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0

aXRsZT5SZWxhdGlvbnNoaXAgb2YgZXBpZGVybWFsIGdyb3d0aCBmYWN0b3IgcmVjZXB0b3JzIHRv

IGdvYmxldCBjZWxsIHByb2R1Y3Rpb24gaW4gaHVtYW4gYnJvbmNoaTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQuPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTExLTUxNjwvcGFnZXM+PHZvbHVtZT4xNjM8

L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjExPC9rZXl3b3JkPjxrZXl3b3JkPjEy

PC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QURVTFQ8L2tl

eXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+

PGtleXdvcmQ+QU5BTFlTSVM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3

b3JkPmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5BU1RITUFUSUNTPC9rZXl3b3JkPjxrZXl3

b3JkPkJJT1BTSUVTPC9rZXl3b3JkPjxrZXl3b3JkPkJJT1BTWTwva2V5d29yZD48a2V5d29yZD5C

Uk9OQ0hJPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlhbDwva2V5d29yZD48a2V5d29yZD5CUk9O

Q0hPU0NPUFk8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwv

a2V5d29yZD48a2V5d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5FcGlkZXJtYWwg

R3Jvd3RoIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5FcGl0aGVsaXVtPC9rZXl3b3JkPjxrZXl3

b3JkPkVYUFJFU1NFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R0VO

RTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+R0VO

RVRJQ1M8L2tleXdvcmQ+PGtleXdvcmQ+R0xZQ09DT05KVUdBVEU8L2tleXdvcmQ+PGtleXdvcmQ+

R2x5Y29jb25qdWdhdGVzPC9rZXl3b3JkPjxrZXl3b3JkPkdPQkxFVDwva2V5d29yZD48a2V5d29y

ZD5HT0JMRVQgQ0VMTDwva2V5d29yZD48a2V5d29yZD5Hb2JsZXQgY2VsbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+R1JPV1RIPC9rZXl3b3JkPjxrZXl3b3JkPkdyb3d0aCBmYWN0b3I8L2tleXdvcmQ+PGtl

eXdvcmQ+SEVBTFRIWTwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5I

VU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SFlCUklESVpBVElPTjwva2V5d29yZD48a2V5d29yZD5J

bWFnZSBQcm9jZXNzaW5nLENvbXB1dGVyLUFzc2lzdGVkPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b2VuenltZSBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0hJU1RPQ0hFTUlDQUw8

L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PUkVBQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5JTjwv

a2V5d29yZD48a2V5d29yZD5JbiBTaXR1IEh5YnJpZGl6YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwv

a2V5d29yZD48a2V5d29yZD5NVUNJTjwva2V5d29yZD48a2V5d29yZD5tdWNpbiA1QUM8L2tleXdv

cmQ+PGtleXdvcmQ+TXVjaW5zPC9rZXl3b3JkPjxrZXl3b3JkPm11Y29zYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+TVVDT1VTPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9HWTwva2V5d29yZD48a2V5d29y

ZD5QQVRURVJOUzwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBST0RVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5y

ZWNlcHRvcjwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcixlcGlkZXJtYWwgZ3Jvd3RoIGZhY3Rv

cjwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05T

SElQPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJlc2VhcmNo

IFN1cHBvcnQ8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLE1lc3Nlbmdlcjwva2V5d29yZD48a2V5d29y

ZD5TRVFVRU5DRTwva2V5d29yZD48a2V5d29yZD5TSVRVPC9rZXl3b3JkPjxrZXl3b3JkPnN0YWlu

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNZTlRIRVNJ

Uzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAxPC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+Mi8yMDAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlRBS0VZQU1BMjAw

MUE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWtleWFtYTwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

PFJlY051bT4xMDE5ODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTI0XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj4xMDE5ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBw

PSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0

YW1wPSIxMzc4NDc4OTgyIj4xMDE5ODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+VGFrZXlhbWEsSy48L2F1dGhvcj48YXV0aG9yPkZhaHksSi5WLjwvYXV0aG9yPjxhdXRo

b3I+TmFkZWwsSi5BLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0

aXRsZT5SZWxhdGlvbnNoaXAgb2YgZXBpZGVybWFsIGdyb3d0aCBmYWN0b3IgcmVjZXB0b3JzIHRv

IGdvYmxldCBjZWxsIHByb2R1Y3Rpb24gaW4gaHVtYW4gYnJvbmNoaTwvdGl0bGU+PHNlY29uZGFy

eS10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQuPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NTExLTUxNjwvcGFnZXM+PHZvbHVtZT4xNjM8

L3ZvbHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9y

ZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjExPC9rZXl3b3JkPjxrZXl3b3JkPjEy

PC9rZXl3b3JkPjxrZXl3b3JkPkFDVElWQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+QURVTFQ8L2tl

eXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+

PGtleXdvcmQ+QU5BTFlTSVM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3

b3JkPmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5BU1RITUFUSUNTPC9rZXl3b3JkPjxrZXl3

b3JkPkJJT1BTSUVTPC9rZXl3b3JkPjxrZXl3b3JkPkJJT1BTWTwva2V5d29yZD48a2V5d29yZD5C

Uk9OQ0hJPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlhbDwva2V5d29yZD48a2V5d29yZD5CUk9O

Q0hPU0NPUFk8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwv

a2V5d29yZD48a2V5d29yZD5DT1JSRUxBVElPTjwva2V5d29yZD48a2V5d29yZD5FcGlkZXJtYWwg

R3Jvd3RoIEZhY3Rvcjwva2V5d29yZD48a2V5d29yZD5FcGl0aGVsaXVtPC9rZXl3b3JkPjxrZXl3

b3JkPkVYUFJFU1NFRDwva2V5d29yZD48a2V5d29yZD5FWFBSRVNTSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GZW1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+R0VO

RTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+R0VO

RVRJQ1M8L2tleXdvcmQ+PGtleXdvcmQ+R0xZQ09DT05KVUdBVEU8L2tleXdvcmQ+PGtleXdvcmQ+

R2x5Y29jb25qdWdhdGVzPC9rZXl3b3JkPjxrZXl3b3JkPkdPQkxFVDwva2V5d29yZD48a2V5d29y

ZD5HT0JMRVQgQ0VMTDwva2V5d29yZD48a2V5d29yZD5Hb2JsZXQgY2VsbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+R1JPV1RIPC9rZXl3b3JkPjxrZXl3b3JkPkdyb3d0aCBmYWN0b3I8L2tleXdvcmQ+PGtl

eXdvcmQ+SEVBTFRIWTwva2V5d29yZD48a2V5d29yZD5odW1hbjwva2V5d29yZD48a2V5d29yZD5I

VU1BTlM8L2tleXdvcmQ+PGtleXdvcmQ+SFlCUklESVpBVElPTjwva2V5d29yZD48a2V5d29yZD5J

bWFnZSBQcm9jZXNzaW5nLENvbXB1dGVyLUFzc2lzdGVkPC9rZXl3b3JkPjxrZXl3b3JkPkltbXVu

b2VuenltZSBUZWNobmlxdWVzPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT0hJU1RPQ0hFTUlDQUw8

L2tleXdvcmQ+PGtleXdvcmQ+SU1NVU5PUkVBQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5JTjwv

a2V5d29yZD48a2V5d29yZD5JbiBTaXR1IEh5YnJpZGl6YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+

SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPk1BTEU8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwv

a2V5d29yZD48a2V5d29yZD5NVUNJTjwva2V5d29yZD48a2V5d29yZD5tdWNpbiA1QUM8L2tleXdv

cmQ+PGtleXdvcmQ+TXVjaW5zPC9rZXl3b3JkPjxrZXl3b3JkPm11Y29zYWw8L2tleXdvcmQ+PGtl

eXdvcmQ+TVVDT1VTPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9HWTwva2V5d29yZD48a2V5d29y

ZD5QQVRURVJOUzwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PlBST0RVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UFJPVEVJTjwva2V5d29yZD48a2V5d29yZD5y

ZWNlcHRvcjwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcixlcGlkZXJtYWwgZ3Jvd3RoIGZhY3Rv

cjwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05T

SElQPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlJlc2VhcmNo

IFN1cHBvcnQ8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLE1lc3Nlbmdlcjwva2V5d29yZD48a2V5d29y

ZD5TRVFVRU5DRTwva2V5d29yZD48a2V5d29yZD5TSVRVPC9rZXl3b3JkPjxrZXl3b3JkPnN0YWlu

aW5nPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNZTlRIRVNJ

Uzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDAxPC95ZWFyPjxwdWItZGF0ZXM+

PGRhdGU+Mi8yMDAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPlRBS0VZQU1BMjAw

MUE8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [124]. Several matrix metalloproteinases (MMP) degrade elastin fibres are important elastolytic enzymes. MMP-9 is the predominant elastolytic enzyme in COPD and is secreted from macrophages, neutrophils and epithelial cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdXNzZWxsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjc3ODY8L1JlY051bT48RGlzcGxheVRleHQ+WzEyNV08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+Nzc4NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQxIj43Nzg2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5SdXNzZWxsLFIuRS48L2F1dGhvcj48YXV0aG9yPkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRo

b3I+RGVNYXRvcyxDLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC48L2F1dGhvcj48YXV0aG9y

PlNtaXRoLE0uPC9hdXRob3I+PGF1dGhvcj5XaWdnaW5zLEouPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5S

ZWxlYXNlIGFuZCBhY3Rpdml0eSBvZiBtYXRyaXggbWV0YWxsb3Byb3RlaW5hc2UtOSBhbmQgdGlz

c3VlIGluaGliaXRvciBvZiBtZXRhbGxvcHJvdGVpbmFzZS0xIGJ5IGFsdmVvbGFyIG1hY3JvcGhh

Z2VzIGZyb20gcGF0aWVudHMgd2l0aCBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNl

YXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENlbGwgTW9sIEJpb2w8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3Bp

ciBDZWxsIE1vbCBCaW9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjAyLTYwOTwv

cGFnZXM+PHZvbHVtZT4yNjwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZJ

VElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BTFZFT0xB

Ujwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdlPC9rZXl3b3JkPjxrZXl3b3Jk

PkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwv

a2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNo

cm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q0lH

QVJFVFRFPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q1VMVFVSRTwv

a2V5d29yZD48a2V5d29yZD5jdWx0dXJlIG1lZGlhPC9rZXl3b3JkPjxrZXl3b3JkPkRFQ1JFQVNF

RDwva2V5d29yZD48a2V5d29yZD5ERVZFTE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5kZXhhbWV0

aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNU

PC9rZXl3b3JkPjxrZXl3b3JkPkVsYXN0aW48L2tleXdvcmQ+PGtleXdvcmQ+RU1QSFlTRU1BPC9r

ZXl3b3JkPjxrZXl3b3JkPkVOWllNRTwva2V5d29yZD48a2V5d29yZD5IRUFMVEhZPC9rZXl3b3Jk

PjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3b3JkPjxrZXl3b3Jk

PklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1I8L2tleXdvcmQ+PGtleXdvcmQ+

SU5ISUJJVE9SUzwva2V5d29yZD48a2V5d29yZD5JTlRFUkxFVUtJTjwva2V5d29yZD48a2V5d29y

ZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFj

cm9waGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFUUklYPC9rZXl3b3JkPjxrZXl3b3JkPm1hdHJp

eCBtZXRhbGxvcHJvdGVpbmFzZTwva2V5d29yZD48a2V5d29yZD5NRURJVU08L2tleXdvcmQ+PGtl

eXdvcmQ+TU1QPC9rZXl3b3JkPjxrZXl3b3JkPk1NUDk8L2tleXdvcmQ+PGtleXdvcmQ+Tk88L2tl

eXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFRDwva2V5d29y

ZD48a2V5d29yZD5TVElNVUxBVEVEPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+

PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdv

cmQ+VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5d29yZD5VTklU

RUQgU1RBVEVTPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT41LzIwMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+UlVT

U0VMTDIwMDJBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdXNzZWxsPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

UmVjTnVtPjc3ODY8L1JlY051bT48RGlzcGxheVRleHQ+WzEyNV08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+Nzc4NjwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQxIj43Nzg2PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5SdXNzZWxsLFIuRS48L2F1dGhvcj48YXV0aG9yPkN1bHBpdHQsUy5WLjwvYXV0aG9yPjxhdXRo

b3I+RGVNYXRvcyxDLjwvYXV0aG9yPjxhdXRob3I+RG9ubmVsbHksTC48L2F1dGhvcj48YXV0aG9y

PlNtaXRoLE0uPC9hdXRob3I+PGF1dGhvcj5XaWdnaW5zLEouPC9hdXRob3I+PGF1dGhvcj5CYXJu

ZXMsUC5KLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5S

ZWxlYXNlIGFuZCBhY3Rpdml0eSBvZiBtYXRyaXggbWV0YWxsb3Byb3RlaW5hc2UtOSBhbmQgdGlz

c3VlIGluaGliaXRvciBvZiBtZXRhbGxvcHJvdGVpbmFzZS0xIGJ5IGFsdmVvbGFyIG1hY3JvcGhh

Z2VzIGZyb20gcGF0aWVudHMgd2l0aCBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNl

YXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENlbGwgTW9sIEJpb2w8L3Nl

Y29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3Bp

ciBDZWxsIE1vbCBCaW9sPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+NjAyLTYwOTwv

cGFnZXM+PHZvbHVtZT4yNjwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVyPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZJ

VElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BTFZFT0xB

Ujwva2V5d29yZD48a2V5d29yZD5BbHZlb2xhciBtYWNyb3BoYWdlPC9rZXl3b3JkPjxrZXl3b3Jk

PkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwv

a2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNo

cm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Q0lH

QVJFVFRFPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdvcmQ+Q1VMVFVSRTwv

a2V5d29yZD48a2V5d29yZD5jdWx0dXJlIG1lZGlhPC9rZXl3b3JkPjxrZXl3b3JkPkRFQ1JFQVNF

RDwva2V5d29yZD48a2V5d29yZD5ERVZFTE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5kZXhhbWV0

aGFzb25lPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNU

PC9rZXl3b3JkPjxrZXl3b3JkPkVsYXN0aW48L2tleXdvcmQ+PGtleXdvcmQ+RU1QSFlTRU1BPC9r

ZXl3b3JkPjxrZXl3b3JkPkVOWllNRTwva2V5d29yZD48a2V5d29yZD5IRUFMVEhZPC9rZXl3b3Jk

PjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFPC9rZXl3b3JkPjxrZXl3b3Jk

PklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1I8L2tleXdvcmQ+PGtleXdvcmQ+

SU5ISUJJVE9SUzwva2V5d29yZD48a2V5d29yZD5JTlRFUkxFVUtJTjwva2V5d29yZD48a2V5d29y

ZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFj

cm9waGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFUUklYPC9rZXl3b3JkPjxrZXl3b3JkPm1hdHJp

eCBtZXRhbGxvcHJvdGVpbmFzZTwva2V5d29yZD48a2V5d29yZD5NRURJVU08L2tleXdvcmQ+PGtl

eXdvcmQ+TU1QPC9rZXl3b3JkPjxrZXl3b3JkPk1NUDk8L2tleXdvcmQ+PGtleXdvcmQ+Tk88L2tl

eXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tl

eXdvcmQ+PGtleXdvcmQ+UFJPRFVDVElPTjwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tl

eXdvcmQ+PGtleXdvcmQ+UkVMRUFTRTwva2V5d29yZD48a2V5d29yZD5SRUxFQVNFRDwva2V5d29y

ZD48a2V5d29yZD5TVElNVUxBVEVEPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+

PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+U1VCSkVDVFM8L2tleXdvcmQ+PGtleXdv

cmQ+VElTU1VFPC9rZXl3b3JkPjxrZXl3b3JkPlVOSVRFRDwva2V5d29yZD48a2V5d29yZD5VTklU

RUQgU1RBVEVTPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT41LzIwMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+UlVT

U0VMTDIwMDJBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [125]. ATPIntracellular ATP is important for cell energetics, but may be released extracellularly and activate surface purinergic receptors that enhance airway inflammation ADDIN EN.CITE <EndNote><Cite><Author>Pelleg</Author><Year>2016</Year><RecNum>12884</RecNum><DisplayText>[126]</DisplayText><record><rec-number>12884</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1473764474">12884</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pelleg, A.</author><author>Schulman, E. S.</author><author>Barnes, P. J.</author></authors></contributors><auth-address>Drexel University, College of Medicine, Department of Medicine, Philadelphia Pennsylvania, USA. Electronic address: apelleg@drexelmed.edu.&#xD;Drexel University, College of Medicine, Department of Medicine, Philadelphia Pennsylvania, USA.&#xD;Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK.</auth-address><titles><title>Extracellular adenosine 5&apos;-triphosphate in obstructive airway diseases</title><secondary-title>Chest</secondary-title><alt-title>Chest</alt-title></titles><periodical><full-title>Chest</full-title></periodical><alt-periodical><full-title>Chest</full-title></alt-periodical><pages>908-915</pages><volume>150</volume><number>4</number><edition>2016/08/30</edition><keywords><keyword>Atp</keyword><keyword>Copd</keyword><keyword>Cough</keyword><keyword>Inflammation</keyword><keyword>P2 receptors</keyword></keywords><dates><year>2016</year><pub-dates><date>Aug 25</date></pub-dates></dates><isbn>0012-3692</isbn><accession-num>27568579</accession-num><urls></urls><electronic-resource-num>10.1016/j.chest.2016.06.045</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[126]. ATP may enhance the release of mast cell mediators via P2Y2 receptors and activation of the inflammasome via P2X7 receptors. ATP is a potent activator of airway afferent nerves via P2X2/3 receptors and an antagonist of P2X3 receptors is effective as an anti-tussive agent PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmR1bHFhd2k8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy

PjxSZWNOdW0+MTI3NTY8L1JlY051bT48RGlzcGxheVRleHQ+WzEyN108L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTI3NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQ1ODIyMjA4OCI+MTI3NTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkFiZHVscWF3aSwgUi48L2F1dGhvcj48YXV0aG9yPkRvY2tyeSwgUi48L2F1dGhvcj48

YXV0aG9yPkhvbHQsIEsuPC9hdXRob3I+PGF1dGhvcj5MYXl0b24sIEcuPC9hdXRob3I+PGF1dGhv

cj5NY0NhcnRoeSwgQi4gRy48L2F1dGhvcj48YXV0aG9yPkZvcmQsIEEuIFAuPC9hdXRob3I+PGF1

dGhvcj5TbWl0aCwgSi4gQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5DZW50cmUgZm9yIFJlc3BpcmF0b3J5IE1lZGljaW5lIGFuZCBBbGxlcmd5LCBJbnN0

aXR1dGUgb2YgSW5mbGFtbWF0aW9uIGFuZCBSZXBhaXIsIE1hbmNoZXN0ZXIgQWNhZGVtaWMgSGVh

bHRoIFNjaWVuY2UgQ2VudHJlLCBVbml2ZXJzaXR5IG9mIE1hbmNoZXN0ZXIsIE1hbmNoZXN0ZXIs

IFVLOyBVbml2ZXJzaXR5IEhvc3BpdGFsIG9mIFNvdXRoIE1hbmNoZXN0ZXIsIEVkdWNhdGlvbiBh

bmQgUmVzZWFyY2ggQ2VudHJlLCBVbml2ZXJzaXR5IEhvc3BpdGFsIG9mIFNvdXRoIE1hbmNoZXN0

ZXIsIE1hbmNoZXN0ZXIsIFVLLiYjeEQ7UGFyYW1TdGF0IEx0ZCwgQXNoLCBVSy4mI3hEO0FmZmVy

ZW50IFBoYXJtYWNldXRpY2FscywgU2FuIE1hdGVvLCBDQSwgVVNBLiYjeEQ7Q2VudHJlIGZvciBS

ZXNwaXJhdG9yeSBNZWRpY2luZSBhbmQgQWxsZXJneSwgSW5zdGl0dXRlIG9mIEluZmxhbW1hdGlv

biBhbmQgUmVwYWlyLCBNYW5jaGVzdGVyIEFjYWRlbWljIEhlYWx0aCBTY2llbmNlIENlbnRyZSwg

VW5pdmVyc2l0eSBvZiBNYW5jaGVzdGVyLCBNYW5jaGVzdGVyLCBVSzsgVW5pdmVyc2l0eSBIb3Nw

aXRhbCBvZiBTb3V0aCBNYW5jaGVzdGVyLCBFZHVjYXRpb24gYW5kIFJlc2VhcmNoIENlbnRyZSwg

VW5pdmVyc2l0eSBIb3NwaXRhbCBvZiBTb3V0aCBNYW5jaGVzdGVyLCBNYW5jaGVzdGVyLCBVSy4g

RWxlY3Ryb25pYyBhZGRyZXNzOiBqYWNreS5zbWl0aEBtYW5jaGVzdGVyLmFjLnVrLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlAyWDMgcmVjZXB0b3IgYW50YWdvbmlzdCAoQUYtMjE5KSBp

biByZWZyYWN0b3J5IGNocm9uaWMgY291Z2g6IGEgcmFuZG9taXNlZCwgZG91YmxlLWJsaW5kLCBw

bGFjZWJvLWNvbnRyb2xsZWQgcGhhc2UgMiBzdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5M

YW5jZXQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkxhbmNldCAoTG9uZG9uLCBFbmdsYW5k

KTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkxhbmNldDwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjExOTgtMjA1PC9wYWdlcz48dm9sdW1lPjM4NTwv

dm9sdW1lPjxudW1iZXI+OTk3NDwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMTIvMDQ8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW50aXR1c3NpdmUgQWdlbnRzL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMg

dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5D

aXJjYWRpYW4gUmh5dGhtPC9rZXl3b3JkPjxrZXl3b3JkPkNvdWdoLypkcnVnIHRoZXJhcHk8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3Jvc3MtT3ZlciBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJs

ZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBB

Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPlB1cmluZXJnaWMgUDJYIFJlY2VwdG9yIEFudGFnb25pc3Rz

L2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlB5cmlt

aWRpbmVzL2FkdmVyc2UgZWZmZWN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0

Y29tZTwva2V5d29yZD48a2V5d29yZD5Zb3VuZyBBZHVsdDwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDI4PC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDE0MC02NzM2PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1NDY3

NTg2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAxNi9zMDE0MC02NzM2KDE0KTYxMjU1LTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxy

ZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxh

bmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmR1bHFhd2k8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy

PjxSZWNOdW0+MTI3NTY8L1JlY051bT48RGlzcGxheVRleHQ+WzEyN108L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTI3NTY8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQ1ODIyMjA4OCI+MTI3NTY8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkFiZHVscWF3aSwgUi48L2F1dGhvcj48YXV0aG9yPkRvY2tyeSwgUi48L2F1dGhvcj48

YXV0aG9yPkhvbHQsIEsuPC9hdXRob3I+PGF1dGhvcj5MYXl0b24sIEcuPC9hdXRob3I+PGF1dGhv

cj5NY0NhcnRoeSwgQi4gRy48L2F1dGhvcj48YXV0aG9yPkZvcmQsIEEuIFAuPC9hdXRob3I+PGF1

dGhvcj5TbWl0aCwgSi4gQS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgt

YWRkcmVzcz5DZW50cmUgZm9yIFJlc3BpcmF0b3J5IE1lZGljaW5lIGFuZCBBbGxlcmd5LCBJbnN0

aXR1dGUgb2YgSW5mbGFtbWF0aW9uIGFuZCBSZXBhaXIsIE1hbmNoZXN0ZXIgQWNhZGVtaWMgSGVh

bHRoIFNjaWVuY2UgQ2VudHJlLCBVbml2ZXJzaXR5IG9mIE1hbmNoZXN0ZXIsIE1hbmNoZXN0ZXIs

IFVLOyBVbml2ZXJzaXR5IEhvc3BpdGFsIG9mIFNvdXRoIE1hbmNoZXN0ZXIsIEVkdWNhdGlvbiBh

bmQgUmVzZWFyY2ggQ2VudHJlLCBVbml2ZXJzaXR5IEhvc3BpdGFsIG9mIFNvdXRoIE1hbmNoZXN0

ZXIsIE1hbmNoZXN0ZXIsIFVLLiYjeEQ7UGFyYW1TdGF0IEx0ZCwgQXNoLCBVSy4mI3hEO0FmZmVy

ZW50IFBoYXJtYWNldXRpY2FscywgU2FuIE1hdGVvLCBDQSwgVVNBLiYjeEQ7Q2VudHJlIGZvciBS

ZXNwaXJhdG9yeSBNZWRpY2luZSBhbmQgQWxsZXJneSwgSW5zdGl0dXRlIG9mIEluZmxhbW1hdGlv

biBhbmQgUmVwYWlyLCBNYW5jaGVzdGVyIEFjYWRlbWljIEhlYWx0aCBTY2llbmNlIENlbnRyZSwg

VW5pdmVyc2l0eSBvZiBNYW5jaGVzdGVyLCBNYW5jaGVzdGVyLCBVSzsgVW5pdmVyc2l0eSBIb3Nw

aXRhbCBvZiBTb3V0aCBNYW5jaGVzdGVyLCBFZHVjYXRpb24gYW5kIFJlc2VhcmNoIENlbnRyZSwg

VW5pdmVyc2l0eSBIb3NwaXRhbCBvZiBTb3V0aCBNYW5jaGVzdGVyLCBNYW5jaGVzdGVyLCBVSy4g

RWxlY3Ryb25pYyBhZGRyZXNzOiBqYWNreS5zbWl0aEBtYW5jaGVzdGVyLmFjLnVrLjwvYXV0aC1h

ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPlAyWDMgcmVjZXB0b3IgYW50YWdvbmlzdCAoQUYtMjE5KSBp

biByZWZyYWN0b3J5IGNocm9uaWMgY291Z2g6IGEgcmFuZG9taXNlZCwgZG91YmxlLWJsaW5kLCBw

bGFjZWJvLWNvbnRyb2xsZWQgcGhhc2UgMiBzdHVkeTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5M

YW5jZXQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkxhbmNldCAoTG9uZG9uLCBFbmdsYW5k

KTwvYWx0LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkxhbmNldDwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjExOTgtMjA1PC9wYWdlcz48dm9sdW1lPjM4NTwv

dm9sdW1lPjxudW1iZXI+OTk3NDwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMTIvMDQ8L2VkaXRpb24+

PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3b3JkPkFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+QW50aXR1c3NpdmUgQWdlbnRzL2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMg

dXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgRGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5D

aXJjYWRpYW4gUmh5dGhtPC9rZXl3b3JkPjxrZXl3b3JkPkNvdWdoLypkcnVnIHRoZXJhcHk8L2tl

eXdvcmQ+PGtleXdvcmQ+Q3Jvc3MtT3ZlciBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPkRvdWJs

ZS1CbGluZCBNZXRob2Q8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3Jk

Pkh1bWFuczwva2V5d29yZD48a2V5d29yZD5NYWxlPC9rZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBB

Z2VkPC9rZXl3b3JkPjxrZXl3b3JkPlB1cmluZXJnaWMgUDJYIFJlY2VwdG9yIEFudGFnb25pc3Rz

L2FkdmVyc2UgZWZmZWN0cy8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3b3JkPlB5cmlt

aWRpbmVzL2FkdmVyc2UgZWZmZWN0cy90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+

U2V2ZXJpdHkgb2YgSWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0

Y29tZTwva2V5d29yZD48a2V5d29yZD5Zb3VuZyBBZHVsdDwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDE1PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+TWFyIDI4PC9kYXRlPjwvcHVi

LWRhdGVzPjwvZGF0ZXM+PGlzYm4+MDE0MC02NzM2PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1NDY3

NTg2PC9hY2Nlc3Npb24tbnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+

MTAuMTAxNi9zMDE0MC02NzM2KDE0KTYxMjU1LTE8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxy

ZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxNPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxh

bmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [127].Senescence-associated secretory phenotype (SASP)There is increasing evidence that COPD involves accelerated ageing of the lung with the accumulation of senescent cells, including airway and alveolar epithelial cells, endothelial cells and fibroblasts ADDIN EN.CITE <EndNote><Cite><Author>Mercado</Author><Year>2015</Year><RecNum>11900</RecNum><DisplayText>[121, 128]</DisplayText><record><rec-number>11900</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1393007939">11900</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mercado, N.</author><author>Ito, K.</author><author>Barnes, P.J.</author></authors></contributors><titles><title>Accelerated ageing in chronic obstructive pulmonary disease: new concepts</title><secondary-title>Thorax</secondary-title></titles><periodical><full-title>Thorax</full-title></periodical><pages>482-489</pages><volume>70</volume><dates><year>2015</year></dates><urls></urls></record></Cite><Cite><Author>Barnes</Author><Year>2016</Year><RecNum>12843</RecNum><record><rec-number>12843</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1468403360">12843</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, P.J.</author></authors></contributors><titles><title>Senescence in COPD and its comorbidities</title><secondary-title>Annu Rev Physiol</secondary-title></titles><periodical><full-title>Annu Rev Physiol</full-title></periodical><dates><year>2016</year></dates><urls></urls></record></Cite></EndNote>[121, 128]. These senescent cells release a particular profile of inflammatory proteins, including TNF-α, IL-β, IL-6, CCL2, CXCL1, CXCL8, TGF-β, MMP-9 and ROS, known as the SASP, which amplifies and spread senescence ADDIN EN.CITE <EndNote><Cite><Author>Salama</Author><Year>2014</Year><RecNum>11934</RecNum><DisplayText>[129]</DisplayText><record><rec-number>11934</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1398263232">11934</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salama, R.</author><author>Sadaie, M.</author><author>Hoare, M.</author><author>Narita, M.</author></authors></contributors><auth-address>Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom;</auth-address><titles><title>Cellular senescence and its effector programs</title><secondary-title>Genes Dev</secondary-title><alt-title>Genes &amp; development</alt-title></titles><periodical><full-title>Genes Dev</full-title></periodical><pages>99-114</pages><volume>28</volume><number>2</number><edition>2014/01/23</edition><keywords><keyword>Animals</keyword><keyword>Cell Aging/genetics/*physiology</keyword><keyword>Cell Nucleus/metabolism</keyword><keyword>Chromatin/metabolism</keyword><keyword>Gene Expression Regulation</keyword><keyword>Humans</keyword><keyword>DNA damage</keyword><keyword>aging</keyword><keyword>inflammation</keyword><keyword>metabolism</keyword><keyword>oncogenes</keyword><keyword>senescence</keyword><keyword>tumor suppressors</keyword></keywords><dates><year>2014</year><pub-dates><date>Jan 15</date></pub-dates></dates><isbn>0890-9369</isbn><accession-num>24449267</accession-num><urls></urls><custom2>Pmc3909793</custom2><electronic-resource-num>10.1101/gad.235184.113</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[129]. These inflammatory proteins are all increased in the lungs of COPD patients and systemically and it is likely that SASP may be a mechanism for comorbidities of COPD (e.g. cardiovascular disease, type 2 diabetes, chronic kidney disease), most of which are also diseases of accelerated ageing. There is growing evidence that SASP is spread from cell to cell by the release of extracellular vesicles.SYSTEMIC INFLAMMATION AND COMORBIDITIESThe inflammation in asthmatic lungs is confined to the airway mucosa and there is little evidence of systemic inflammation. Comorbidities associated with asthma are mainly other manifestations of allergy, including rhinitis and atopic dermatitis. Other comorbidities are gastroesophageal reflux, which may be explained mainly by bronchodilator therapy that relaxes the gastroesophageal sphincter. Obesity is a risk factor for asthma, which is mostly manifest as late onset disease that responds poorly to therapy ADDIN EN.CITE <EndNote><Cite><Author>Sideleva</Author><Year>2014</Year><RecNum>12938</RecNum><DisplayText>[130]</DisplayText><record><rec-number>12938</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1483696520">12938</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sideleva, O.</author><author>Dixon, A. E.</author></authors></contributors><auth-address>Department of Medicine, Fletcher Allen Health Care, University of Vermont, Given D209, 89 Beaumont Avenue, Burlington, Vermont, 05405.</auth-address><titles><title>The many faces of asthma in obesity</title><secondary-title>J Cell Biochem</secondary-title><alt-title>Journal of cellular biochemistry</alt-title></titles><periodical><full-title>J Cell Biochem</full-title></periodical><pages>421-6</pages><volume>115</volume><number>3</number><edition>2013/10/12</edition><keywords><keyword>Adipokines/metabolism</keyword><keyword>Age of Onset</keyword><keyword>Asthma/complications/*pathology/therapy</keyword><keyword>Diet</keyword><keyword>Humans</keyword><keyword>Hypersensitivity/complications/*pathology</keyword><keyword>Insulin Resistance/genetics</keyword><keyword>Nitric Oxide/metabolism</keyword><keyword>Obesity/complications/*pathology/therapy</keyword><keyword>Ozone/metabolism</keyword><keyword>Risk Factors</keyword><keyword>Weight Loss</keyword><keyword>Adipokines</keyword><keyword>Airway reactivity</keyword><keyword>Asthma</keyword><keyword>Obesity</keyword></keywords><dates><year>2014</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0730-2312</isbn><accession-num>24115053</accession-num><urls></urls><electronic-resource-num>10.1002/jcb.24678</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[130]. There is growing evidence that inflammatory mediators produced by adipose tissue, such as adipokines, may have effects on airway inflammation and that altered microbiome in obesity has immunological effects in the lung though the production of short chain fatty acids and other metabolites from bacteria in the gut ADDIN EN.CITE <EndNote><Cite><Author>Shore</Author><Year>2016</Year><RecNum>12937</RecNum><DisplayText>[131]</DisplayText><record><rec-number>12937</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1482949693">12937</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shore, S. A.</author><author>Cho, Y.</author></authors></contributors><auth-address>Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.</auth-address><titles><title>Obesity and asthma: microbiome-metabolome interactions</title><secondary-title>Am J Respir Cell Mol Biol</secondary-title><alt-title>American journal of respiratory cell and molecular biology</alt-title></titles><periodical><full-title>Am J Respir Cell Mol Biol</full-title></periodical><pages>609-17</pages><volume>54</volume><number>5</number><edition>2016/03/08</edition><keywords><keyword>airway</keyword><keyword>bile acids</keyword><keyword>immune system</keyword><keyword>short-chain fatty acids</keyword></keywords><dates><year>2016</year><pub-dates><date>May</date></pub-dates></dates><isbn>1044-1549</isbn><accession-num>26949916</accession-num><urls></urls><custom2>PMC4942201</custom2><electronic-resource-num>10.1165/rcmb.2016-0052PS</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[131].In contrast to asthma systemic inflammation is commonly seen in COPD, particularly in patients with severe disease and during exacerbations, with increased circulating cytokines, chemokines and acute phase proteins, or abnormalities in circulating cells QUOTE "" ADDIN REFMAN ?\11\05‘\19\01\00\00\00\00\01\00\00\1BD:\5CRef Man Database\5CThormed\03\00\0CVANEEDEN2008%van Eeden & Sin 2008 VANEEDEN2008 /id\00%\00 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO

dW0+OTIxNTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTMyLCAxMzNdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjkyMTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk2NSI+OTIxNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+R2FuLFcuUS48L2F1dGhvcj48YXV0aG9yPk1hbixTLkYuPC9hdXRob3I+PGF1dGhvcj5TZW50

aGlsc2VsdmFuLEEuPC9hdXRob3I+PGF1dGhvcj5TaW4sRC5ELjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Bc3NvY2lhdGlvbiBiZXR3ZWVuIGNocm9uaWMg

b2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2UgYW5kIHN5c3RlbWljIGluZmxhbW1hdGlvbjog

YSBzeXN0ZW1hdGljIHJldmlldyBhbmQgYSBtZXRhLWFuYWx5c2lzPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPlRob3JheDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU3NC01ODA8L3Bh

Z2VzPjx2b2x1bWU+NTk8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48cmVwcmludC1lZGl0aW9u

Pk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdv

cmQ+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29y

ZD5CTE9PRDwva2V5d29yZD48a2V5d29yZD5jLXJlYWN0aXZlIHByb3RlaW48L2tleXdvcmQ+PGtl

eXdvcmQ+Q0FSRElPVkFTQ1VMQVI8L2tleXdvcmQ+PGtleXdvcmQ+Y2FyZGlvdmFzY3VsYXIgZGlz

ZWFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklD

IE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9u

YXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2lyY3VsYXRpbmc8L2tleXdvcmQ+PGtleXdv

cmQ+Q29tcGFyYXRpdmUgU3R1ZHk8L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5

d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtl

eXdvcmQ+Q1lUT0tJTkU8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3

b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29y

ZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5ESVNPUkRFUlM8L2tleXdvcmQ+PGtleXdvcmQ+

RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+RVhQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5maWJyaW5v

Z2VuPC9rZXl3b3JkPjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5d29yZD48

a2V5d29yZD5mdW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdv

cmQ+SU1QTElDQVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklO

Q1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3

b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOUzwva2V5d29yZD48

a2V5d29yZD5MRVVDT0NZVEVTPC9rZXl3b3JkPjxrZXl3b3JkPmxldWtvY3l0ZXM8L2tleXdvcmQ+

PGtleXdvcmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5tZXRhLWFuYWx5c2lzPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1PREVMPC9rZXl3b3JkPjxrZXl3b3JkPk1VU0NMRTwva2V5d29yZD48a2V5d29yZD5ORUNST1NJ

Uzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5Pc3Rlb3Bv

cm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9nZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBB

VEhPUEhZU0lPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3

b3JkPlB1bG1vbmFyeSBEaXNlYXNlLENocm9uaWMgT2JzdHJ1Y3RpdmU8L2tleXdvcmQ+PGtleXdv

cmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTlNISVA8L2tleXdvcmQ+PGtleXdv

cmQ+UmVzZWFyY2ggU3VwcG9ydCxOb24tVS5TLkdvdiZhcG9zO3Q8L2tleXdvcmQ+PGtleXdvcmQ+

UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPnJpc2s8L2tleXdvcmQ+PGtleXdvcmQ+U0VDT05EPC9r

ZXl3b3JkPjxrZXl3b3JkPlNFUlVNPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29yZD48

a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3Jk

PlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNVTU1BUlk8L2tleXdvcmQ+PGtleXdvcmQ+U1lT

VEVNSUM8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQRVVUSUM8L2tleXdvcmQ+PGtleXdvcmQ+VFVN

T1VSPC9rZXl3b3JkPjxrZXl3b3JkPlZJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPlZpdGFsIENhcGFj

aXR5PC9rZXl3b3JkPjxrZXl3b3JkPlZPTFVNRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDA0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Ny8yMDA0PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPkdBTjIwMDQ8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5BZ3VzdGk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNOdW0+

MTE2MjE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjExNjIxPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3Zy

NXd3emV6d2UwIiB0aW1lc3RhbXA9IjEzNzg0NzkwMDQiPjExNjIxPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5BZ3VzdGksQS48L2F1dGhvcj48YXV0aG9yPkVkd2FyZHMs

TC5ELjwvYXV0aG9yPjxhdXRob3I+UmVubmFyZCxTLkkuPC9hdXRob3I+PGF1dGhvcj5NYWNuZWUs

Vy48L2F1dGhvcj48YXV0aG9yPlRhbC1TaW5nZXIsUi48L2F1dGhvcj48YXV0aG9yPk1pbGxlcixC

LkUuPC9hdXRob3I+PGF1dGhvcj5WZXN0Ym8sSi48L2F1dGhvcj48YXV0aG9yPkxvbWFzLEQuQS48

L2F1dGhvcj48YXV0aG9yPkNhbHZlcmxleSxQLk0uPC9hdXRob3I+PGF1dGhvcj5Xb3V0ZXJzLEUu

PC9hdXRob3I+PGF1dGhvcj5DcmltLEMuPC9hdXRob3I+PGF1dGhvcj5ZYXRlcyxKLkMuPC9hdXRo

b3I+PGF1dGhvcj5TaWx2ZXJtYW4sRS5LLjwvYXV0aG9yPjxhdXRob3I+Q294c29uLEguTy48L2F1

dGhvcj48YXV0aG9yPkJha2tlLFAuPC9hdXRob3I+PGF1dGhvcj5NYXllcixSLkouPC9hdXRob3I+

PGF1dGhvcj5DZWxsaSxCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5QZXJzaXN0ZW50IHN5c3RlbWljIGluZmxhbW1hdGlvbiBpcyBhc3NvY2lhdGVkIHdp

dGggcG9vciBjbGluaWNhbCBvdXRjb21lcyBpbiBDT1BEOiBhIG5vdmVsIHBoZW5vdHlwZTwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TLk9uZS48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TLk9uZS48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz5lMzc0ODM8L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVy

PjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QUJOT1JNQUxJVElFUzwva2V5d29yZD48a2V5d29yZD5BU1NFU1NFRDwva2V5d29y

ZD48a2V5d29yZD5CTE9PRDwva2V5d29yZD48a2V5d29yZD5ibG9vZCBjZWxsczwva2V5d29yZD48

a2V5d29yZD5DYXVzYWxpdHk8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29y

ZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9O

SUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxt

b25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29y

ZD5DT01QTEVYRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5D

T1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8

L2tleXdvcmQ+PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmZpYnJpbm9n

ZW48L2tleXdvcmQ+PGtleXdvcmQ+SE9TUElUQUw8L2tleXdvcmQ+PGtleXdvcmQ+SURFTlRJRklD

QVRJT048L2tleXdvcmQ+PGtleXdvcmQ+SUwtNjwva2V5d29yZD48a2V5d29yZD5JTC04PC9rZXl3

b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5

d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3

b3JkPk1PUlRBTElUWTwva2V5d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+

Tk9WRUw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5d29yZD48a2V5d29yZD5QRVJT

SVNURU5UPC9rZXl3b3JkPjxrZXl3b3JkPlBIRU5PVFlQRTwva2V5d29yZD48a2V5d29yZD5QVUxN

T05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9O

U0U8L2tleXdvcmQ+PGtleXdvcmQ+U3BhaW48L2tleXdvcmQ+PGtleXdvcmQ+U1BFQ0lGSUM8L2tl

eXdvcmQ+PGtleXdvcmQ+U3Bpcm9tZXRyeTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3

b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNZU1RFTUlDPC9rZXl3b3JkPjxr

ZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5USEVSQVBJRVM8L2tleXdvcmQ+PGtleXdv

cmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5UaG9yYXg8L2tleXdvcmQ+PGtleXdvcmQ+VFJF

QVRNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlRXTzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5BR1VTVEkyMDEyQTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYW48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxSZWNO

dW0+OTIxNTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTMyLCAxMzNdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjkyMTU8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk2NSI+OTIxNTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+R2FuLFcuUS48L2F1dGhvcj48YXV0aG9yPk1hbixTLkYuPC9hdXRob3I+PGF1dGhvcj5TZW50

aGlsc2VsdmFuLEEuPC9hdXRob3I+PGF1dGhvcj5TaW4sRC5ELjwvYXV0aG9yPjwvYXV0aG9ycz48

L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Bc3NvY2lhdGlvbiBiZXR3ZWVuIGNocm9uaWMg

b2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2UgYW5kIHN5c3RlbWljIGluZmxhbW1hdGlvbjog

YSBzeXN0ZW1hdGljIHJldmlldyBhbmQgYSBtZXRhLWFuYWx5c2lzPC90aXRsZT48c2Vjb25kYXJ5

LXRpdGxlPlRob3JheDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxs

LXRpdGxlPlRob3JheDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjU3NC01ODA8L3Bh

Z2VzPjx2b2x1bWU+NTk8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48cmVwcmludC1lZGl0aW9u

Pk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPjA8L2tleXdv

cmQ+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29yZD48a2V5d29y

ZD5CTE9PRDwva2V5d29yZD48a2V5d29yZD5jLXJlYWN0aXZlIHByb3RlaW48L2tleXdvcmQ+PGtl

eXdvcmQ+Q0FSRElPVkFTQ1VMQVI8L2tleXdvcmQ+PGtleXdvcmQ+Y2FyZGlvdmFzY3VsYXIgZGlz

ZWFzZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklD

IE9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9u

YXJ5IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2lyY3VsYXRpbmc8L2tleXdvcmQ+PGtleXdv

cmQ+Q29tcGFyYXRpdmUgU3R1ZHk8L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5

d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtl

eXdvcmQ+Q1lUT0tJTkU8L2tleXdvcmQ+PGtleXdvcmQ+Q1lUT0tJTkVTPC9rZXl3b3JkPjxrZXl3

b3JkPkRJRkZFUkVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29y

ZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5ESVNPUkRFUlM8L2tleXdvcmQ+PGtleXdvcmQ+

RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVFM8L2tleXdvcmQ+PGtleXdvcmQ+ZXRpb2xv

Z3k8L2tleXdvcmQ+PGtleXdvcmQ+RVhQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5maWJyaW5v

Z2VuPC9rZXl3b3JkPjxrZXl3b3JkPkZvcmNlZCBFeHBpcmF0b3J5IFZvbHVtZTwva2V5d29yZD48

a2V5d29yZD5mdW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5IVU1BTlM8L2tleXdvcmQ+PGtleXdv

cmQ+SU1QTElDQVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklO

Q1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5p

bmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3JkPjxrZXl3

b3JkPklOVEVSTEVVS0lOPC9rZXl3b3JkPjxrZXl3b3JkPklOVEVSTEVVS0lOUzwva2V5d29yZD48

a2V5d29yZD5MRVVDT0NZVEVTPC9rZXl3b3JkPjxrZXl3b3JkPmxldWtvY3l0ZXM8L2tleXdvcmQ+

PGtleXdvcmQ+THVuZzwva2V5d29yZD48a2V5d29yZD5tZXRhLWFuYWx5c2lzPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1PREVMPC9rZXl3b3JkPjxrZXl3b3JkPk1VU0NMRTwva2V5d29yZD48a2V5d29yZD5ORUNST1NJ

Uzwva2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5Pc3Rlb3Bv

cm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9nZW5lc2lzPC9rZXl3b3JkPjxrZXl3b3JkPlBB

VEhPUEhZU0lPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5PC9rZXl3b3JkPjxr

ZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3

b3JkPlB1bG1vbmFyeSBEaXNlYXNlLENocm9uaWMgT2JzdHJ1Y3RpdmU8L2tleXdvcmQ+PGtleXdv

cmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTlNISVA8L2tleXdvcmQ+PGtleXdv

cmQ+UmVzZWFyY2ggU3VwcG9ydCxOb24tVS5TLkdvdiZhcG9zO3Q8L2tleXdvcmQ+PGtleXdvcmQ+

UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPnJpc2s8L2tleXdvcmQ+PGtleXdvcmQ+U0VDT05EPC9r

ZXl3b3JkPjxrZXl3b3JkPlNFUlVNPC9rZXl3b3JkPjxrZXl3b3JkPlNUQUJMRTwva2V5d29yZD48

a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3Jk

PlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlNVTU1BUlk8L2tleXdvcmQ+PGtleXdvcmQ+U1lT

VEVNSUM8L2tleXdvcmQ+PGtleXdvcmQ+VEhFUkFQRVVUSUM8L2tleXdvcmQ+PGtleXdvcmQ+VFVN

T1VSPC9rZXl3b3JkPjxrZXl3b3JkPlZJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPlZpdGFsIENhcGFj

aXR5PC9rZXl3b3JkPjxrZXl3b3JkPlZPTFVNRTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDA0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+Ny8yMDA0PC9kYXRlPjwvcHViLWRhdGVz

PjwvZGF0ZXM+PGxhYmVsPkdBTjIwMDQ8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0Np

dGU+PENpdGU+PEF1dGhvcj5BZ3VzdGk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNOdW0+

MTE2MjE8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjExNjIxPC9yZWMtbnVtYmVyPjxmb3Jl

aWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3Zy

NXd3emV6d2UwIiB0aW1lc3RhbXA9IjEzNzg0NzkwMDQiPjExNjIxPC9rZXk+PC9mb3JlaWduLWtl

eXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmli

dXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5BZ3VzdGksQS48L2F1dGhvcj48YXV0aG9yPkVkd2FyZHMs

TC5ELjwvYXV0aG9yPjxhdXRob3I+UmVubmFyZCxTLkkuPC9hdXRob3I+PGF1dGhvcj5NYWNuZWUs

Vy48L2F1dGhvcj48YXV0aG9yPlRhbC1TaW5nZXIsUi48L2F1dGhvcj48YXV0aG9yPk1pbGxlcixC

LkUuPC9hdXRob3I+PGF1dGhvcj5WZXN0Ym8sSi48L2F1dGhvcj48YXV0aG9yPkxvbWFzLEQuQS48

L2F1dGhvcj48YXV0aG9yPkNhbHZlcmxleSxQLk0uPC9hdXRob3I+PGF1dGhvcj5Xb3V0ZXJzLEUu

PC9hdXRob3I+PGF1dGhvcj5DcmltLEMuPC9hdXRob3I+PGF1dGhvcj5ZYXRlcyxKLkMuPC9hdXRo

b3I+PGF1dGhvcj5TaWx2ZXJtYW4sRS5LLjwvYXV0aG9yPjxhdXRob3I+Q294c29uLEguTy48L2F1

dGhvcj48YXV0aG9yPkJha2tlLFAuPC9hdXRob3I+PGF1dGhvcj5NYXllcixSLkouPC9hdXRob3I+

PGF1dGhvcj5DZWxsaSxCLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVz

Pjx0aXRsZT5QZXJzaXN0ZW50IHN5c3RlbWljIGluZmxhbW1hdGlvbiBpcyBhc3NvY2lhdGVkIHdp

dGggcG9vciBjbGluaWNhbCBvdXRjb21lcyBpbiBDT1BEOiBhIG5vdmVsIHBoZW5vdHlwZTwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5QTG9TLk9uZS48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48

cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5QTG9TLk9uZS48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2Fs

PjxwYWdlcz5lMzc0ODM8L3BhZ2VzPjx2b2x1bWU+Nzwvdm9sdW1lPjxudW1iZXI+NTwvbnVtYmVy

PjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QUJOT1JNQUxJVElFUzwva2V5d29yZD48a2V5d29yZD5BU1NFU1NFRDwva2V5d29y

ZD48a2V5d29yZD5CTE9PRDwva2V5d29yZD48a2V5d29yZD5ibG9vZCBjZWxsczwva2V5d29yZD48

a2V5d29yZD5DYXVzYWxpdHk8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29y

ZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9O

SUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxt

b25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29y

ZD5DT01QTEVYRVM8L2tleXdvcmQ+PGtleXdvcmQ+Q09OVFJPTDwva2V5d29yZD48a2V5d29yZD5D

T1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8

L2tleXdvcmQ+PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmZpYnJpbm9n

ZW48L2tleXdvcmQ+PGtleXdvcmQ+SE9TUElUQUw8L2tleXdvcmQ+PGtleXdvcmQ+SURFTlRJRklD

QVRJT048L2tleXdvcmQ+PGtleXdvcmQ+SUwtNjwva2V5d29yZD48a2V5d29yZD5JTC04PC9rZXl3

b3JkPjxrZXl3b3JkPklOPC9rZXl3b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5

d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0b3J5PC9rZXl3b3Jk

PjxrZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3

b3JkPk1PUlRBTElUWTwva2V5d29yZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+

Tk9WRUw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UEFU

SUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UEVSSVBIRVJBTDwva2V5d29yZD48a2V5d29yZD5QRVJT

SVNURU5UPC9rZXl3b3JkPjxrZXl3b3JkPlBIRU5PVFlQRTwva2V5d29yZD48a2V5d29yZD5QVUxN

T05BUlk8L2tleXdvcmQ+PGtleXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9O

U0U8L2tleXdvcmQ+PGtleXdvcmQ+U3BhaW48L2tleXdvcmQ+PGtleXdvcmQ+U1BFQ0lGSUM8L2tl

eXdvcmQ+PGtleXdvcmQ+U3Bpcm9tZXRyeTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3

b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNZU1RFTUlDPC9rZXl3b3JkPjxr

ZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5USEVSQVBJRVM8L2tleXdvcmQ+PGtleXdv

cmQ+dGhlcmFweTwva2V5d29yZD48a2V5d29yZD5UaG9yYXg8L2tleXdvcmQ+PGtleXdvcmQ+VFJF

QVRNRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlRXTzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48

eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MjAxMjwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5BR1VTVEkyMDEyQTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [132, 133]. Systemic inflammation is associated with poorer clinical outcomes. It is uncertain whether systemic markers of inflammation are a “spill-over” from inflammation in the peripheral lung or are a parallel abnormality or related to comorbid diseases. In a large population study systemic inflammation (increased CRP, fibrinogen and leukocytes) was associated with a 2-4-fold increased risk of cardiovascular disease, diabetes, lung cancer and pneumonia, but not with depression PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaG9tc2VuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjExNjM4PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMzRdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjExNjM4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0NzkwMDQiPjExNjM4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5UaG9tc2VuLE0uPC9hdXRob3I+PGF1dGhvcj5EYWhsLE0uPC9hdXRob3I+PGF1dGhvcj5M

YW5nZSxQLjwvYXV0aG9yPjxhdXRob3I+VmVzdGJvLEouPC9hdXRob3I+PGF1dGhvcj5Ob3JkZXN0

Z2FhcmQsQi5HLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRs

ZT5JbmZsYW1tYXRvcnkgYmlvbWFya2VycyBhbmQgY29tb3JiaWRpdGllcyBpbiBjaHJvbmljIG9i

c3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtLkou

UmVzcGlyLkNyaXQgQ2FyZSBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QW0uSi5SZXNwaXIuQ3JpdCBDYXJlIE1lZC48L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz45ODItOTg4PC9wYWdlcz48dm9sdW1lPjE4Njwvdm9sdW1lPjxudW1i

ZXI+MTA8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPjI8L2tleXdvcmQ+PGtleXdvcmQ+Mzwva2V5d29yZD48a2V5

d29yZD5hZG1pc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+QklPQ0hFTUlTVFJZPC9rZXl3b3JkPjxr

ZXl3b3JkPmMtcmVhY3RpdmUgcHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25p

YyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNh

bDwva2V5d29yZD48a2V5d29yZD5Db21vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD5DT1BEPC9r

ZXl3b3JkPjxrZXl3b3JkPkRFUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+REVWRUxPUE1FTlQ8

L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5DRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9r

ZXl3b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29y

ZD48a2V5d29yZD5maWJyaW5vZ2VuPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPkhFQVJUPC9rZXl3b3JkPjxrZXl3b3JkPkhlYXJ0IEZhaWx1cmU8L2tleXdvcmQ+

PGtleXdvcmQ+SE9TUElUQUw8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+

SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORElWSURVQUxTPC9rZXl3b3JkPjxrZXl3b3Jk

PmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtl

eXdvcmQ+TEFSR0U8L2tleXdvcmQ+PGtleXdvcmQ+TEVVS09DWVRFPC9rZXl3b3JkPjxrZXl3b3Jk

PkxldWtvY3l0ZSBDb3VudDwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1BSk9SPC9rZXl3b3JkPjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVB

U1VSRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhv

ZHM8L2tleXdvcmQ+PGtleXdvcmQ+TXlvY2FyZGlhbCBJbmZhcmN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBB

VElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPnBuZXVtb25pYTwva2V5d29yZD48a2V5d29yZD5QT1BV

TEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9O

QVJZPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFyeSBFbWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8

L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNSUM8L2tleXdvcmQ+PGtleXdvcmQ+VFdPPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVh

cj48cHViLWRhdGVzPjxkYXRlPjkvMTMvMjAxMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD5USE9NU0VOMjAxMjwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaG9tc2VuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

UmVjTnVtPjExNjM4PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMzRdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjExNjM4PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0NzkwMDQiPjExNjM4PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5UaG9tc2VuLE0uPC9hdXRob3I+PGF1dGhvcj5EYWhsLE0uPC9hdXRob3I+PGF1dGhvcj5M

YW5nZSxQLjwvYXV0aG9yPjxhdXRob3I+VmVzdGJvLEouPC9hdXRob3I+PGF1dGhvcj5Ob3JkZXN0

Z2FhcmQsQi5HLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRs

ZT5JbmZsYW1tYXRvcnkgYmlvbWFya2VycyBhbmQgY29tb3JiaWRpdGllcyBpbiBjaHJvbmljIG9i

c3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtLkou

UmVzcGlyLkNyaXQgQ2FyZSBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGlj

YWw+PGZ1bGwtdGl0bGU+QW0uSi5SZXNwaXIuQ3JpdCBDYXJlIE1lZC48L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxwYWdlcz45ODItOTg4PC9wYWdlcz48dm9sdW1lPjE4Njwvdm9sdW1lPjxudW1i

ZXI+MTA8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPjI8L2tleXdvcmQ+PGtleXdvcmQ+Mzwva2V5d29yZD48a2V5

d29yZD5hZG1pc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+QklPQ0hFTUlTVFJZPC9rZXl3b3JkPjxr

ZXl3b3JkPmMtcmVhY3RpdmUgcHJvdGVpbjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3

b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25p

YyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNh

bDwva2V5d29yZD48a2V5d29yZD5Db21vcmJpZGl0eTwva2V5d29yZD48a2V5d29yZD5DT1BEPC9r

ZXl3b3JkPjxrZXl3b3JkPkRFUFJFU1NJT048L2tleXdvcmQ+PGtleXdvcmQ+REVWRUxPUE1FTlQ8

L2tleXdvcmQ+PGtleXdvcmQ+RElGRkVSRU5DRTwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9r

ZXl3b3JkPjxrZXl3b3JkPkVWSURFTkNFPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29y

ZD48a2V5d29yZD5maWJyaW5vZ2VuPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPkhFQVJUPC9rZXl3b3JkPjxrZXl3b3JkPkhlYXJ0IEZhaWx1cmU8L2tleXdvcmQ+

PGtleXdvcmQ+SE9TUElUQUw8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+

SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPklORElWSURVQUxTPC9rZXl3b3JkPjxrZXl3b3Jk

PmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtl

eXdvcmQ+TEFSR0U8L2tleXdvcmQ+PGtleXdvcmQ+TEVVS09DWVRFPC9rZXl3b3JkPjxrZXl3b3Jk

PkxldWtvY3l0ZSBDb3VudDwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1BSk9SPC9rZXl3b3JkPjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVB

U1VSRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3JkPk1ldGhv

ZHM8L2tleXdvcmQ+PGtleXdvcmQ+TXlvY2FyZGlhbCBJbmZhcmN0aW9uPC9rZXl3b3JkPjxrZXl3

b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBB

VElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPnBuZXVtb25pYTwva2V5d29yZD48a2V5d29yZD5QT1BV

TEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9O

QVJZPC9rZXl3b3JkPjxrZXl3b3JkPlB1bG1vbmFyeSBFbWJvbGlzbTwva2V5d29yZD48a2V5d29y

ZD5yaXNrPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8

L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNSUM8L2tleXdvcmQ+PGtleXdvcmQ+VFdPPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMjwveWVh

cj48cHViLWRhdGVzPjxkYXRlPjkvMTMvMjAxMjwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxs

YWJlbD5USE9NU0VOMjAxMjwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0Vu

ZE5vdGU+AG==

ADDIN EN.CITE.DATA [134]. Using six inflammatory markers (CRP, IL-6, CXCL8, fibrinogen, TNF-α, leukocyte numbers), 70% of COPD patients have some components of systemic inflammation and in 16% this inflammation is persistent, with increased mortality and more exacerbations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ3VzdGk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE2MjE8L1JlY051bT48RGlzcGxheVRleHQ+WzEzM108L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE2MjE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwNCI+MTE2MjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkFndXN0aSxBLjwvYXV0aG9yPjxhdXRob3I+RWR3YXJkcyxMLkQuPC9hdXRob3I+PGF1dGhv

cj5SZW5uYXJkLFMuSS48L2F1dGhvcj48YXV0aG9yPk1hY25lZSxXLjwvYXV0aG9yPjxhdXRob3I+

VGFsLVNpbmdlcixSLjwvYXV0aG9yPjxhdXRob3I+TWlsbGVyLEIuRS48L2F1dGhvcj48YXV0aG9y

PlZlc3RibyxKLjwvYXV0aG9yPjxhdXRob3I+TG9tYXMsRC5BLjwvYXV0aG9yPjxhdXRob3I+Q2Fs

dmVybGV5LFAuTS48L2F1dGhvcj48YXV0aG9yPldvdXRlcnMsRS48L2F1dGhvcj48YXV0aG9yPkNy

aW0sQy48L2F1dGhvcj48YXV0aG9yPllhdGVzLEouQy48L2F1dGhvcj48YXV0aG9yPlNpbHZlcm1h

bixFLksuPC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+QmFra2Us

UC48L2F1dGhvcj48YXV0aG9yPk1heWVyLFIuSi48L2F1dGhvcj48YXV0aG9yPkNlbGxpLEIuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlBlcnNpc3RlbnQg

c3lzdGVtaWMgaW5mbGFtbWF0aW9uIGlzIGFzc29jaWF0ZWQgd2l0aCBwb29yIGNsaW5pY2FsIG91

dGNvbWVzIGluIENPUEQ6IGEgbm92ZWwgcGhlbm90eXBlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PlBMb1MuT25lLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPlBMb1MuT25lLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUzNzQ4MzwvcGFn

ZXM+PHZvbHVtZT43PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5O

b3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQk5PUk1BTElU

SUVTPC9rZXl3b3JkPjxrZXl3b3JkPkFTU0VTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9r

ZXl3b3JkPjxrZXl3b3JkPmJsb29kIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkNhdXNhbGl0eTwv

a2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxr

ZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5

d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBMRVhFUzwva2V5d29y

ZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdv

cmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FVklERU5DRTwva2V5d29yZD48a2V5d29yZD5F

WEFDRVJCQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Zmlicmlub2dlbjwva2V5d29yZD48a2V5d29y

ZD5IT1NQSVRBTDwva2V5d29yZD48a2V5d29yZD5JREVOVElGSUNBVElPTjwva2V5d29yZD48a2V5

d29yZD5JTC02PC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tl

eXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwv

a2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9r

ZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TU9SVEFMSVRZPC9rZXl3

b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5d29yZD5OT1ZFTDwva2V5d29yZD48a2V5

d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5

d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBFUlNJU1RFTlQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UEhFTk9UWVBFPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5

d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5d29y

ZD5TcGFpbjwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5d29yZD5TcGly

b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8

L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNSUM8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VUPC9rZXl3

b3JkPjxrZXl3b3JkPlRIRVJBUElFUzwva2V5d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3Jk

PjxrZXl3b3JkPlRob3JheDwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtl

eXdvcmQ+VFdPPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkFHVVNU

STIwMTJBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZ3VzdGk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE2MjE8L1JlY051bT48RGlzcGxheVRleHQ+WzEzM108L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE2MjE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwNCI+MTE2MjE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkFndXN0aSxBLjwvYXV0aG9yPjxhdXRob3I+RWR3YXJkcyxMLkQuPC9hdXRob3I+PGF1dGhv

cj5SZW5uYXJkLFMuSS48L2F1dGhvcj48YXV0aG9yPk1hY25lZSxXLjwvYXV0aG9yPjxhdXRob3I+

VGFsLVNpbmdlcixSLjwvYXV0aG9yPjxhdXRob3I+TWlsbGVyLEIuRS48L2F1dGhvcj48YXV0aG9y

PlZlc3RibyxKLjwvYXV0aG9yPjxhdXRob3I+TG9tYXMsRC5BLjwvYXV0aG9yPjxhdXRob3I+Q2Fs

dmVybGV5LFAuTS48L2F1dGhvcj48YXV0aG9yPldvdXRlcnMsRS48L2F1dGhvcj48YXV0aG9yPkNy

aW0sQy48L2F1dGhvcj48YXV0aG9yPllhdGVzLEouQy48L2F1dGhvcj48YXV0aG9yPlNpbHZlcm1h

bixFLksuPC9hdXRob3I+PGF1dGhvcj5Db3hzb24sSC5PLjwvYXV0aG9yPjxhdXRob3I+QmFra2Us

UC48L2F1dGhvcj48YXV0aG9yPk1heWVyLFIuSi48L2F1dGhvcj48YXV0aG9yPkNlbGxpLEIuPC9h

dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlBlcnNpc3RlbnQg

c3lzdGVtaWMgaW5mbGFtbWF0aW9uIGlzIGFzc29jaWF0ZWQgd2l0aCBwb29yIGNsaW5pY2FsIG91

dGNvbWVzIGluIENPUEQ6IGEgbm92ZWwgcGhlbm90eXBlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxl

PlBMb1MuT25lLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRp

dGxlPlBMb1MuT25lLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPmUzNzQ4MzwvcGFn

ZXM+PHZvbHVtZT43PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5O

b3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BQk5PUk1BTElU

SUVTPC9rZXl3b3JkPjxrZXl3b3JkPkFTU0VTU0VEPC9rZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9r

ZXl3b3JkPjxrZXl3b3JkPmJsb29kIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkNhdXNhbGl0eTwv

a2V5d29yZD48a2V5d29yZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxr

ZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5

d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3

b3JkPjxrZXl3b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBMRVhFUzwva2V5d29y

ZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNPUEQ8L2tleXdvcmQ+PGtleXdv

cmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FVklERU5DRTwva2V5d29yZD48a2V5d29yZD5F

WEFDRVJCQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+Zmlicmlub2dlbjwva2V5d29yZD48a2V5d29y

ZD5IT1NQSVRBTDwva2V5d29yZD48a2V5d29yZD5JREVOVElGSUNBVElPTjwva2V5d29yZD48a2V5

d29yZD5JTC02PC9rZXl3b3JkPjxrZXl3b3JkPklMLTg8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tl

eXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwv

a2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9r

ZXl3b3JkPjxrZXl3b3JkPk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TU9SVEFMSVRZPC9rZXl3

b3JkPjxrZXl3b3JkPm5vcm1hbDwva2V5d29yZD48a2V5d29yZD5OT1ZFTDwva2V5d29yZD48a2V5

d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5

d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlBFUlNJU1RFTlQ8L2tleXdvcmQ+PGtl

eXdvcmQ+UEhFTk9UWVBFPC9rZXl3b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5

d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5d29y

ZD5TcGFpbjwva2V5d29yZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5d29yZD5TcGly

b21ldHJ5PC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8

L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNSUM8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VUPC9rZXl3

b3JkPjxrZXl3b3JkPlRIRVJBUElFUzwva2V5d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3Jk

PjxrZXl3b3JkPlRob3JheDwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtl

eXdvcmQ+VFdPPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTI8L3llYXI+PHB1

Yi1kYXRlcz48ZGF0ZT4yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkFHVVNU

STIwMTJBPC9sYWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [133]. Systemic inflammation is also associated with greater decline in lung function PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXJzdDwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT45NTY3PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMzVdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjk1Njc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk3MSI+OTU2Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

SHVyc3QsSi5SLjwvYXV0aG9yPjxhdXRob3I+RG9uYWxkc29uLEcuQy48L2F1dGhvcj48YXV0aG9y

PlBlcmVhLFcuUi48L2F1dGhvcj48YXV0aG9yPldpbGtpbnNvbixULk0uPC9hdXRob3I+PGF1dGhv

cj5CaWxlbGxvLEouQS48L2F1dGhvcj48YXV0aG9yPkhhZ2FuLEcuVy48L2F1dGhvcj48YXV0aG9y

PlZlc3NleSxSLlMuPC9hdXRob3I+PGF1dGhvcj5XZWR6aWNoYSxKLkEuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlV0aWxpdHkgb2YgcGxhc21hIGJpb21h

cmtlcnMgYXQgZXhhY2VyYmF0aW9uIG9mIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIuQ3JpdCBDYXJlIE1lZC48

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3Bpci5Dcml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg2Ny04

NzQ8L3BhZ2VzPjx2b2x1bWU+MTc0PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48

a2V5d29yZD5jLXJlYWN0aXZlIHByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+Q0hBUkFDVEVSSVNU

SUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9C

U1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5

IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2xpbmljYWw8L2tleXdvcmQ+PGtleXdvcmQ+Q09O

Q0VOVFJBVElPTjwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJQUdO

T1NJUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRZU1BOT0VB

PC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTjwva2V5d29yZD48a2V5d29yZD5mdW5jdGlv

bjwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdv

cmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29y

ZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRUFTVVJFTUVOVDwva2V5d29yZD48

a2V5d29yZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5d29yZD48

a2V5d29yZD5NRURJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3

b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1P

Tk9DWVRFPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZF

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhXQVk8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdBWVM8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UExBU01BPC9rZXl3b3Jk

PjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxr

ZXl3b3JkPlNDSE9PTDwva2V5d29yZD48a2V5d29yZD5TRUxFQ1RJVkU8L2tleXdvcmQ+PGtleXdv

cmQ+U0VOU0lUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3Jk

PlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TWVNU

RU1JQzwva2V5d29yZD48a2V5d29yZD5VTklURUQ8L2tleXdvcmQ+PGtleXdvcmQ+Vk9MVU1FPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT42LzIzLzIwMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+SFVSU1QyMDA2PC9s

YWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXJzdDwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl

Y051bT45NTY3PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMzVdPC9EaXNwbGF5VGV4dD48cmVjb3Jk

PjxyZWMtbnVtYmVyPjk1Njc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4i

IGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0i

MTM3ODQ3ODk3MSI+OTU2Nzwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3Vy

bmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+

SHVyc3QsSi5SLjwvYXV0aG9yPjxhdXRob3I+RG9uYWxkc29uLEcuQy48L2F1dGhvcj48YXV0aG9y

PlBlcmVhLFcuUi48L2F1dGhvcj48YXV0aG9yPldpbGtpbnNvbixULk0uPC9hdXRob3I+PGF1dGhv

cj5CaWxlbGxvLEouQS48L2F1dGhvcj48YXV0aG9yPkhhZ2FuLEcuVy48L2F1dGhvcj48YXV0aG9y

PlZlc3NleSxSLlMuPC9hdXRob3I+PGF1dGhvcj5XZWR6aWNoYSxKLkEuPC9hdXRob3I+PC9hdXRo

b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlV0aWxpdHkgb2YgcGxhc21hIGJpb21h

cmtlcnMgYXQgZXhhY2VyYmF0aW9uIG9mIGNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRp

c2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW0gSiBSZXNwaXIuQ3JpdCBDYXJlIE1lZC48

L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJl

c3Bpci5Dcml0IENhcmUgTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg2Ny04

NzQ8L3BhZ2VzPjx2b2x1bWU+MTc0PC92b2x1bWU+PHJlcHJpbnQtZWRpdGlvbj5Ob3QgaW4gRmls

ZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BU1NFU1NFRDwva2V5d29yZD48

a2V5d29yZD5jLXJlYWN0aXZlIHByb3RlaW48L2tleXdvcmQ+PGtleXdvcmQ+Q0hBUkFDVEVSSVNU

SUM8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDIE9C

U1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgb2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5

IGRpc2Vhc2U8L2tleXdvcmQ+PGtleXdvcmQ+Y2xpbmljYWw8L2tleXdvcmQ+PGtleXdvcmQ+Q09O

Q0VOVFJBVElPTjwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkRJQUdO

T1NJUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRZU1BOT0VB

PC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTjwva2V5d29yZD48a2V5d29yZD5mdW5jdGlv

bjwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdv

cmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmxvbmRvbjwva2V5d29y

ZD48a2V5d29yZD5NQUpPUjwva2V5d29yZD48a2V5d29yZD5NRUFTVVJFTUVOVDwva2V5d29yZD48

a2V5d29yZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVDSEFOSVNNUzwva2V5d29yZD48

a2V5d29yZD5NRURJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3

b3JkPk1FVEhPRDwva2V5d29yZD48a2V5d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1P

Tk9DWVRFPC9rZXl3b3JkPjxrZXl3b3JkPk5PPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZF

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhXQVk8L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdBWVM8L2tl

eXdvcmQ+PGtleXdvcmQ+UEFUSUVOVFM8L2tleXdvcmQ+PGtleXdvcmQ+UExBU01BPC9rZXl3b3Jk

PjxrZXl3b3JkPlBST1RFSU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFTEFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVMQVRJT05TSElQPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFU1BJUkFUT1JZPC9rZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxr

ZXl3b3JkPlNDSE9PTDwva2V5d29yZD48a2V5d29yZD5TRUxFQ1RJVkU8L2tleXdvcmQ+PGtleXdv

cmQ+U0VOU0lUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3b3JkPjxrZXl3b3Jk

PlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3b3JkPlNQVVRVTTwva2V5d29yZD48a2V5d29yZD5TWVNU

RU1JQzwva2V5d29yZD48a2V5d29yZD5VTklURUQ8L2tleXdvcmQ+PGtleXdvcmQ+Vk9MVU1FPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT42LzIzLzIwMDY8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+SFVSU1QyMDA2PC9s

YWJlbD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [135]. INFLAMMATORY AND STRUCTURAL CONSEQUENCESIn view of the different patterns and localization of inflammation between asthma and COPD it is not surprising that there are different consequences, including the pattern of structural changes.Airway smooth muscleBronchoconstriction, in response to mediators mainly released from mast cells, is the major mechanism of airway narrowing in asthma. In vitro airway smooth muscle from asthmatic patients usually shows increased contractility and there may also be reduced bronchodilator responses PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGFjazwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTcxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTM2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTcxODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTcxODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+QmxhY2ssSi5MLjwvYXV0aG9yPjxhdXRob3I+UGFuZXR0aWVyaSxSLkEuLEpyLjwvYXV0aG9y

PjxhdXRob3I+QmFuZXJqZWUsQS48L2F1dGhvcj48YXV0aG9yPkJlcmdlcixQLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BaXJ3YXkgc21vb3RoIG11c2Ns

ZSBpbiBhc3RobWE6IGp1c3QgYSB0YXJnZXQgZm9yIGJyb25jaG9kaWxhdGlvbj88L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+NTQzLTU1ODwvcGFnZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3Jk

PjM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBSZW1v

ZGVsaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBzbW9vdGggbXVzY2xlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3Jk

PmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+

YnJvbmNoaWFsIGh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJvbmNob2Rp

bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09NUExFWEVTPC9rZXl3b3JkPjxrZXl3b3JkPmNvbmNlcHRzPC9rZXl3

b3JkPjxrZXl3b3JkPkNPTlRSQUNUSUxFPC9rZXl3b3JkPjxrZXl3b3JkPkZFQVRVUkVTPC9rZXl3

b3JkPjxrZXl3b3JkPmh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tl

eXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwv

a2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9rZXl3

b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUNBTDwva2V5d29y

ZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3Jk

PnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTlNISVA8L2tleXdvcmQ+PGtl

eXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdv

cmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8

L2tleXdvcmQ+PGtleXdvcmQ+U01PT1RIPC9rZXl3b3JkPjxrZXl3b3JkPlNtb290aCBtdXNjbGU8

L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdv

cmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5UT05FPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+V0FMRVM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjkvMjAxMjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CTEFDSzIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGFjazwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTcxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTM2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTcxODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTcxODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+QmxhY2ssSi5MLjwvYXV0aG9yPjxhdXRob3I+UGFuZXR0aWVyaSxSLkEuLEpyLjwvYXV0aG9y

PjxhdXRob3I+QmFuZXJqZWUsQS48L2F1dGhvcj48YXV0aG9yPkJlcmdlcixQLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BaXJ3YXkgc21vb3RoIG11c2Ns

ZSBpbiBhc3RobWE6IGp1c3QgYSB0YXJnZXQgZm9yIGJyb25jaG9kaWxhdGlvbj88L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+NTQzLTU1ODwvcGFnZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3Jk

PjM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBSZW1v

ZGVsaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBzbW9vdGggbXVzY2xlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3Jk

PmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+

YnJvbmNoaWFsIGh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJvbmNob2Rp

bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09NUExFWEVTPC9rZXl3b3JkPjxrZXl3b3JkPmNvbmNlcHRzPC9rZXl3

b3JkPjxrZXl3b3JkPkNPTlRSQUNUSUxFPC9rZXl3b3JkPjxrZXl3b3JkPkZFQVRVUkVTPC9rZXl3

b3JkPjxrZXl3b3JkPmh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tl

eXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwv

a2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9rZXl3

b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUNBTDwva2V5d29y

ZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3Jk

PnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTlNISVA8L2tleXdvcmQ+PGtl

eXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdv

cmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8

L2tleXdvcmQ+PGtleXdvcmQ+U01PT1RIPC9rZXl3b3JkPjxrZXl3b3JkPlNtb290aCBtdXNjbGU8

L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdv

cmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5UT05FPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+V0FMRVM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjkvMjAxMjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CTEFDSzIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [136]. In asthmatic airways there is also a characteristic hypertrophy and hyperplasia of airway smooth muscle, which is presumably the result of stimulation of airway smooth-muscle cells by various growth factors, such as platelet-derived growth factor or endothelin-1 released from inflammatory or epithelial cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGFjazwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTcxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTM2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTcxODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTcxODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+QmxhY2ssSi5MLjwvYXV0aG9yPjxhdXRob3I+UGFuZXR0aWVyaSxSLkEuLEpyLjwvYXV0aG9y

PjxhdXRob3I+QmFuZXJqZWUsQS48L2F1dGhvcj48YXV0aG9yPkJlcmdlcixQLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BaXJ3YXkgc21vb3RoIG11c2Ns

ZSBpbiBhc3RobWE6IGp1c3QgYSB0YXJnZXQgZm9yIGJyb25jaG9kaWxhdGlvbj88L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+NTQzLTU1ODwvcGFnZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3Jk

PjM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBSZW1v

ZGVsaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBzbW9vdGggbXVzY2xlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3Jk

PmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+

YnJvbmNoaWFsIGh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJvbmNob2Rp

bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09NUExFWEVTPC9rZXl3b3JkPjxrZXl3b3JkPmNvbmNlcHRzPC9rZXl3

b3JkPjxrZXl3b3JkPkNPTlRSQUNUSUxFPC9rZXl3b3JkPjxrZXl3b3JkPkZFQVRVUkVTPC9rZXl3

b3JkPjxrZXl3b3JkPmh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tl

eXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwv

a2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9rZXl3

b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUNBTDwva2V5d29y

ZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3Jk

PnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTlNISVA8L2tleXdvcmQ+PGtl

eXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdv

cmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8

L2tleXdvcmQ+PGtleXdvcmQ+U01PT1RIPC9rZXl3b3JkPjxrZXl3b3JkPlNtb290aCBtdXNjbGU8

L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdv

cmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5UT05FPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+V0FMRVM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjkvMjAxMjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CTEFDSzIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGFjazwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTcxODwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTM2XTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj4xMTcxODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc5MDA2Ij4xMTcxODwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJK

b3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRo

b3I+QmxhY2ssSi5MLjwvYXV0aG9yPjxhdXRob3I+UGFuZXR0aWVyaSxSLkEuLEpyLjwvYXV0aG9y

PjxhdXRob3I+QmFuZXJqZWUsQS48L2F1dGhvcj48YXV0aG9yPkJlcmdlcixQLjwvYXV0aG9yPjwv

YXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5BaXJ3YXkgc21vb3RoIG11c2Ns

ZSBpbiBhc3RobWE6IGp1c3QgYSB0YXJnZXQgZm9yIGJyb25jaG9kaWxhdGlvbj88L3RpdGxlPjxz

ZWNvbmRhcnktdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2xpbi5DaGVzdCBNZWQuPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+NTQzLTU1ODwvcGFnZXM+PHZvbHVtZT4zMzwvdm9sdW1lPjxudW1iZXI+

MzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48

a2V5d29yZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3Jk

PjM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBSZW1v

ZGVsaW5nPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheSBzbW9vdGggbXVzY2xlPC9rZXl3b3JkPjxr

ZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdvcmQ+QXN0aG1hPC9rZXl3b3JkPjxrZXl3b3Jk

PmFzdGhtYXRpYzwva2V5d29yZD48a2V5d29yZD5icm9uY2hpYWw8L2tleXdvcmQ+PGtleXdvcmQ+

YnJvbmNoaWFsIGh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+QnJvbmNob2Rp

bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkNFTEw8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09NUExFWEVTPC9rZXl3b3JkPjxrZXl3b3JkPmNvbmNlcHRzPC9rZXl3

b3JkPjxrZXl3b3JkPkNPTlRSQUNUSUxFPC9rZXl3b3JkPjxrZXl3b3JkPkZFQVRVUkVTPC9rZXl3

b3JkPjxrZXl3b3JkPmh5cGVycmVzcG9uc2l2ZW5lc3M8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tl

eXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwv

a2V5d29yZD48a2V5d29yZD5MWU1QSE9DWVRFPC9rZXl3b3JkPjxrZXl3b3JkPkx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9rZXl3

b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUNBTDwva2V5d29y

ZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3Jk

PnBoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5SRUxBVElPTlNISVA8L2tleXdvcmQ+PGtl

eXdvcmQ+UkVTRUFSQ0g8L2tleXdvcmQ+PGtleXdvcmQ+UkVTUE9OU0U8L2tleXdvcmQ+PGtleXdv

cmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3JkPlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+Uk9MRVM8

L2tleXdvcmQ+PGtleXdvcmQ+U01PT1RIPC9rZXl3b3JkPjxrZXl3b3JkPlNtb290aCBtdXNjbGU8

L2tleXdvcmQ+PGtleXdvcmQ+VDwva2V5d29yZD48a2V5d29yZD5UIGx5bXBob2N5dGU8L2tleXdv

cmQ+PGtleXdvcmQ+VCBMWU1QSE9DWVRFUzwva2V5d29yZD48a2V5d29yZD5ULWx5bXBob2N5dGVz

PC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5UT05FPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+V0FMRVM8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAxMjwveWVhcj48cHViLWRhdGVzPjxkYXRlPjkvMjAxMjwvZGF0ZT48

L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CTEFDSzIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48

L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [136]. Airway smooth muscle also releases several inflammatory mediators and may be important in maintaining inflammation in the airway. Bronchial thermoplasty, which selectively ablates airway smooth muscle, provides some clinical benefit in highly selected patients with severe asthma PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb21icmV0PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

UmVjTnVtPjEyNDQxPC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMzddPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyNDQxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0NDY4MDEyNDgiPjEyNDQxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5Eb21icmV0LCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+QWxhZ2hhLCBLLjwvYXV0aG9yPjxh

dXRob3I+Qm91bGV0LCBMLiBQLjwvYXV0aG9yPjxhdXRob3I+QnJpbGxldCwgUC4gWS48L2F1dGhv

cj48YXV0aG9yPkpvb3MsIEcuPC9hdXRob3I+PGF1dGhvcj5MYXZpb2xldHRlLCBNLjwvYXV0aG9y

PjxhdXRob3I+TG91aXMsIFIuPC9hdXRob3I+PGF1dGhvcj5Sb2NoYXQsIFQuPC9hdXRob3I+PGF1

dGhvcj5Tb2NjYWwsIFAuPC9hdXRob3I+PGF1dGhvcj5BdWJpZXIsIE0uPC9hdXRob3I+PGF1dGhv

cj5DaGFuZXosIFAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+RGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgQmljaGF0IEFQSFAsIFU3MDAgSU5TRVJN

IFVuaXZlcnNpdHkgSG9zcGl0YWxzIERlcHQsIERpZGVyb3QgVW5pdmVyc2l0eSwgUGFyaXMsIEZy

YW5jZSBEZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBBUEhNLCBJTlNFUk0gVTEwNjcgQ05S

UyBVTVIgNzMzMywgQWl4IE1hcnNlaWxsZSBVbml2ZXJzaXR5LCBNYXJzZWlsbGUsIEZyYW5jZVJl

c2VhcmNoIENlbnRyZSBhdCB0aGUgSW5zdGl0dXRlIG9mIENhcmRpb2xvZ3kgYW5kIFJlc3BpcmF0

b3J5IE1lZGljaW5lLCBMYXZhbCBVbml2ZXJzaXR5LCBRdWViZWMsIFFDLCBDYW5hZGFEZXB0IG9m

IFJhZGlvbG9neSwgQXZpY2VubmUgUHVibGljIEhvc3BpdGFsLCBCb2JpZ255LCBGcmFuY2UgRGVw

dCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3NwaXRhbCwgR2hl

bnQgVW5pdmVyc2l0eSwgR2hlbnQsIEJlbGdpdW1EZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5l

LCBMaWVnZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBHSUdBSTMgUmVzZWFyY2ggR3JvdXAsIFVuaXZl

cnNpdHkgb2YgTGllZ2UsIExpZWdlLCBCZWxnaXVtRGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2lu

ZSwgSFVHIEdlbmV2YSwgU3dpdHplcmxhbmRCb3RoIGF1dGhvcnMgY29udHJpYnV0ZWQgZXF1YWxs

eSBEZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBCaWNoYXQgQVBIUCwgVTcwMCBJTlNFUk0g

VW5pdmVyc2l0eSBIb3NwaXRhbHMgRGVwdCwgRGlkZXJvdCBVbml2ZXJzaXR5LCBQYXJpcywgRnJh

bmNlIERlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEFQSE0sIElOU0VSTSBVMTA2NyBDTlJT

IFVNUiA3MzMzLCBBaXggTWFyc2VpbGxlIFVuaXZlcnNpdHksIE1hcnNlaWxsZSwgRnJhbmNlUmVz

ZWFyY2ggQ2VudHJlIGF0IHRoZSBJbnN0aXR1dGUgb2YgQ2FyZGlvbG9neSBhbmQgUmVzcGlyYXRv

cnkgTWVkaWNpbmUsIExhdmFsIFVuaXZlcnNpdHksIFF1ZWJlYywgUUMsIENhbmFkYURlcHQgb2Yg

UmFkaW9sb2d5LCBBdmljZW5uZSBQdWJsaWMgSG9zcGl0YWwsIEJvYmlnbnksIEZyYW5jZSBEZXB0

IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHaGVudCBVbml2ZXJzaXR5IEhvc3BpdGFsLCBHaGVu

dCBVbml2ZXJzaXR5LCBHaGVudCwgQmVsZ2l1bURlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUs

IExpZWdlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEdJR0FJMyBSZXNlYXJjaCBHcm91cCwgVW5pdmVy

c2l0eSBvZiBMaWVnZSwgTGllZ2UsIEJlbGdpdW1EZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5l

LCBIVUcgR2VuZXZhLCBTd2l0emVybGFuZEJvdGggYXV0aG9ycyBjb250cmlidXRlZCBlcXVhbGx5

LiYjeEQ7RGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgQmljaGF0IEFQSFAsIFU3MDAgSU5T

RVJNIFVuaXZlcnNpdHkgSG9zcGl0YWxzIERlcHQsIERpZGVyb3QgVW5pdmVyc2l0eSwgUGFyaXMs

IEZyYW5jZSBEZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBBUEhNLCBJTlNFUk0gVTEwNjcg

Q05SUyBVTVIgNzMzMywgQWl4IE1hcnNlaWxsZSBVbml2ZXJzaXR5LCBNYXJzZWlsbGUsIEZyYW5j

ZVJlc2VhcmNoIENlbnRyZSBhdCB0aGUgSW5zdGl0dXRlIG9mIENhcmRpb2xvZ3kgYW5kIFJlc3Bp

cmF0b3J5IE1lZGljaW5lLCBMYXZhbCBVbml2ZXJzaXR5LCBRdWViZWMsIFFDLCBDYW5hZGFEZXB0

IG9mIFJhZGlvbG9neSwgQXZpY2VubmUgUHVibGljIEhvc3BpdGFsLCBCb2JpZ255LCBGcmFuY2Ug

RGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3NwaXRhbCwg

R2hlbnQgVW5pdmVyc2l0eSwgR2hlbnQsIEJlbGdpdW1EZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGlj

aW5lLCBMaWVnZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBHSUdBSTMgUmVzZWFyY2ggR3JvdXAsIFVu

aXZlcnNpdHkgb2YgTGllZ2UsIExpZWdlLCBCZWxnaXVtRGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRp

Y2luZSwgSFVHIEdlbmV2YSwgU3dpdHplcmxhbmRCb3RoIGF1dGhvcnMgY29udHJpYnV0ZWQgZXF1

YWxseS4mI3hEO0RlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEJpY2hhdCBBUEhQLCBVNzAw

IElOU0VSTSBVbml2ZXJzaXR5IEhvc3BpdGFscyBEZXB0LCBEaWRlcm90IFVuaXZlcnNpdHksIFBh

cmlzLCBGcmFuY2UgRGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgQVBITSwgSU5TRVJNIFUx

MDY3IENOUlMgVU1SIDczMzMsIEFpeCBNYXJzZWlsbGUgVW5pdmVyc2l0eSwgTWFyc2VpbGxlLCBG

cmFuY2VSZXNlYXJjaCBDZW50cmUgYXQgdGhlIEluc3RpdHV0ZSBvZiBDYXJkaW9sb2d5IGFuZCBS

ZXNwaXJhdG9yeSBNZWRpY2luZSwgTGF2YWwgVW5pdmVyc2l0eSwgUXVlYmVjLCBRQywgQ2FuYWRh

RGVwdCBvZiBSYWRpb2xvZ3ksIEF2aWNlbm5lIFB1YmxpYyBIb3NwaXRhbCwgQm9iaWdueSwgRnJh

bmNlIERlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEdoZW50IFVuaXZlcnNpdHkgSG9zcGl0

YWwsIEdoZW50IFVuaXZlcnNpdHksIEdoZW50LCBCZWxnaXVtRGVwdCBvZiBSZXNwaXJhdG9yeSBN

ZWRpY2luZSwgTGllZ2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgR0lHQUkzIFJlc2VhcmNoIEdyb3Vw

LCBVbml2ZXJzaXR5IG9mIExpZWdlLCBMaWVnZSwgQmVsZ2l1bURlcHQgb2YgUmVzcGlyYXRvcnkg

TWVkaWNpbmUsIEhVRyBHZW5ldmEsIFN3aXR6ZXJsYW5kQm90aCBhdXRob3JzIGNvbnRyaWJ1dGVk

IGVxdWFsbHkgcGFzY2FsLmNoYW5lekB1bml2LWFtdS5mci48L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5Ccm9uY2hpYWwgdGhlcm1vcGxhc3R5OiBhIG5ldyB0aGVyYXBldXRpYyBvcHRpb24g

Zm9yIHRoZSB0cmVhdG1lbnQgb2Ygc2V2ZXJlLCB1bmNvbnRyb2xsZWQgYXN0aG1hIGluIGFkdWx0

czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FdXIgUmVzcGlyIFJldjwvc2Vjb25kYXJ5LXRpdGxl

PjxhbHQtdGl0bGU+RXVyb3BlYW4gcmVzcGlyYXRvcnkgcmV2aWV3IDogYW4gb2ZmaWNpYWwgam91

cm5hbCBvZiB0aGUgRXVyb3BlYW4gUmVzcGlyYXRvcnkgU29jaWV0eTwvYWx0LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkV1ciBSZXNwaXIgUmV2PC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+NTEwLTg8L3BhZ2VzPjx2b2x1bWU+MjM8L3ZvbHVtZT48bnVtYmVy

PjEzNDwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMTIvMDM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3

b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+

QWdlZDwva2V5d29yZD48a2V5d29yZD5Bc3RobWEvcGh5c2lvcGF0aG9sb2d5Lyp0aGVyYXB5PC9r

ZXl3b3JkPjxrZXl3b3JkPkJyb25jaGkvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkJyb25jaG9zY29weS9hZHZlcnNlIGVmZmVjdHMvaW5zdHJ1bWVudGF0aW9uLyptZXRob2RzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNhdGhldGVyczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+SHlwZXJ0aGVybWlhLCBJbmR1Y2VkL2FkdmVyc2UgZWZmZWN0cy9pbnN0cnVt

ZW50YXRpb24vKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+UGF0aWVudCBTZWxlY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJpdHkgb2Yg

SWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29y

ZD48a2V5d29yZD5Zb3VuZyBBZHVsdDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDkwNS05MTgwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1NDQ1OTUwPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4My8wOTA1OTE4

MC4wMDAwNTExNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFn

ZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb21icmV0PC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

UmVjTnVtPjEyNDQxPC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxMzddPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEyNDQxPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjE0NDY4MDEyNDgiPjEyNDQxPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5Eb21icmV0LCBNLiBDLjwvYXV0aG9yPjxhdXRob3I+QWxhZ2hhLCBLLjwvYXV0aG9yPjxh

dXRob3I+Qm91bGV0LCBMLiBQLjwvYXV0aG9yPjxhdXRob3I+QnJpbGxldCwgUC4gWS48L2F1dGhv

cj48YXV0aG9yPkpvb3MsIEcuPC9hdXRob3I+PGF1dGhvcj5MYXZpb2xldHRlLCBNLjwvYXV0aG9y

PjxhdXRob3I+TG91aXMsIFIuPC9hdXRob3I+PGF1dGhvcj5Sb2NoYXQsIFQuPC9hdXRob3I+PGF1

dGhvcj5Tb2NjYWwsIFAuPC9hdXRob3I+PGF1dGhvcj5BdWJpZXIsIE0uPC9hdXRob3I+PGF1dGhv

cj5DaGFuZXosIFAuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJl

c3M+RGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgQmljaGF0IEFQSFAsIFU3MDAgSU5TRVJN

IFVuaXZlcnNpdHkgSG9zcGl0YWxzIERlcHQsIERpZGVyb3QgVW5pdmVyc2l0eSwgUGFyaXMsIEZy

YW5jZSBEZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBBUEhNLCBJTlNFUk0gVTEwNjcgQ05S

UyBVTVIgNzMzMywgQWl4IE1hcnNlaWxsZSBVbml2ZXJzaXR5LCBNYXJzZWlsbGUsIEZyYW5jZVJl

c2VhcmNoIENlbnRyZSBhdCB0aGUgSW5zdGl0dXRlIG9mIENhcmRpb2xvZ3kgYW5kIFJlc3BpcmF0

b3J5IE1lZGljaW5lLCBMYXZhbCBVbml2ZXJzaXR5LCBRdWViZWMsIFFDLCBDYW5hZGFEZXB0IG9m

IFJhZGlvbG9neSwgQXZpY2VubmUgUHVibGljIEhvc3BpdGFsLCBCb2JpZ255LCBGcmFuY2UgRGVw

dCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3NwaXRhbCwgR2hl

bnQgVW5pdmVyc2l0eSwgR2hlbnQsIEJlbGdpdW1EZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5l

LCBMaWVnZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBHSUdBSTMgUmVzZWFyY2ggR3JvdXAsIFVuaXZl

cnNpdHkgb2YgTGllZ2UsIExpZWdlLCBCZWxnaXVtRGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2lu

ZSwgSFVHIEdlbmV2YSwgU3dpdHplcmxhbmRCb3RoIGF1dGhvcnMgY29udHJpYnV0ZWQgZXF1YWxs

eSBEZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBCaWNoYXQgQVBIUCwgVTcwMCBJTlNFUk0g

VW5pdmVyc2l0eSBIb3NwaXRhbHMgRGVwdCwgRGlkZXJvdCBVbml2ZXJzaXR5LCBQYXJpcywgRnJh

bmNlIERlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEFQSE0sIElOU0VSTSBVMTA2NyBDTlJT

IFVNUiA3MzMzLCBBaXggTWFyc2VpbGxlIFVuaXZlcnNpdHksIE1hcnNlaWxsZSwgRnJhbmNlUmVz

ZWFyY2ggQ2VudHJlIGF0IHRoZSBJbnN0aXR1dGUgb2YgQ2FyZGlvbG9neSBhbmQgUmVzcGlyYXRv

cnkgTWVkaWNpbmUsIExhdmFsIFVuaXZlcnNpdHksIFF1ZWJlYywgUUMsIENhbmFkYURlcHQgb2Yg

UmFkaW9sb2d5LCBBdmljZW5uZSBQdWJsaWMgSG9zcGl0YWwsIEJvYmlnbnksIEZyYW5jZSBEZXB0

IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBHaGVudCBVbml2ZXJzaXR5IEhvc3BpdGFsLCBHaGVu

dCBVbml2ZXJzaXR5LCBHaGVudCwgQmVsZ2l1bURlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUs

IExpZWdlIFVuaXZlcnNpdHkgSG9zcGl0YWwsIEdJR0FJMyBSZXNlYXJjaCBHcm91cCwgVW5pdmVy

c2l0eSBvZiBMaWVnZSwgTGllZ2UsIEJlbGdpdW1EZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5l

LCBIVUcgR2VuZXZhLCBTd2l0emVybGFuZEJvdGggYXV0aG9ycyBjb250cmlidXRlZCBlcXVhbGx5

LiYjeEQ7RGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgQmljaGF0IEFQSFAsIFU3MDAgSU5T

RVJNIFVuaXZlcnNpdHkgSG9zcGl0YWxzIERlcHQsIERpZGVyb3QgVW5pdmVyc2l0eSwgUGFyaXMs

IEZyYW5jZSBEZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGljaW5lLCBBUEhNLCBJTlNFUk0gVTEwNjcg

Q05SUyBVTVIgNzMzMywgQWl4IE1hcnNlaWxsZSBVbml2ZXJzaXR5LCBNYXJzZWlsbGUsIEZyYW5j

ZVJlc2VhcmNoIENlbnRyZSBhdCB0aGUgSW5zdGl0dXRlIG9mIENhcmRpb2xvZ3kgYW5kIFJlc3Bp

cmF0b3J5IE1lZGljaW5lLCBMYXZhbCBVbml2ZXJzaXR5LCBRdWViZWMsIFFDLCBDYW5hZGFEZXB0

IG9mIFJhZGlvbG9neSwgQXZpY2VubmUgUHVibGljIEhvc3BpdGFsLCBCb2JpZ255LCBGcmFuY2Ug

RGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3NwaXRhbCwg

R2hlbnQgVW5pdmVyc2l0eSwgR2hlbnQsIEJlbGdpdW1EZXB0IG9mIFJlc3BpcmF0b3J5IE1lZGlj

aW5lLCBMaWVnZSBVbml2ZXJzaXR5IEhvc3BpdGFsLCBHSUdBSTMgUmVzZWFyY2ggR3JvdXAsIFVu

aXZlcnNpdHkgb2YgTGllZ2UsIExpZWdlLCBCZWxnaXVtRGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRp

Y2luZSwgSFVHIEdlbmV2YSwgU3dpdHplcmxhbmRCb3RoIGF1dGhvcnMgY29udHJpYnV0ZWQgZXF1

YWxseS4mI3hEO0RlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEJpY2hhdCBBUEhQLCBVNzAw

IElOU0VSTSBVbml2ZXJzaXR5IEhvc3BpdGFscyBEZXB0LCBEaWRlcm90IFVuaXZlcnNpdHksIFBh

cmlzLCBGcmFuY2UgRGVwdCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgQVBITSwgSU5TRVJNIFUx

MDY3IENOUlMgVU1SIDczMzMsIEFpeCBNYXJzZWlsbGUgVW5pdmVyc2l0eSwgTWFyc2VpbGxlLCBG

cmFuY2VSZXNlYXJjaCBDZW50cmUgYXQgdGhlIEluc3RpdHV0ZSBvZiBDYXJkaW9sb2d5IGFuZCBS

ZXNwaXJhdG9yeSBNZWRpY2luZSwgTGF2YWwgVW5pdmVyc2l0eSwgUXVlYmVjLCBRQywgQ2FuYWRh

RGVwdCBvZiBSYWRpb2xvZ3ksIEF2aWNlbm5lIFB1YmxpYyBIb3NwaXRhbCwgQm9iaWdueSwgRnJh

bmNlIERlcHQgb2YgUmVzcGlyYXRvcnkgTWVkaWNpbmUsIEdoZW50IFVuaXZlcnNpdHkgSG9zcGl0

YWwsIEdoZW50IFVuaXZlcnNpdHksIEdoZW50LCBCZWxnaXVtRGVwdCBvZiBSZXNwaXJhdG9yeSBN

ZWRpY2luZSwgTGllZ2UgVW5pdmVyc2l0eSBIb3NwaXRhbCwgR0lHQUkzIFJlc2VhcmNoIEdyb3Vw

LCBVbml2ZXJzaXR5IG9mIExpZWdlLCBMaWVnZSwgQmVsZ2l1bURlcHQgb2YgUmVzcGlyYXRvcnkg

TWVkaWNpbmUsIEhVRyBHZW5ldmEsIFN3aXR6ZXJsYW5kQm90aCBhdXRob3JzIGNvbnRyaWJ1dGVk

IGVxdWFsbHkgcGFzY2FsLmNoYW5lekB1bml2LWFtdS5mci48L2F1dGgtYWRkcmVzcz48dGl0bGVz

Pjx0aXRsZT5Ccm9uY2hpYWwgdGhlcm1vcGxhc3R5OiBhIG5ldyB0aGVyYXBldXRpYyBvcHRpb24g

Zm9yIHRoZSB0cmVhdG1lbnQgb2Ygc2V2ZXJlLCB1bmNvbnRyb2xsZWQgYXN0aG1hIGluIGFkdWx0

czwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FdXIgUmVzcGlyIFJldjwvc2Vjb25kYXJ5LXRpdGxl

PjxhbHQtdGl0bGU+RXVyb3BlYW4gcmVzcGlyYXRvcnkgcmV2aWV3IDogYW4gb2ZmaWNpYWwgam91

cm5hbCBvZiB0aGUgRXVyb3BlYW4gUmVzcGlyYXRvcnkgU29jaWV0eTwvYWx0LXRpdGxlPjwvdGl0

bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkV1ciBSZXNwaXIgUmV2PC9mdWxsLXRpdGxlPjwv

cGVyaW9kaWNhbD48cGFnZXM+NTEwLTg8L3BhZ2VzPjx2b2x1bWU+MjM8L3ZvbHVtZT48bnVtYmVy

PjEzNDwvbnVtYmVyPjxlZGl0aW9uPjIwMTQvMTIvMDM8L2VkaXRpb24+PGtleXdvcmRzPjxrZXl3

b3JkPkFkb2xlc2NlbnQ8L2tleXdvcmQ+PGtleXdvcmQ+QWR1bHQ8L2tleXdvcmQ+PGtleXdvcmQ+

QWdlZDwva2V5d29yZD48a2V5d29yZD5Bc3RobWEvcGh5c2lvcGF0aG9sb2d5Lyp0aGVyYXB5PC9r

ZXl3b3JkPjxrZXl3b3JkPkJyb25jaGkvcGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3Jk

PkJyb25jaG9zY29weS9hZHZlcnNlIGVmZmVjdHMvaW5zdHJ1bWVudGF0aW9uLyptZXRob2RzPC9r

ZXl3b3JkPjxrZXl3b3JkPkNhdGhldGVyczwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdv

cmQ+PGtleXdvcmQ+SHlwZXJ0aGVybWlhLCBJbmR1Y2VkL2FkdmVyc2UgZWZmZWN0cy9pbnN0cnVt

ZW50YXRpb24vKm1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TWlkZGxlIEFnZWQ8L2tleXdvcmQ+

PGtleXdvcmQ+UGF0aWVudCBTZWxlY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+U2V2ZXJpdHkgb2Yg

SWxsbmVzcyBJbmRleDwva2V5d29yZD48a2V5d29yZD5UcmVhdG1lbnQgT3V0Y29tZTwva2V5d29y

ZD48a2V5d29yZD5Zb3VuZyBBZHVsdDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4y

MDE0PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+RGVjPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGlzYm4+MDkwNS05MTgwPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI1NDQ1OTUwPC9hY2Nlc3Npb24t

bnVtPjx1cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE4My8wOTA1OTE4

MC4wMDAwNTExNDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PHJlbW90ZS1kYXRhYmFzZS1wcm92

aWRlcj5OTE08L3JlbW90ZS1kYXRhYmFzZS1wcm92aWRlcj48bGFuZ3VhZ2U+ZW5nPC9sYW5ndWFn

ZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [137].By contrast, there is little increase in airway smooth muscle bulk in patients with COPD, presumably because inflammation does not generate appropriate growth factors for airway smooth muscle cells.Blood vesselsThere is increased airway mucosal blood flow in asthma, which may contribute to airway narrowing. There is an increase in the number of blood vessels in asthmatic airways as a result of angiogenesis in response to growth factors, particularly vascular-endothelial growth factor (VEGF) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJlZGk8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MTA3Mzc8L1JlY051bT48RGlzcGxheVRleHQ+WzEzOF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTA3Mzc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk5MCI+MTA3Mzc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBhcmVkaSxQLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+VGhlIGFpcndheSB2YXNjdWxhdHVyZTog

cmVjZW50IGFkdmFuY2VzIGFuZCBjbGluaWNhbCBpbXBsaWNhdGlvbnM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+VGhvcmF4Ljwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPlRob3JheC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40NDQtNDUw

PC9wYWdlcz48dm9sdW1lPjY0PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PHJlcHJpbnQtZWRp

dGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BRFZB

TkNFUzwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QU5BVE9NWTwv

a2V5d29yZD48a2V5d29yZD5BTklNQUw8L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTTUVOVDwva2V5

d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+QklPQVZBSUxBQklMSVRZPC9r

ZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlhbDwva2V5d29y

ZD48a2V5d29yZD5DSEFOR0VTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJUkNVTEFUSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkRFVkVMT1BNRU5UPC9r

ZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8L2tleXdv

cmQ+PGtleXdvcmQ+RFJVRzwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdv

cmQ+RkxPVzwva2V5d29yZD48a2V5d29yZD5HRU5FUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmh1

bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29yZD5JTVBMSUNBVElP

TlM8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklWTzwva2V5d29y

ZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5JTlZFU1RJR0FUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPklOVkVTVElHQVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPkxFQUs8

L2tleXdvcmQ+PGtleXdvcmQ+TEVBS0FHRTwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3Jk

PjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUNBTDwva2V5d29yZD48

a2V5d29yZD5NRURJQ0FUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5

d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ1JPVkFTQ1VMQVI8L2tleXdvcmQ+PGtl

eXdvcmQ+TUlDUk9WQVNDVUxBUiBMRUFLQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk5FVzwva2V5d29y

ZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+

PGtleXdvcmQ+UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxr

ZXl3b3JkPnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UExBU01BPC9rZXl3b3JkPjxrZXl3

b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UVVBTlRJRklDQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+UkVDRU5UPC9rZXl3b3JkPjxrZXl3

b3JkPlJFR1VMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3Jk

PlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwv

a2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5ERVJTVEFORElO

Rzwva2V5d29yZD48a2V5d29yZD5VU0U8L2tleXdvcmQ+PGtleXdvcmQ+VkFTQ1VMQVI8L2tleXdv

cmQ+PGtleXdvcmQ+VkVTU0VMUzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+NS8yMDA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGxhYmVsPlBBUkVESTIwMDk8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJlZGk8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MTA3Mzc8L1JlY051bT48RGlzcGxheVRleHQ+WzEzOF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTA3Mzc8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3ODk5MCI+MTA3Mzc8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlBhcmVkaSxQLjwvYXV0aG9yPjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhv

cnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+VGhlIGFpcndheSB2YXNjdWxhdHVyZTog

cmVjZW50IGFkdmFuY2VzIGFuZCBjbGluaWNhbCBpbXBsaWNhdGlvbnM8L3RpdGxlPjxzZWNvbmRh

cnktdGl0bGU+VGhvcmF4Ljwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxm

dWxsLXRpdGxlPlRob3JheC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz40NDQtNDUw

PC9wYWdlcz48dm9sdW1lPjY0PC92b2x1bWU+PG51bWJlcj41PC9udW1iZXI+PHJlcHJpbnQtZWRp

dGlvbj5Ob3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BRFZB

TkNFUzwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QU5BVE9NWTwv

a2V5d29yZD48a2V5d29yZD5BTklNQUw8L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNTTUVOVDwva2V5

d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+QklPQVZBSUxBQklMSVRZPC9r

ZXl3b3JkPjxrZXl3b3JkPkJMT09EPC9rZXl3b3JkPjxrZXl3b3JkPmJyb25jaGlhbDwva2V5d29y

ZD48a2V5d29yZD5DSEFOR0VTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8L2tleXdvcmQ+PGtl

eXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5DaHJvbmljIG9ic3Ry

dWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJUkNVTEFUSU9OPC9r

ZXl3b3JkPjxrZXl3b3JkPmNsaW5pY2FsPC9rZXl3b3JkPjxrZXl3b3JkPkRFVkVMT1BNRU5UPC9r

ZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRVM8L2tleXdv

cmQ+PGtleXdvcmQ+RFJVRzwva2V5d29yZD48a2V5d29yZD5FRkZFQ1Q8L2tleXdvcmQ+PGtleXdv

cmQ+RkxPVzwva2V5d29yZD48a2V5d29yZD5HRU5FUkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPmh1

bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29yZD5JTVBMSUNBVElP

TlM8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+SU4gVklWTzwva2V5d29y

ZD48a2V5d29yZD5JTkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+aW5mbGFtbWF0aW9uPC9rZXl3

b3JkPjxrZXl3b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5JTlZFU1RJR0FUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPklOVkVTVElHQVRJT05TPC9rZXl3b3JkPjxrZXl3b3JkPkxFQUs8

L2tleXdvcmQ+PGtleXdvcmQ+TEVBS0FHRTwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3Jk

PjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUVESUNBTDwva2V5d29yZD48

a2V5d29yZD5NRURJQ0FUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPk1FVEhPRDwva2V5d29yZD48a2V5

d29yZD5NZXRob2RzPC9rZXl3b3JkPjxrZXl3b3JkPk1JQ1JPVkFTQ1VMQVI8L2tleXdvcmQ+PGtl

eXdvcmQ+TUlDUk9WQVNDVUxBUiBMRUFLQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk5FVzwva2V5d29y

ZD48a2V5d29yZD5ub3JtYWw8L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+

PGtleXdvcmQ+UEFUSE9MT0dZPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxr

ZXl3b3JkPnBoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+UExBU01BPC9rZXl3b3JkPjxrZXl3

b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UVVBTlRJRklDQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+UkVDRU5UPC9rZXl3b3JkPjxrZXl3

b3JkPlJFR1VMQVRJT048L2tleXdvcmQ+PGtleXdvcmQ+UmV2aWV3PC9rZXl3b3JkPjxrZXl3b3Jk

PlJPTEU8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRElFUzwva2V5d29yZD48a2V5d29yZD5TVFVEWTwv

a2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5ERVJTVEFORElO

Rzwva2V5d29yZD48a2V5d29yZD5VU0U8L2tleXdvcmQ+PGtleXdvcmQ+VkFTQ1VMQVI8L2tleXdv

cmQ+PGtleXdvcmQ+VkVTU0VMUzwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDA5

PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+NS8yMDA5PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+

PGxhYmVsPlBBUkVESTIwMDk8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9F

bmROb3RlPgB=

ADDIN EN.CITE.DATA [138]. Microvascular leakage from postcapillary venules in response to inflammatory mediators is observed in asthma, resulting in airway oedema and plasma exudation into the airway lumen. By contrast, the vascularity of the airways appears to be reduced in COPD patients and this may be due to reduced VEGF production ADDIN EN.CITE <EndNote><Cite><Author>Kanazawa</Author><Year>2014</Year><RecNum>11956</RecNum><DisplayText>[139]</DisplayText><record><rec-number>11956</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1399977048">11956</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kanazawa, H.; Tochino, Y.; Asai, K.; Hirata, K.</author></authors></contributors><titles><title>Simultaneous assessment of HGF and VEGF in epithelial lining fluid from patients with COPD</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1159-65</pages><volume>146</volume><dates><year>2014</year></dates><urls></urls></record></Cite></EndNote>[139].Mucus hypersecretionMucus hypersecretion is an important component of asthma and COPD and contributes to occlusion of the airways, particularly is mucociliary function is impaired ADDIN EN.CITE <EndNote><Cite><Author>Fahy</Author><Year>2010</Year><RecNum>11222</RecNum><DisplayText>[65]</DisplayText><record><rec-number>11222</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1378478998">11222</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fahy,J.V.</author><author>Dickey,B.F.</author></authors></contributors><titles><title>Airway mucus function and dysfunction</title><secondary-title>N.Engl.J Med.</secondary-title></titles><periodical><full-title>N.Engl.J Med.</full-title></periodical><pages>2233-2247</pages><volume>363</volume><number>23</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>AIRWAY</keyword><keyword>anatomy &amp; histology</keyword><keyword>Asthma</keyword><keyword>CARDIOVASCULAR</keyword><keyword>CYSTIC FIBROSIS</keyword><keyword>DYSFUNCTION</keyword><keyword>function</keyword><keyword>HUMANS</keyword><keyword>lung diseases</keyword><keyword>MEDICINE</keyword><keyword>Mucociliary Clearance</keyword><keyword>MUCUS</keyword><keyword>physiology</keyword><keyword>physiopathology</keyword><keyword>Pulmonary Disease,Chronic Obstructive</keyword><keyword>RESEARCH</keyword><keyword>Respiratory Physiological Processes</keyword><keyword>respiratory system</keyword><keyword>SECRETION</keyword></keywords><dates><year>2010</year><pub-dates><date>12/2/2010</date></pub-dates></dates><label>FAHY2010</label><urls></urls></record></Cite></EndNote>[65]. Increased mucus secretion contributes to the viscid mucous plugs that occlude asthmatic airways, particularly in fatal asthma. There is hyperplasia of submucosal glands that are confined to large airways and of increased numbers of epithelial goblet cells in both asthma and COPD. IL-13 is a potent induces mucus hypersecretion in experimental models of asthma and suppression of IL-13 expression by corticosteroids may account efficacy in reducing mucus hypersecretion in asthma. Epidermal growth factor receptors (EGFR) play an important role in regulating mucin gene expression and may be activated directly by TGF-α or indirectly via oxidative stress and neutrophil elastase PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJnZWw8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+OTA4NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTQwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj45MDg1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NjMiPjkwODU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkJ1cmdlbCxQLlIuPC9hdXRob3I+PGF1dGhvcj5OYWRlbCxKLkEuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlJvbGVzIG9mIGVwaWRlcm1hbCBncm93dGgg

ZmFjdG9yIHJlY2VwdG9yIGFjdGl2YXRpb24gaW4gZXBpdGhlbGlhbCBjZWxsIHJlcGFpciBhbmQg

bXVjaW4gcHJvZHVjdGlvbiBpbiBhaXJ3YXkgZXBpdGhlbGl1bTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5UaG9yYXg8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz45OTItOTk2PC9wYWdl

cz48dm9sdW1lPjU5PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+

Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MDwva2V5d29y

ZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48

a2V5d29yZD5BaXJ3YXlzPC9rZXl3b3JkPjxrZXl3b3JkPkJMT0NLQURFPC9rZXl3b3JkPjxrZXl3

b3JkPkJST05DSEk8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkRBTUFHRTwva2V5

d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaWRlcm1hbCBHcm93dGggRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPkVQSVRI

RUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpdGhlbGlhbCBjZWxsczwva2V5d29yZD48a2V5d29y

ZD5FcGl0aGVsaXVtPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5m

dW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5GVU5DVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+ZnV0

dXJlPC9rZXl3b3JkPjxrZXl3b3JkPkdST1dUSDwva2V5d29yZD48a2V5d29yZD5Hcm93dGggZmFj

dG9yPC9rZXl3b3JkPjxrZXl3b3JkPkhFQUxUSFk8L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9r

ZXl3b3JkPjxrZXl3b3JkPkhZUEVSU0VDUkVUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPklORElWSURVQUxTPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlvbjwva2V5

d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5IQUxFRDwva2V5

d29yZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1VQ0lOPC9rZXl3b3Jk

PjxrZXl3b3JkPk11Y2luczwva2V5d29yZD48a2V5d29yZD5NVUNPQ0lMSUFSWTwva2V5d29yZD48

a2V5d29yZD5NVUNPVVM8L2tleXdvcmQ+PGtleXdvcmQ+TVVDVVM8L2tleXdvcmQ+PGtleXdvcmQ+

Tk88L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdB

WTwva2V5d29yZD48a2V5d29yZD5QQVRIV0FZUzwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9EVUNUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8

L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3IsZXBpZGVybWFsIGdyb3d0aCBmYWN0b3I8L2tleXdv

cmQ+PGtleXdvcmQ+UmVzcGlyYXRvcnkgTXVjb3NhPC9rZXl3b3JkPjxrZXl3b3JkPlJldmlldzwv

a2V5d29yZD48a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEVTPC9rZXl3b3JkPjxr

ZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3b3JkPnN0ZW0gY2VsbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+U1RJTVVMSTwva2V5d29yZD48a2V5d29yZD5TVVJGQUNFPC9rZXl3b3JkPjxrZXl3b3Jk

PlRSQU5TUE9SVDwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjExLzIwMDQ8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+QlVSR0VMMjAwNDwvbGFiZWw+PHVybHM+PC91cmxz

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJnZWw8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS

ZWNOdW0+OTA4NTwvUmVjTnVtPjxEaXNwbGF5VGV4dD5bMTQwXTwvRGlzcGxheVRleHQ+PHJlY29y

ZD48cmVjLW51bWJlcj45MDg1PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVO

IiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9

IjEzNzg0Nzg5NjMiPjkwODU8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91

cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9y

PkJ1cmdlbCxQLlIuPC9hdXRob3I+PGF1dGhvcj5OYWRlbCxKLkEuPC9hdXRob3I+PC9hdXRob3Jz

PjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPlJvbGVzIG9mIGVwaWRlcm1hbCBncm93dGgg

ZmFjdG9yIHJlY2VwdG9yIGFjdGl2YXRpb24gaW4gZXBpdGhlbGlhbCBjZWxsIHJlcGFpciBhbmQg

bXVjaW4gcHJvZHVjdGlvbiBpbiBhaXJ3YXkgZXBpdGhlbGl1bTwvdGl0bGU+PHNlY29uZGFyeS10

aXRsZT5UaG9yYXg8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10

aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz45OTItOTk2PC9wYWdl

cz48dm9sdW1lPjU5PC92b2x1bWU+PG51bWJlcj4xMTwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+

Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MDwva2V5d29y

ZD48a2V5d29yZD5BQ1RJVkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48

a2V5d29yZD5BaXJ3YXlzPC9rZXl3b3JkPjxrZXl3b3JkPkJMT0NLQURFPC9rZXl3b3JkPjxrZXl3

b3JkPkJST05DSEk8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxM

Uzwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkRBTUFHRTwva2V5

d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0VTPC9rZXl3b3Jk

PjxrZXl3b3JkPkVwaWRlcm1hbCBHcm93dGggRmFjdG9yPC9rZXl3b3JkPjxrZXl3b3JkPkVQSVRI

RUxJQUw8L2tleXdvcmQ+PGtleXdvcmQ+ZXBpdGhlbGlhbCBjZWxsczwva2V5d29yZD48a2V5d29y

ZD5FcGl0aGVsaXVtPC9rZXl3b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5m

dW5jdGlvbjwva2V5d29yZD48a2V5d29yZD5GVU5DVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+ZnV0

dXJlPC9rZXl3b3JkPjxrZXl3b3JkPkdST1dUSDwva2V5d29yZD48a2V5d29yZD5Hcm93dGggZmFj

dG9yPC9rZXl3b3JkPjxrZXl3b3JkPkhFQUxUSFk8L2tleXdvcmQ+PGtleXdvcmQ+SFVNQU5TPC9r

ZXl3b3JkPjxrZXl3b3JkPkhZUEVSU0VDUkVUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPklORElWSURVQUxTPC9rZXl3b3JkPjxrZXl3b3JkPkluZmVjdGlvbjwva2V5

d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8L2tleXdvcmQ+PGtleXdvcmQ+SU5IQUxFRDwva2V5

d29yZD48a2V5d29yZD5NRVRBQk9MSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1VQ0lOPC9rZXl3b3Jk

PjxrZXl3b3JkPk11Y2luczwva2V5d29yZD48a2V5d29yZD5NVUNPQ0lMSUFSWTwva2V5d29yZD48

a2V5d29yZD5NVUNPVVM8L2tleXdvcmQ+PGtleXdvcmQ+TVVDVVM8L2tleXdvcmQ+PGtleXdvcmQ+

Tk88L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJT048L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdB

WTwva2V5d29yZD48a2V5d29yZD5QQVRIV0FZUzwva2V5d29yZD48a2V5d29yZD5waHlzaW9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVElBTDwva2V5d29yZD48a2V5d29yZD5QUk9EVUNUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPlBST1RFQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3I8

L2tleXdvcmQ+PGtleXdvcmQ+cmVjZXB0b3IsZXBpZGVybWFsIGdyb3d0aCBmYWN0b3I8L2tleXdv

cmQ+PGtleXdvcmQ+UmVzcGlyYXRvcnkgTXVjb3NhPC9rZXl3b3JkPjxrZXl3b3JkPlJldmlldzwv

a2V5d29yZD48a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlJPTEVTPC9rZXl3b3JkPjxr

ZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxrZXl3b3JkPnN0ZW0gY2VsbHM8L2tleXdvcmQ+PGtl

eXdvcmQ+U1RJTVVMSTwva2V5d29yZD48a2V5d29yZD5TVVJGQUNFPC9rZXl3b3JkPjxrZXl3b3Jk

PlRSQU5TUE9SVDwva2V5d29yZD48a2V5d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PC9rZXl3b3Jk

cz48ZGF0ZXM+PHllYXI+MjAwNDwveWVhcj48cHViLWRhdGVzPjxkYXRlPjExLzIwMDQ8L2RhdGU+

PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+QlVSR0VMMjAwNDwvbGFiZWw+PHVybHM+PC91cmxz

PjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [140]. Neutrophil elastase and related serine proteases from neutrophils are potent stimulants of mucus secretion, which explains the link between mucus hypersecretion (chronic bronchitis) and airway neutrophilic inflammation in normal smokers, COPD patients and some patients with severe asthma.Neural regulationNeural mechanisms may play a more important role in asthma and COPD than previously recognized, as it is difficult to measure neuronal effects directly in patients and in animal models of airway disease it is likely that anaesthesia abolishes any neuronal effects. Neuronal pathways may be activated in the airways because of sensitization of airway afferent nerves by inflammatory mediators and this may trigger cough, which is a common symptom of asthma and COPD. Autonomic motor nerves may also be activated by inflammatory mediators acting on prejunctional receptors to enhance neurotransmitter release and through enhancement of local parasympathetic ganglia in the airways. Sensory nerves may also release neuropeptides, such as substance P, which have local inflammatory effects, thus enhancing inflammation.Cholinergic pathways, through the release of acetylcholine acting on muscarinic receptors, cause bronchoconstriction and may be via a neural reflex by triggers acting on airway sensory nerves. Inflammatory mediator activation of sensory nerves, results in reflex cholinergic bronchoconstriction or release of proinflammatory neuropeptides. Cholinergic mechanisms are also mediated through the release of acetylcholine from non-neuronal cells in the airways, such as airway epithelial cells and inflammatory cells and this may be particularly important in peripheral airways, where cholinergic innervation is very sparse. Thus, anticholinergic therapy is effective in may be effective through neuronal and non-neuronal mechanisms PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXRlbWFuPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

UmVjTnVtPjEwODA3PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxNDFdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEwODA3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5OTEiPjEwODA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5CYXRlbWFuLEUuRC48L2F1dGhvcj48YXV0aG9yPlJlbm5hcmQsUy48L2F1dGhvcj48YXV0

aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5EaWNwaW5pZ2FpdGlzLFAuVi48L2F1dGhv

cj48YXV0aG9yPkdvc2VucyxSLjwvYXV0aG9yPjxhdXRob3I+R3Jvc3MsTi5KLjwvYXV0aG9yPjxh

dXRob3I+TmFkZWwsSi5BLjwvYXV0aG9yPjxhdXRob3I+UGZlaWZlcixNLjwvYXV0aG9yPjxhdXRo

b3I+UmFja2UsSy48L2F1dGhvcj48YXV0aG9yPlJhYmUsSy5GLjwvYXV0aG9yPjxhdXRob3I+UnVi

aW4sQi5LLjwvYXV0aG9yPjxhdXRob3I+V2VsdGUsVC48L2F1dGhvcj48YXV0aG9yPldlc3NsZXIs

SS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx0ZXJu

YXRpdmUgbWVjaGFuaXNtcyBmb3IgdGlvdHJvcGl1bTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Q

dWxtLlBoYXJtYWNvbCBUaGVyLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPlB1bG0uUGhhcm1hY29sIFRoZXIuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+NTMzLTU0MjwvcGFnZXM+PHZvbHVtZT4yMjwvdm9sdW1lPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPkJBU0lDPC9rZXl3b3JkPjxrZXl3b3JkPkJlbmVmaXRzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyb25jaG9kaWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5icm9uY2hvZGls

YXRvcjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMg

T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25h

cnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5E

RUNMSU5FPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUFSTFk8

L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVFM8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGSUNBQ1k8L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+

PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5WRVNUSUdBVElPTjwva2V5d29yZD48a2V5d29yZD5JTlZFU1RJR0FUSU9OUzwva2V5

d29yZD48a2V5d29yZD5MT05HIEFDVElORzwva2V5d29yZD48a2V5d29yZD5MT05HLUFDVElORzwv

a2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTTwva2V5d29y

ZD48a2V5d29yZD5NRUNIQU5JU01TPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3

b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5SQVRFPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFRFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVQT1JUPC9rZXl3b3JkPjxrZXl3b3Jk

PlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RV

RFk8L2tleXdvcmQ+PGtleXdvcmQ+dGlvdHJvcGl1bTwva2V5d29yZD48a2V5d29yZD5UUkVBVE1F

TlQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjcvMjQvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CQVRFTUFO

MjAwOTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXRlbWFuPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

UmVjTnVtPjEwODA3PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxNDFdPC9EaXNwbGF5VGV4dD48cmVj

b3JkPjxyZWMtbnVtYmVyPjEwODA3PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5OTEiPjEwODA3PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9

IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1

dGhvcj5CYXRlbWFuLEUuRC48L2F1dGhvcj48YXV0aG9yPlJlbm5hcmQsUy48L2F1dGhvcj48YXV0

aG9yPkJhcm5lcyxQLkouPC9hdXRob3I+PGF1dGhvcj5EaWNwaW5pZ2FpdGlzLFAuVi48L2F1dGhv

cj48YXV0aG9yPkdvc2VucyxSLjwvYXV0aG9yPjxhdXRob3I+R3Jvc3MsTi5KLjwvYXV0aG9yPjxh

dXRob3I+TmFkZWwsSi5BLjwvYXV0aG9yPjxhdXRob3I+UGZlaWZlcixNLjwvYXV0aG9yPjxhdXRo

b3I+UmFja2UsSy48L2F1dGhvcj48YXV0aG9yPlJhYmUsSy5GLjwvYXV0aG9yPjxhdXRob3I+UnVi

aW4sQi5LLjwvYXV0aG9yPjxhdXRob3I+V2VsdGUsVC48L2F1dGhvcj48YXV0aG9yPldlc3NsZXIs

SS48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+QWx0ZXJu

YXRpdmUgbWVjaGFuaXNtcyBmb3IgdGlvdHJvcGl1bTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5Q

dWxtLlBoYXJtYWNvbCBUaGVyLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs

PjxmdWxsLXRpdGxlPlB1bG0uUGhhcm1hY29sIFRoZXIuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNh

bD48cGFnZXM+NTMzLTU0MjwvcGFnZXM+PHZvbHVtZT4yMjwvdm9sdW1lPjxyZXByaW50LWVkaXRp

b24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSU9O

PC9rZXl3b3JkPjxrZXl3b3JkPkJBU0lDPC9rZXl3b3JkPjxrZXl3b3JkPkJlbmVmaXRzPC9rZXl3

b3JkPjxrZXl3b3JkPkJyb25jaG9kaWxhdGlvbjwva2V5d29yZD48a2V5d29yZD5icm9uY2hvZGls

YXRvcjwva2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMg

T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25h

cnkgZGlzZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5E

RUNMSU5FPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RUFSTFk8

L2tleXdvcmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVFM8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGSUNBQ1k8L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+

PGtleXdvcmQ+RVhBQ0VSQkFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVYQUNFUkJBVElPTlM8L2tl

eXdvcmQ+PGtleXdvcmQ+ZnVuY3Rpb248L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5WRVNUSUdBVElPTjwva2V5d29yZD48a2V5d29yZD5JTlZFU1RJR0FUSU9OUzwva2V5

d29yZD48a2V5d29yZD5MT05HIEFDVElORzwva2V5d29yZD48a2V5d29yZD5MT05HLUFDVElORzwv

a2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTTwva2V5d29y

ZD48a2V5d29yZD5NRUNIQU5JU01TPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3

b3JkPjxrZXl3b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5SQVRFPC9rZXl3b3JkPjxr

ZXl3b3JkPlJFRFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVQT1JUPC9rZXl3b3JkPjxrZXl3b3Jk

PlJFU0VBUkNIPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RV

RFk8L2tleXdvcmQ+PGtleXdvcmQ+dGlvdHJvcGl1bTwva2V5d29yZD48a2V5d29yZD5UUkVBVE1F

TlQ8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAwOTwveWVhcj48cHViLWRhdGVz

PjxkYXRlPjcvMjQvMjAwOTwvZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5CQVRFTUFO

MjAwOTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [141]. Long-acting muscarinic antagonists (LAMA) are effective bronchodilators in COPD and because they have equivalent bronchodilator action to long-acting β2-agonists (LABA), it is likely that cholinergic tone is the only reversible component of airway narrowing, whereas in asthma LABA are usually far more effective bronchodilators than anticholinergics, as they counteract the additional effects of bronchoconstrictor mediators, such as leukotrienes and prostaglandins. Inflammatory products may also sensitize sensory nerve endings in the airway epithelium so that the nerves become hyperalgesic. Various ion channels on sensory nerves, including transient receptor potential (TRP) channels may be important in mediating the coughing of asthma and COPD, triggered by inflammatory mediators such as prostaglandins, bradykinin and ATP as well as acitily (low pH) due to inflammation ADDIN EN.CITE <EndNote><Cite><Author>Grace</Author><Year>2014</Year><RecNum>12442</RecNum><DisplayText>[142]</DisplayText><record><rec-number>12442</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1446802883">12442</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grace, M. S.</author><author>Baxter, M.</author><author>Dubuis, E.</author><author>Birrell, M. A.</author><author>Belvisi, M. G.</author></authors></contributors><auth-address>Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK.</auth-address><titles><title>Transient receptor potential (TRP) channels in the airway: role in airway disease</title><secondary-title>Br J Pharmacol</secondary-title><alt-title>British journal of pharmacology</alt-title></titles><periodical><full-title>Br J Pharmacol</full-title></periodical><pages>2593-607</pages><volume>171</volume><number>10</number><edition>2013/11/30</edition><keywords><keyword>Animals</keyword><keyword>Anti-Asthmatic Agents/pharmacology</keyword><keyword>Asthma/drug therapy/*metabolism/physiopathology</keyword><keyword>Humans</keyword><keyword>Ligands</keyword><keyword>Lung/drug effects/*metabolism/physiopathology</keyword><keyword>Membrane Transport Modulators/pharmacology</keyword><keyword>Pulmonary Disease, Chronic Obstructive/drug therapy/*metabolism/physiopathology</keyword><keyword>Signal Transduction</keyword><keyword>Transient Receptor Potential Channels/drug effects/*metabolism</keyword><keyword>Copd</keyword><keyword>TRP channels</keyword><keyword>airway</keyword><keyword>asthma</keyword></keywords><dates><year>2014</year><pub-dates><date>May</date></pub-dates></dates><isbn>0007-1188</isbn><accession-num>24286227</accession-num><urls></urls><custom2>Pmc4009002</custom2><electronic-resource-num>10.1111/bph.12538</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[142]. Neurotrophins, such as nerve growth factor, which may be released from various cell types in airways of asthmatic patients, including epithelial cells and mast cells, may cause proliferation and sensitization of airway sensory nerves, although their role in COPD is uncertain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYXNzZW5zdGVpbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1ll

YXI+PFJlY051bT45NjY5PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxNDNdPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjk2Njk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTM3ODQ3ODk3MyI+OTY2OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+TmFzc2Vuc3RlaW4sQy48L2F1dGhvcj48YXV0aG9yPlNjaHVsdGUtSGVyYnJ1Z2dlbixP

LjwvYXV0aG9yPjxhdXRob3I+UmVueixILjwvYXV0aG9yPjxhdXRob3I+QnJhdW4sQS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmVydmUgZ3Jvd3RoIGZh

Y3RvcjogdGhlIGNlbnRyYWwgaHViIGluIHRoZSBkZXZlbG9wbWVudCBvZiBhbGxlcmdpYyBhc3Ro

bWE/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ci5KLlBoYXJtYWNvbC48L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIuSi5QaGFybWFjb2wuPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTk1LTIwNjwvcGFnZXM+PHZvbHVtZT41MzM8

L3ZvbHVtZT48bnVtYmVyPjEtMzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8

L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkFDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFM

TEVSR0lDPC9rZXl3b3JkPjxrZXl3b3JkPmFsbGVyZ2ljIGFzdGhtYTwva2V5d29yZD48a2V5d29y

ZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5DRU5U

UkFMPC9rZXl3b3JkPjxrZXl3b3JkPmNoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5jbGluaWNh

bDwva2V5d29yZD48a2V5d29yZD5ERVZFTE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNF

PC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RTPC9rZXl3

b3JkPjxrZXl3b3JkPmVtYnJ5b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RU5IQU5DRVM8L2tleXdv

cmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RVhQRVJJTUVOVEFMPC9rZXl3

b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNUT1JTPC9rZXl3b3JkPjxr

ZXl3b3JkPkdST1dUSDwva2V5d29yZD48a2V5d29yZD5Hcm93dGggZmFjdG9yPC9rZXl3b3JkPjxr

ZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29y

ZD5oeXBlcnJlYWN0aXZpdHk8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+

SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29y

ZD5JTk5FUlZBVElPTjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1B

Sk9SPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJ

U008L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPk5FUlZFPC9r

ZXl3b3JkPjxrZXl3b3JkPk5lcnZlIEdyb3d0aCBGYWN0b3I8L2tleXdvcmQ+PGtleXdvcmQ+bmVy

dmUgZ3Jvd3RoIGZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+TkVVUk9HRU5JQzwva2V5d29yZD48

a2V5d29yZD5OZXVyb2dlbmljIEluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5ORVVST05B

TDwva2V5d29yZD48a2V5d29yZD5QSFlTSU9MT0dJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9yLE5lcnZlIEdyb3d0aCBGYWN0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3IsdHJrQTwv

a2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5yZXNwaXJhdG9y

eSBzeW5jeXRpYWwgdmlydXMgaW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3

b3JkPjxrZXl3b3JkPlNZTVBUT01TPC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwva2V5

d29yZD48a2V5d29yZD5USVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VFUzwva2V5d29yZD48

a2V5d29yZD5Ub3hpY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnZpcnVzPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4zLzgvMjAwNjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5OQVNTRU5TVEVJTjIwMDY8L2xhYmVsPjx1

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYXNzZW5zdGVpbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1ll

YXI+PFJlY051bT45NjY5PC9SZWNOdW0+PERpc3BsYXlUZXh0PlsxNDNdPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjk2Njk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTM3ODQ3ODk3MyI+OTY2OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1l

PSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxh

dXRob3I+TmFzc2Vuc3RlaW4sQy48L2F1dGhvcj48YXV0aG9yPlNjaHVsdGUtSGVyYnJ1Z2dlbixP

LjwvYXV0aG9yPjxhdXRob3I+UmVueixILjwvYXV0aG9yPjxhdXRob3I+QnJhdW4sQS48L2F1dGhv

cj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+TmVydmUgZ3Jvd3RoIGZh

Y3RvcjogdGhlIGNlbnRyYWwgaHViIGluIHRoZSBkZXZlbG9wbWVudCBvZiBhbGxlcmdpYyBhc3Ro

bWE/PC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkV1ci5KLlBoYXJtYWNvbC48L3NlY29uZGFyeS10

aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5FdXIuSi5QaGFybWFjb2wuPC9m

dWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTk1LTIwNjwvcGFnZXM+PHZvbHVtZT41MzM8

L3ZvbHVtZT48bnVtYmVyPjEtMzwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8

L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPkFDVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFM

TEVSR0lDPC9rZXl3b3JkPjxrZXl3b3JkPmFsbGVyZ2ljIGFzdGhtYTwva2V5d29yZD48a2V5d29y

ZD5BbmltYWxzPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5DRU5U

UkFMPC9rZXl3b3JkPjxrZXl3b3JkPmNoZW1pc3RyeTwva2V5d29yZD48a2V5d29yZD5jbGluaWNh

bDwva2V5d29yZD48a2V5d29yZD5ERVZFTE9QTUVOVDwva2V5d29yZD48a2V5d29yZD5ESVNFQVNF

PC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVDwva2V5d29yZD48a2V5d29yZD5FRkZFQ1RTPC9rZXl3

b3JkPjxrZXl3b3JkPmVtYnJ5b2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RU5IQU5DRVM8L2tleXdv

cmQ+PGtleXdvcmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RVhQRVJJTUVOVEFMPC9rZXl3

b3JkPjxrZXl3b3JkPkZBQ1RPUjwva2V5d29yZD48a2V5d29yZD5GQUNUT1JTPC9rZXl3b3JkPjxr

ZXl3b3JkPkdST1dUSDwva2V5d29yZD48a2V5d29yZD5Hcm93dGggZmFjdG9yPC9rZXl3b3JkPjxr

ZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48a2V5d29y

ZD5oeXBlcnJlYWN0aXZpdHk8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtleXdvcmQ+

SW5mZWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPmluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29y

ZD5JTk5FUlZBVElPTjwva2V5d29yZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPk1B

Sk9SPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJ

U008L2tleXdvcmQ+PGtleXdvcmQ+TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPk5FUlZFPC9r

ZXl3b3JkPjxrZXl3b3JkPk5lcnZlIEdyb3d0aCBGYWN0b3I8L2tleXdvcmQ+PGtleXdvcmQ+bmVy

dmUgZ3Jvd3RoIGZhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+TkVVUk9HRU5JQzwva2V5d29yZD48

a2V5d29yZD5OZXVyb2dlbmljIEluZmxhbW1hdGlvbjwva2V5d29yZD48a2V5d29yZD5ORVVST05B

TDwva2V5d29yZD48a2V5d29yZD5QSFlTSU9MT0dJQ0FMPC9rZXl3b3JkPjxrZXl3b3JkPlJlY2Vw

dG9yLE5lcnZlIEdyb3d0aCBGYWN0b3I8L2tleXdvcmQ+PGtleXdvcmQ+UmVjZXB0b3IsdHJrQTwv

a2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5yZXNwaXJhdG9y

eSBzeW5jeXRpYWwgdmlydXMgaW5mZWN0aW9uczwva2V5d29yZD48a2V5d29yZD5yaXNrPC9rZXl3

b3JkPjxrZXl3b3JkPlNZTVBUT01TPC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwva2V5

d29yZD48a2V5d29yZD5USVNTVUU8L2tleXdvcmQ+PGtleXdvcmQ+VElTU1VFUzwva2V5d29yZD48

a2V5d29yZD5Ub3hpY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPnZpcnVzPC9rZXl3b3JkPjwva2V5

d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDY8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4zLzgvMjAwNjwv

ZGF0ZT48L3B1Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5OQVNTRU5TVEVJTjIwMDY8L2xhYmVsPjx1

cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [143]. As indicated above, airway nerves may also release neurotransmitters, such as substance P, which have proinflammatory effects, bit the role of neurogenic inflammation in asthma and COPD is uncertain as blocker of receptors for substance P and other neurokinins have provided no clinical benefit in airway disease.FibrosisAirway fibrosis is seen in asthma and COPD and represents aberrant repair in response to persistence epithelial injury. In all asthmatic patients, the basement membrane is apparently thickened due to subepithelial fibrosis with deposition of types III and V collagen below the true basement membrane and is associated with eosinophil infiltration, presumably through the release of profibrotic mediators, such as TGF-β secreted from epithelial cells. Mechanical manipulations can alter the phenotype of airway epithelial cells in a profibrotic fashion. In more severe patients, there is also fibrosis within the airway wall, which may contribute to irreversible narrowing of the airways.Increasing small airway (peribronchiolar) fibrosis is an important mechanism of disease progression in COPD and is presumed to result from chronic inflammation, suggesting that effective anti-inflammatory treatments should prevent fibrosis. Fibrosis may be mediated via the activation of fibroblasts in small airways by fibrogenic mediators, such as TGFβ, connective tissue growth factor (CTGF) and endothelin, secreted from epithelial cells and macrophages PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBCb2VyPC9BdXRob3I+PFllYXI+MTk5ODwvWWVhcj48

UmVjTnVtPjc4MTE8L1JlY051bT48RGlzcGxheVRleHQ+WzE0NF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+NzgxMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQyIj43ODExPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5kZSBCb2VyLFcuSS48L2F1dGhvcj48YXV0aG9yPnZhbiBTY2hhZGV3aWprLEEuPC9hdXRob3I+

PGF1dGhvcj5Tb250LEouSy48L2F1dGhvcj48YXV0aG9yPlNoYXJtYSxILlMuPC9hdXRob3I+PGF1

dGhvcj5TdG9sayxKLjwvYXV0aG9yPjxhdXRob3I+SGllbXN0cmEsUC5TLjwvYXV0aG9yPjxhdXRo

b3I+dmFuIEtyaWVrZW4sSi5ILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0

bGVzPjx0aXRsZT5UcmFuc2Zvcm1pbmcgZ3Jvd3RoIGZhY3RvciBiZXRhMSBhbmQgcmVjcnVpdG1l

bnQgb2YgbWFjcm9waGFnZXMgYW5kIG1hc3QgY2VsbHMgaW4gYWlyd2F5cyBpbiBjaHJvbmljIG9i

c3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEog

UmVzcGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+MTk1MS0xOTU3PC9wYWdlcz48dm9sdW1lPjE1ODwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlv

bj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklU

WTwva2V5d29yZD48a2V5d29yZD5BRFVMVDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9rZXl3b3JkPjxrZXl3

b3JkPkFMVkVPTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3Jk

PkJFVEE8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNISTwva2V5d29yZD48a2V5d29yZD5DRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdv

cmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hlbW90YXhpczwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5D

T1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VB

U0U8L2tleXdvcmQ+PGtleXdvcmQ+RVBJVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lcGl0aGVs

aWFsIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+

RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+RkVB

VFVSRVM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZFVjE8L2tl

eXdvcmQ+PGtleXdvcmQ+Rm9yY2VkIEV4cGlyYXRvcnkgVm9sdW1lPC9rZXl3b3JkPjxrZXl3b3Jk

PkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkVUSUNTPC9r

ZXl3b3JkPjxrZXl3b3JkPkdST1dUSDwva2V5d29yZD48a2V5d29yZD5Hcm93dGggZmFjdG9yPC9r

ZXl3b3JkPjxrZXl3b3JkPmh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkhZQlJJRElaQVRJT048L2tl

eXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SU48

L2tleXdvcmQ+PGtleXdvcmQ+SW4gU2l0dSBIeWJyaWRpemF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+SU5GTFVYPC9rZXl3b3JkPjxrZXl3b3JkPklOVFJBRVBJVEhFTElBTDwva2V5d29yZD48a2V5

d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXMsb2JzdHJ1Y3RpdmU8L2tl

eXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwv

a2V5d29yZD48a2V5d29yZD5tYWNyb3BoYWdlcyxhbHZlb2xhcjwva2V5d29yZD48a2V5d29yZD5N

QUxFPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVTU0VOR0VSPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2U8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwva2V5d29y

ZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+bXVzY2xlLHNtb290aCx2YXNjdWxh

cjwva2V5d29yZD48a2V5d29yZD5OVU1CRVJTPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZF

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9HWTwva2V5d29yZD48a2V5d29yZD5QQVRURVJOUzwv

a2V5d29yZD48a2V5d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBST1RF

SU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPnB1bG1vbmFy

eSBhbHZlb2xpPC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJl

Y2VwdG9yczwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsVHJhbnNmb3JtaW5nIEdyb3d0aCBG

YWN0b3IgYmV0YTwva2V5d29yZD48a2V5d29yZD5STkE8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLE1l

c3Nlbmdlcjwva2V5d29yZD48a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNJVFU8L2tl

eXdvcmQ+PGtleXdvcmQ+U01PS0lORzwva2V5d29yZD48a2V5d29yZD5TTU9PVEg8L2tleXdvcmQ+

PGtleXdvcmQ+U21vb3RoIG11c2NsZTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3Jk

PjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3

b3JkPnN1cHBvcnQsbm9uLXUucy5nb3YmYXBvczt0PC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRTwv

a2V5d29yZD48a2V5d29yZD5UcmFuc2Zvcm1pbmcgR3Jvd3RoIEZhY3RvciBiZXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3b3JkPjxrZXl3b3Jk

PlVOSVRFRCBTVEFURVM8L2tleXdvcmQ+PGtleXdvcmQ+VkFTQ1VMQVI8L2tleXdvcmQ+PGtleXdv

cmQ+VmFzY3VsYXIgc21vb3RoIG11c2NsZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4xOTk4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMTk5ODwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5ERUJPRVIxOTk4QTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBCb2VyPC9BdXRob3I+PFllYXI+MTk5ODwvWWVhcj48

UmVjTnVtPjc4MTE8L1JlY051bT48RGlzcGxheVRleHQ+WzE0NF08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+NzgxMTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJF

TiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1w

PSIxMzc4NDc4OTQyIj43ODExPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9Ikpv

dXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhv

cj5kZSBCb2VyLFcuSS48L2F1dGhvcj48YXV0aG9yPnZhbiBTY2hhZGV3aWprLEEuPC9hdXRob3I+

PGF1dGhvcj5Tb250LEouSy48L2F1dGhvcj48YXV0aG9yPlNoYXJtYSxILlMuPC9hdXRob3I+PGF1

dGhvcj5TdG9sayxKLjwvYXV0aG9yPjxhdXRob3I+SGllbXN0cmEsUC5TLjwvYXV0aG9yPjxhdXRo

b3I+dmFuIEtyaWVrZW4sSi5ILjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0

bGVzPjx0aXRsZT5UcmFuc2Zvcm1pbmcgZ3Jvd3RoIGZhY3RvciBiZXRhMSBhbmQgcmVjcnVpdG1l

bnQgb2YgbWFjcm9waGFnZXMgYW5kIG1hc3QgY2VsbHMgaW4gYWlyd2F5cyBpbiBjaHJvbmljIG9i

c3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEog

UmVzcGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNh

bD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVy

aW9kaWNhbD48cGFnZXM+MTk1MS0xOTU3PC9wYWdlcz48dm9sdW1lPjE1ODwvdm9sdW1lPjxudW1i

ZXI+NjwvbnVtYmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlv

bj48a2V5d29yZHM+PGtleXdvcmQ+QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklU

WTwva2V5d29yZD48a2V5d29yZD5BRFVMVDwva2V5d29yZD48a2V5d29yZD5BZ2VkPC9rZXl3b3Jk

PjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3YXlzPC9rZXl3b3JkPjxrZXl3

b3JkPkFMVkVPTEFSPC9rZXl3b3JkPjxrZXl3b3JkPkFOQUxZU0lTPC9rZXl3b3JkPjxrZXl3b3Jk

PkJFVEE8L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNISTwva2V5d29yZD48a2V5d29yZD5DRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPkNlbGwgQ291bnQ8L2tleXdvcmQ+PGtleXdvcmQ+Q0VMTFM8L2tleXdv

cmQ+PGtleXdvcmQ+Q0hFTU9UQUNUSUM8L2tleXdvcmQ+PGtleXdvcmQ+Q2hlbW90YXhpczwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5Db21wYXJhdGl2ZSBTdHVkeTwva2V5d29yZD48a2V5d29yZD5D

T1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlJFTEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VB

U0U8L2tleXdvcmQ+PGtleXdvcmQ+RVBJVEhFTElBTDwva2V5d29yZD48a2V5d29yZD5lcGl0aGVs

aWFsIGNlbGxzPC9rZXl3b3JkPjxrZXl3b3JkPkVwaXRoZWxpdW08L2tleXdvcmQ+PGtleXdvcmQ+

RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdvcmQ+RkVB

VFVSRVM8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkZFVjE8L2tl

eXdvcmQ+PGtleXdvcmQ+Rm9yY2VkIEV4cGlyYXRvcnkgVm9sdW1lPC9rZXl3b3JkPjxrZXl3b3Jk

PkdlbmUgRXhwcmVzc2lvbiBSZWd1bGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkdFTkVUSUNTPC9r

ZXl3b3JkPjxrZXl3b3JkPkdST1dUSDwva2V5d29yZD48a2V5d29yZD5Hcm93dGggZmFjdG9yPC9r

ZXl3b3JkPjxrZXl3b3JkPmh1bWFuPC9rZXl3b3JkPjxrZXl3b3JkPkhZQlJJRElaQVRJT048L2tl

eXdvcmQ+PGtleXdvcmQ+SW1tdW5vaGlzdG9jaGVtaXN0cnk8L2tleXdvcmQ+PGtleXdvcmQ+SU48

L2tleXdvcmQ+PGtleXdvcmQ+SW4gU2l0dSBIeWJyaWRpemF0aW9uPC9rZXl3b3JkPjxrZXl3b3Jk

PklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+SU5GTFVYPC9rZXl3b3JkPjxrZXl3b3JkPklOVFJBRVBJVEhFTElBTDwva2V5d29yZD48a2V5

d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgZGlzZWFzZXMsb2JzdHJ1Y3RpdmU8L2tl

eXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwv

a2V5d29yZD48a2V5d29yZD5tYWNyb3BoYWdlcyxhbHZlb2xhcjwva2V5d29yZD48a2V5d29yZD5N

QUxFPC9rZXl3b3JkPjxrZXl3b3JkPk1BU1Q8L2tleXdvcmQ+PGtleXdvcmQ+TUFTVCBDRUxMPC9r

ZXl3b3JkPjxrZXl3b3JkPm1hc3QgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+TUVTU0VOR0VSPC9r

ZXl3b3JkPjxrZXl3b3JkPk1pZGRsZSBBZ2U8L2tleXdvcmQ+PGtleXdvcmQ+bVJOQTwva2V5d29y

ZD48a2V5d29yZD5NVVNDTEU8L2tleXdvcmQ+PGtleXdvcmQ+bXVzY2xlLHNtb290aCx2YXNjdWxh

cjwva2V5d29yZD48a2V5d29yZD5OVU1CRVJTPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZF

PC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPTE9HWTwva2V5d29yZD48a2V5d29yZD5QQVRURVJOUzwv

a2V5d29yZD48a2V5d29yZD5QRVJJUEhFUkFMPC9rZXl3b3JkPjxrZXl3b3JkPnBoeXNpb2xvZ3k8

L2tleXdvcmQ+PGtleXdvcmQ+cGh5c2lvcGF0aG9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBST1RF

SU48L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPnB1bG1vbmFy

eSBhbHZlb2xpPC9rZXl3b3JkPjxrZXl3b3JkPnJlY2VwdG9yPC9rZXl3b3JkPjxrZXl3b3JkPlJl

Y2VwdG9yczwva2V5d29yZD48a2V5d29yZD5SZWNlcHRvcnMsVHJhbnNmb3JtaW5nIEdyb3d0aCBG

YWN0b3IgYmV0YTwva2V5d29yZD48a2V5d29yZD5STkE8L2tleXdvcmQ+PGtleXdvcmQ+Uk5BLE1l

c3Nlbmdlcjwva2V5d29yZD48a2V5d29yZD5ST0xFPC9rZXl3b3JkPjxrZXl3b3JkPlNJVFU8L2tl

eXdvcmQ+PGtleXdvcmQ+U01PS0lORzwva2V5d29yZD48a2V5d29yZD5TTU9PVEg8L2tleXdvcmQ+

PGtleXdvcmQ+U21vb3RoIG11c2NsZTwva2V5d29yZD48a2V5d29yZD5TVFVESUVTPC9rZXl3b3Jk

PjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3JkPlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3

b3JkPnN1cHBvcnQsbm9uLXUucy5nb3YmYXBvczt0PC9rZXl3b3JkPjxrZXl3b3JkPlRJU1NVRTwv

a2V5d29yZD48a2V5d29yZD5UcmFuc2Zvcm1pbmcgR3Jvd3RoIEZhY3RvciBiZXRhPC9rZXl3b3Jk

PjxrZXl3b3JkPlRZUEU8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3b3JkPjxrZXl3b3Jk

PlVOSVRFRCBTVEFURVM8L2tleXdvcmQ+PGtleXdvcmQ+VkFTQ1VMQVI8L2tleXdvcmQ+PGtleXdv

cmQ+VmFzY3VsYXIgc21vb3RoIG11c2NsZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVh

cj4xOTk4PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTIvMTk5ODwvZGF0ZT48L3B1Yi1kYXRlcz48

L2RhdGVzPjxsYWJlbD5ERUJPRVIxOTk4QTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwv

Q2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [144]. Small airway fibrosis appears to be an early lesion in the development of COPD and usually precedes the development of emphysema PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0Rvbm91Z2g8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

PjxSZWNOdW0+MTE0NDE8L1JlY051bT48RGlzcGxheVRleHQ+WzE5LCAyMF08L0Rpc3BsYXlUZXh0

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE0NDE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRp

bWVzdGFtcD0iMTM3ODQ3OTAwMSI+MTE0NDE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPk1jRG9ub3VnaCxKLkUuPC9hdXRob3I+PGF1dGhvcj5ZdWFuLFIuPC9hdXRob3I+

PGF1dGhvcj5TdXp1a2ksTS48L2F1dGhvcj48YXV0aG9yPlNleWVkbmVqYWQsTi48L2F1dGhvcj48

YXV0aG9yPkVsbGlvdHQsVy5NLjwvYXV0aG9yPjxhdXRob3I+U2FuY2hleixQLkcuPC9hdXRob3I+

PGF1dGhvcj5XcmlnaHQsQS5DLjwvYXV0aG9yPjxhdXRob3I+R2VmdGVyLFcuQi48L2F1dGhvcj48

YXV0aG9yPkxpdHpreSxMLjwvYXV0aG9yPjxhdXRob3I+Q294c29uLEguTy48L2F1dGhvcj48YXV0

aG9yPlBhcmUsUC5ELjwvYXV0aG9yPjxhdXRob3I+U2luLEQuRC48L2F1dGhvcj48YXV0aG9yPlBp

ZXJjZSxSLkEuPC9hdXRob3I+PGF1dGhvcj5Xb29kcyxKLkMuPC9hdXRob3I+PGF1dGhvcj5NY1dp

bGxpYW1zLEEuTS48L2F1dGhvcj48YXV0aG9yPk1heW8sSi5SLjwvYXV0aG9yPjxhdXRob3I+TGFt

LFMuQy48L2F1dGhvcj48YXV0aG9yPkNvb3BlcixKLkQuPC9hdXRob3I+PGF1dGhvcj5Ib2dnLEou

Qy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U21hbGwt

YWlyd2F5IG9ic3RydWN0aW9uIGFuZCBlbXBoeXNlbWEgaW4gY2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OLkVuZ2wuSiBNZWQuPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Ti5FbmdsLkog

TWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE1NjctMTU3NTwvcGFnZXM+PHZv

bHVtZT4zNjU8L3ZvbHVtZT48bnVtYmVyPjE3PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3Qg

aW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4xPC9rZXl3b3JkPjxr

ZXl3b3JkPjI8L2tleXdvcmQ+PGtleXdvcmQ+Mzwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tl

eXdvcmQ+PGtleXdvcmQ+QWlyd2F5IFJlc2lzdGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5

czwva2V5d29yZD48a2V5d29yZD5CTE9PRDwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpb2xlczwv

a2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJV

Q1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRSBMVU5HIERJU0VBU0U8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5DT01QQVJJU09OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ESU1FTlNJT05TPC9rZXl3b3Jk

PjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RU1QSFlTRU1BPC9rZXl3b3JkPjxr

ZXl3b3JkPmdsb2JhbDwva2V5d29yZD48a2V5d29yZD5HT0xEPC9rZXl3b3JkPjxrZXl3b3JkPkhF

QVJUPC9rZXl3b3JkPjxrZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JU09MQVRFRDwva2V5d29y

ZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgdHJhbnNwbGFudGF0aW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPkxVTkdTPC9rZXl3b3JkPjxrZXl3b3JkPk1BSk9SPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FQVNVUkU8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TkFSUk9XSU5HPC9rZXl3b3JkPjxrZXl3b3JkPk5B

VElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPk9C

U1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBF

UklQSEVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlJF

RFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlJFTEFU

SU9OU0hJUDwva2V5d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SRVNJ

U1RBTkNFPC9rZXl3b3JkPjxrZXl3b3JkPlNDQUxFPC9rZXl3b3JkPjxrZXl3b3JkPlNJVEVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlNNQUxMPC9rZXl3b3JkPjxrZXl3b3JkPlRPTU9HUkFQSFk8L2tleXdv

cmQ+PGtleXdvcmQ+VFJBTlNQTEFOVEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlZhbmNvdXZlcjwv

a2V5d29yZD48a2V5d29yZD5WT0xVTUU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjEwLzI3LzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48bGFiZWw+TUNET05PVUdIMjAxMTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkdhbGJhbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTczNzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE3Mzc8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpk

c2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3OTAwNiI+MTE3Mzc8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdhbGJhbixDLkouPC9hdXRob3I+PGF1dGhvcj5I

YW4sTS5LLjwvYXV0aG9yPjxhdXRob3I+Qm9lcyxKLkwuPC9hdXRob3I+PGF1dGhvcj5DaHVnaHRh

aSxLLkEuPC9hdXRob3I+PGF1dGhvcj5NZXllcixDLlIuPC9hdXRob3I+PGF1dGhvcj5Kb2huc29u

LFQuRC48L2F1dGhvcj48YXV0aG9yPkdhbGJhbixTLjwvYXV0aG9yPjxhdXRob3I+UmVoZW10dWxs

YSxBLjwvYXV0aG9yPjxhdXRob3I+S2F6ZXJvb25pLEUuQS48L2F1dGhvcj48YXV0aG9yPk1hcnRp

bmV6LEYuSi48L2F1dGhvcj48YXV0aG9yPlJvc3MsQi5ELjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Db21wdXRlZCB0b21vZ3JhcGh5LWJhc2VkIGJpb21h

cmtlciBwcm92aWRlcyB1bmlxdWUgc2lnbmF0dXJlIGZvciBkaWFnbm9zaXMgb2YgQ09QRCBwaGVu

b3R5cGVzIGFuZCBkaXNlYXNlIHByb2dyZXNzaW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5h

dCBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

TmF0IE1lZC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNzExLTE3MTU8L3BhZ2Vz

Pjx2b2x1bWU+MTg8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5O

b3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BSVJXQVk8L2tl

eXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29y

ZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3Jk

PjxrZXl3b3JkPkRFVEVDVElPTjwva2V5d29yZD48a2V5d29yZD5ESUFHTk9TSVM8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5kaXNlYXNlIHByb2dyZXNzaW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPkRJU1RSSUJVVElPTjwva2V5d29yZD48a2V5d29yZD5FTVBIWVNFTUE8

L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RlVOQ1RJT05BTDwv

a2V5d29yZD48a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5taWNoaWdhbjwv

a2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwv

a2V5d29yZD48a2V5d29yZD5QSEVOT1RZUEU8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9r

ZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3

b3JkPjxrZXl3b3JkPlNNQUxMPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxr

ZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+

U1VCVFlQRTwva2V5d29yZD48a2V5d29yZD5zdWJ0eXBlczwva2V5d29yZD48a2V5d29yZD5UT01P

R1JBUEhZPC9rZXl3b3JkPjxrZXl3b3JkPlRSRUFUTUVOVDwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5HQUxCQU4yMDEyPC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0Rvbm91Z2g8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

PjxSZWNOdW0+MTE0NDE8L1JlY051bT48RGlzcGxheVRleHQ+WzE5LCAyMF08L0Rpc3BsYXlUZXh0

PjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE0NDE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5

IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRp

bWVzdGFtcD0iMTM3ODQ3OTAwMSI+MTE0NDE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUg

bmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9y

cz48YXV0aG9yPk1jRG9ub3VnaCxKLkUuPC9hdXRob3I+PGF1dGhvcj5ZdWFuLFIuPC9hdXRob3I+

PGF1dGhvcj5TdXp1a2ksTS48L2F1dGhvcj48YXV0aG9yPlNleWVkbmVqYWQsTi48L2F1dGhvcj48

YXV0aG9yPkVsbGlvdHQsVy5NLjwvYXV0aG9yPjxhdXRob3I+U2FuY2hleixQLkcuPC9hdXRob3I+

PGF1dGhvcj5XcmlnaHQsQS5DLjwvYXV0aG9yPjxhdXRob3I+R2VmdGVyLFcuQi48L2F1dGhvcj48

YXV0aG9yPkxpdHpreSxMLjwvYXV0aG9yPjxhdXRob3I+Q294c29uLEguTy48L2F1dGhvcj48YXV0

aG9yPlBhcmUsUC5ELjwvYXV0aG9yPjxhdXRob3I+U2luLEQuRC48L2F1dGhvcj48YXV0aG9yPlBp

ZXJjZSxSLkEuPC9hdXRob3I+PGF1dGhvcj5Xb29kcyxKLkMuPC9hdXRob3I+PGF1dGhvcj5NY1dp

bGxpYW1zLEEuTS48L2F1dGhvcj48YXV0aG9yPk1heW8sSi5SLjwvYXV0aG9yPjxhdXRob3I+TGFt

LFMuQy48L2F1dGhvcj48YXV0aG9yPkNvb3BlcixKLkQuPC9hdXRob3I+PGF1dGhvcj5Ib2dnLEou

Qy48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+U21hbGwt

YWlyd2F5IG9ic3RydWN0aW9uIGFuZCBlbXBoeXNlbWEgaW4gY2hyb25pYyBvYnN0cnVjdGl2ZSBw

dWxtb25hcnkgZGlzZWFzZTwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5OLkVuZ2wuSiBNZWQuPC9z

ZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Ti5FbmdsLkog

TWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE1NjctMTU3NTwvcGFnZXM+PHZv

bHVtZT4zNjU8L3ZvbHVtZT48bnVtYmVyPjE3PC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5Ob3Qg

aW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD4xPC9rZXl3b3JkPjxr

ZXl3b3JkPjI8L2tleXdvcmQ+PGtleXdvcmQ+Mzwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tl

eXdvcmQ+PGtleXdvcmQ+QWlyd2F5IFJlc2lzdGFuY2U8L2tleXdvcmQ+PGtleXdvcmQ+QWlyd2F5

czwva2V5d29yZD48a2V5d29yZD5CTE9PRDwva2V5d29yZD48a2V5d29yZD5Ccm9uY2hpb2xlczwv

a2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJV

Q1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRSBMVU5HIERJU0VBU0U8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5DT01QQVJJU09OPC9rZXl3b3JkPjxrZXl3b3JkPkNPTlRST0w8L2tl

eXdvcmQ+PGtleXdvcmQ+Q09QRDwva2V5d29yZD48a2V5d29yZD5ESU1FTlNJT05TPC9rZXl3b3Jk

PjxrZXl3b3JkPkRJU0VBU0U8L2tleXdvcmQ+PGtleXdvcmQ+RU1QSFlTRU1BPC9rZXl3b3JkPjxr

ZXl3b3JkPmdsb2JhbDwva2V5d29yZD48a2V5d29yZD5HT0xEPC9rZXl3b3JkPjxrZXl3b3JkPkhF

QVJUPC9rZXl3b3JkPjxrZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPklOPC9rZXl3

b3JkPjxrZXl3b3JkPklOQ1JFQVNFRDwva2V5d29yZD48a2V5d29yZD5JU09MQVRFRDwva2V5d29y

ZD48a2V5d29yZD5MdW5nPC9rZXl3b3JkPjxrZXl3b3JkPmx1bmcgdHJhbnNwbGFudGF0aW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPkxVTkdTPC9rZXl3b3JkPjxrZXl3b3JkPk1BSk9SPC9rZXl3b3JkPjxr

ZXl3b3JkPk1FQVNVUkU8L2tleXdvcmQ+PGtleXdvcmQ+TUVUSE9EPC9rZXl3b3JkPjxrZXl3b3Jk

Pk1ldGhvZHM8L2tleXdvcmQ+PGtleXdvcmQ+TkFSUk9XSU5HPC9rZXl3b3JkPjxrZXl3b3JkPk5B

VElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPk9C

U1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPlBBVElFTlRTPC9rZXl3b3JkPjxrZXl3b3JkPlBF

UklQSEVSQUw8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9rZXl3b3JkPjxrZXl3b3JkPlJF

RFVDRUQ8L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlJFTEFU

SU9OU0hJUDwva2V5d29yZD48a2V5d29yZD5SRVNFQVJDSDwva2V5d29yZD48a2V5d29yZD5SRVNJ

U1RBTkNFPC9rZXl3b3JkPjxrZXl3b3JkPlNDQUxFPC9rZXl3b3JkPjxrZXl3b3JkPlNJVEVTPC9r

ZXl3b3JkPjxrZXl3b3JkPlNNQUxMPC9rZXl3b3JkPjxrZXl3b3JkPlRPTU9HUkFQSFk8L2tleXdv

cmQ+PGtleXdvcmQ+VFJBTlNQTEFOVEFUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPlZhbmNvdXZlcjwv

a2V5d29yZD48a2V5d29yZD5WT0xVTUU8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+

MjAxMTwveWVhcj48cHViLWRhdGVzPjxkYXRlPjEwLzI3LzIwMTE8L2RhdGU+PC9wdWItZGF0ZXM+

PC9kYXRlcz48bGFiZWw+TUNET05PVUdIMjAxMTwvbGFiZWw+PHVybHM+PC91cmxzPjwvcmVjb3Jk

PjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkdhbGJhbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

Y051bT4xMTczNzwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTE3Mzc8L3JlYy1udW1iZXI+

PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpk

c2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTM3ODQ3OTAwNiI+MTE3Mzc8L2tleT48L2ZvcmVp

Z24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNv

bnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPkdhbGJhbixDLkouPC9hdXRob3I+PGF1dGhvcj5I

YW4sTS5LLjwvYXV0aG9yPjxhdXRob3I+Qm9lcyxKLkwuPC9hdXRob3I+PGF1dGhvcj5DaHVnaHRh

aSxLLkEuPC9hdXRob3I+PGF1dGhvcj5NZXllcixDLlIuPC9hdXRob3I+PGF1dGhvcj5Kb2huc29u

LFQuRC48L2F1dGhvcj48YXV0aG9yPkdhbGJhbixTLjwvYXV0aG9yPjxhdXRob3I+UmVoZW10dWxs

YSxBLjwvYXV0aG9yPjxhdXRob3I+S2F6ZXJvb25pLEUuQS48L2F1dGhvcj48YXV0aG9yPk1hcnRp

bmV6LEYuSi48L2F1dGhvcj48YXV0aG9yPlJvc3MsQi5ELjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv

bnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Db21wdXRlZCB0b21vZ3JhcGh5LWJhc2VkIGJpb21h

cmtlciBwcm92aWRlcyB1bmlxdWUgc2lnbmF0dXJlIGZvciBkaWFnbm9zaXMgb2YgQ09QRCBwaGVu

b3R5cGVzIGFuZCBkaXNlYXNlIHByb2dyZXNzaW9uPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPk5h

dCBNZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+

TmF0IE1lZC48L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz4xNzExLTE3MTU8L3BhZ2Vz

Pjx2b2x1bWU+MTg8L3ZvbHVtZT48bnVtYmVyPjExPC9udW1iZXI+PHJlcHJpbnQtZWRpdGlvbj5O

b3QgaW4gRmlsZTwvcmVwcmludC1lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5BSVJXQVk8L2tl

eXdvcmQ+PGtleXdvcmQ+QWlyd2F5czwva2V5d29yZD48a2V5d29yZD5BTkFMWVNJUzwva2V5d29y

ZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJVkU8

L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFzZTwv

a2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3Jk

PjxrZXl3b3JkPkRFVEVDVElPTjwva2V5d29yZD48a2V5d29yZD5ESUFHTk9TSVM8L2tleXdvcmQ+

PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5kaXNlYXNlIHByb2dyZXNzaW9uPC9r

ZXl3b3JkPjxrZXl3b3JkPkRJU1RSSUJVVElPTjwva2V5d29yZD48a2V5d29yZD5FTVBIWVNFTUE8

L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RlVOQ1RJT05BTDwv

a2V5d29yZD48a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5taWNoaWdhbjwv

a2V5d29yZD48a2V5d29yZD5PQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwv

a2V5d29yZD48a2V5d29yZD5QSEVOT1RZUEU8L2tleXdvcmQ+PGtleXdvcmQ+UFVMTU9OQVJZPC9r

ZXl3b3JkPjxrZXl3b3JkPlJFU1BPTlNFPC9rZXl3b3JkPjxrZXl3b3JkPlNFVkVSSVRZPC9rZXl3

b3JkPjxrZXl3b3JkPlNNQUxMPC9rZXl3b3JkPjxrZXl3b3JkPlNQRUNJRklDPC9rZXl3b3JkPjxr

ZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RVRFk8L2tleXdvcmQ+PGtleXdvcmQ+

U1VCVFlQRTwva2V5d29yZD48a2V5d29yZD5zdWJ0eXBlczwva2V5d29yZD48a2V5d29yZD5UT01P

R1JBUEhZPC9rZXl3b3JkPjxrZXl3b3JkPlRSRUFUTUVOVDwva2V5d29yZD48L2tleXdvcmRzPjxk

YXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+MTEvMjAxMjwvZGF0ZT48L3B1

Yi1kYXRlcz48L2RhdGVzPjxsYWJlbD5HQUxCQU4yMDEyPC9sYWJlbD48dXJscz48L3VybHM+PC9y

ZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [19, 20]. The persistence of fibrosis leads to irreversible airway narrowing, particularly in COPD and may reflect a failure to resolve inflammation that is seen in both diseases. The mechanisms for failure to resolve inflammation, even when the causal mechanisms, such as allergen, occupational sensitizers and smoking are not understood. Resolution of inflammation is an active process that may be facilitated by several endogenous pro-resolving mediators, including lipoxins, E-series resolvins, D-series protectins and maresins, all of which are derived from poly-unsaturated fatty acids and act on distinct receptors ADDIN EN.CITE <EndNote><Cite><Author>Serhan</Author><Year>2014</Year><RecNum>12117</RecNum><DisplayText>[145]</DisplayText><record><rec-number>12117</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1416935836">12117</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Serhan, C. N.</author></authors></contributors><auth-address>Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women&apos;s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.</auth-address><titles><title>Pro-resolving lipid mediators are leads for resolution physiology</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title></periodical><alt-periodical><full-title>Nature</full-title></alt-periodical><pages>92-101</pages><volume>510</volume><number>7503</number><edition>2014/06/06</edition><keywords><keyword>Animals</keyword><keyword>Chronic Disease</keyword><keyword>Docosahexaenoic Acids/metabolism</keyword><keyword>Fatty Acids, Omega-3/*metabolism</keyword><keyword>Fatty Acids, Unsaturated/metabolism</keyword><keyword>Humans</keyword><keyword>Immunity</keyword><keyword>Infection/metabolism</keyword><keyword>Inflammation/drug therapy/*metabolism/pathology</keyword><keyword>Inflammation Mediators/*metabolism/therapeutic use</keyword><keyword>Models, Biological</keyword><keyword>Pain/metabolism</keyword><keyword>Regeneration</keyword><keyword>Translational Medical Research</keyword><keyword>Wound Healing</keyword></keywords><dates><year>2014</year><pub-dates><date>Jun 5</date></pub-dates></dates><isbn>0028-0836</isbn><accession-num>24899309</accession-num><urls></urls><electronic-resource-num>10.1038/nature13479</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[145]. These mediators promote the resolution of neutrophilic inflammation by preventing neutrophil recruitment and enhancing neutrophil removal by efferocytosis. Maresin-1 is the most potent pro-resolving mediator that stimulates macrophage efferocytosis so a stable analogue of this mediator may be useful in COPD PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXJoYW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MTE1Mzk8L1JlY051bT48RGlzcGxheVRleHQ+WzE0Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE1Mzk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMyI+MTE1Mzk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlNlcmhhbixDLk4uPC9hdXRob3I+PGF1dGhvcj5ZYW5nLFIuPC9hdXRob3I+PGF1dGhvcj5N

YXJ0aW5vZCxLLjwvYXV0aG9yPjxhdXRob3I+S2FzdWdhLEsuPC9hdXRob3I+PGF1dGhvcj5QaWxs

YWksUC5TLjwvYXV0aG9yPjxhdXRob3I+UG9ydGVyLFQuRi48L2F1dGhvcj48YXV0aG9yPk9oLFMu

Ri48L2F1dGhvcj48YXV0aG9yPlNwaXRlLE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPk1hcmVzaW5zOiBub3ZlbCBtYWNyb3BoYWdlIG1lZGlhdG9ycyB3

aXRoIHBvdGVudCBhbnRpaW5mbGFtbWF0b3J5IGFuZCBwcm9yZXNvbHZpbmcgYWN0aW9uczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KLkV4cC5NZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Si5FeHAuTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjE1LTIzPC9wYWdlcz48dm9sdW1lPjIwNjwvdm9sdW1lPjxudW1iZXI+MTwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QUNJRDwva2V5d29yZD48a2V5d29yZD5BQ1RJT048L2tleXdvcmQ+PGtleXdv

cmQ+QUNUSU9OUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+

QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5B

Q1VURTwva2V5d29yZD48a2V5d29yZD5hbmFsb2dzICZhbXA7IGRlcml2YXRpdmVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS1pbmZsYW1tYXRvcnkgYWdl

bnRzLG5vbi1zdGVyb2lkYWw8L2tleXdvcmQ+PGtleXdvcmQ+QXV0YWNvaWRzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJJT0xPR0lDQUw8L2tleXdvcmQ+PGtleXdvcmQ+Qmlvc3ludGhlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJvc3Rvbjwva2V5d29yZD48a2V5d29yZD5DZWxsIE1vdmVtZW50PC9rZXl3b3Jk

PjxrZXl3b3JkPkNFTExVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPmNoYXJhY3Rlcml6YXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+Y2hlbWljYWxseSBpbmR1Y2VkPC9rZXl3b3JkPjxrZXl3b3JkPmNoZW1p

c3RyeTwva2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPmN5dG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkRpbm9wcm9zdG9uZTwva2V5d29yZD48a2V5d29yZD5Eb2Nvc2Fo

ZXhhZW5vaWMgQWNpZHM8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPkVpY29zYXBlbnRhZW5vaWMgQWNpZDwva2V5d29yZD48a2V5d29yZD5FTkRPR0VOT1VT

PC9rZXl3b3JkPjxrZXl3b3JkPkVOSEFOQ0VTPC9rZXl3b3JkPjxrZXl3b3JkPkVYUEVSSU1FTlRB

TDwva2V5d29yZD48a2V5d29yZD5FWFVEQVRFUzwva2V5d29yZD48a2V5d29yZD5HRU5FVElDUzwv

a2V5d29yZD48a2V5d29yZD5Ib21lb3N0YXNpczwva2V5d29yZD48a2V5d29yZD5IT1NQSVRBTDwv

a2V5d29yZD48a2V5d29yZD5IT1NUPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48

a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+SW5mbGFtbWF0aW9uIE1lZGlhdG9yczwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8

L2tleXdvcmQ+PGtleXdvcmQ+aW5qdXJpZXM8L2tleXdvcmQ+PGtleXdvcmQ+SU5KVVJZPC9rZXl3

b3JkPjxrZXl3b3JkPmxldWtvY3l0ZXMsbW9ub251Y2xlYXI8L2tleXdvcmQ+PGtleXdvcmQ+TGlw

aWQgTWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5MSVBPWFlHRU5BU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48

a2V5d29yZD5tYWNyb3BoYWdlcyxwZXJpdG9uZWFsPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklT

TTwva2V5d29yZD48a2V5d29yZD5NRUNIQU5JU01TPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElBVE9S

PC9rZXl3b3JkPjxrZXl3b3JkPm1lZGlhdG9yczwva2V5d29yZD48a2V5d29yZD5NRURJQ0FMPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJU008L2tl

eXdvcmQ+PGtleXdvcmQ+TUlDRTwva2V5d29yZD48a2V5d29yZD5taWNlLGluYnJlZCBzdHJhaW5z

PC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVDVUxBUjwva2V5d29yZD48a2V5d29yZD5tb2xlY3VsYXIg

c3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPk48L2tleXdvcmQ+PGtleXdvcmQ+TmV1dHJvcGhp

bHM8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3JkPk5PVkVMPC9rZXl3b3Jk

PjxrZXl3b3JkPlBBSU48L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdBWTwva2V5d29yZD48a2V5d29y

ZD5QZXJpdG9uaXRpczwva2V5d29yZD48a2V5d29yZD5QaGFnb2N5dG9zaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+cGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVDwva2V5d29yZD48a2V5

d29yZD5QUk9QRVJUSUVTPC9rZXl3b3JkPjxrZXl3b3JkPlJlcGVyZnVzaW9uIEluanVyeTwva2V5

d29yZD48a2V5d29yZD5TQ0hPT0w8L2tleXdvcmQ+PGtleXdvcmQ+U0VSSUVTPC9rZXl3b3JkPjxr

ZXl3b3JkPlNUQUJMRTwva2V5d29yZD48a2V5d29yZD5TdGVyZW9pc29tZXJpc208L2tleXdvcmQ+

PGtleXdvcmQ+U1VCU1RSQVRFPC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3Jk

PjxrZXl3b3JkPlRJU1NVRTwva2V5d29yZD48a2V5d29yZD5UT1hJQ0lUWTwva2V5d29yZD48a2V5

d29yZD5VU0E8L2tleXdvcmQ+PGtleXdvcmQ+V09NRU48L2tleXdvcmQ+PGtleXdvcmQ+V291bmQg

SGVhbGluZzwva2V5d29yZD48a2V5d29yZD5aWU1PU0FOPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzE2LzIwMDk8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+U0VSSEFOMjAwOTwvbGFiZWw+PHVybHM+PC91cmxzPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZXJoYW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

ZWNOdW0+MTE1Mzk8L1JlY051bT48RGlzcGxheVRleHQ+WzE0Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE1Mzk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMyI+MTE1Mzk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlNlcmhhbixDLk4uPC9hdXRob3I+PGF1dGhvcj5ZYW5nLFIuPC9hdXRob3I+PGF1dGhvcj5N

YXJ0aW5vZCxLLjwvYXV0aG9yPjxhdXRob3I+S2FzdWdhLEsuPC9hdXRob3I+PGF1dGhvcj5QaWxs

YWksUC5TLjwvYXV0aG9yPjxhdXRob3I+UG9ydGVyLFQuRi48L2F1dGhvcj48YXV0aG9yPk9oLFMu

Ri48L2F1dGhvcj48YXV0aG9yPlNwaXRlLE0uPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0

b3JzPjx0aXRsZXM+PHRpdGxlPk1hcmVzaW5zOiBub3ZlbCBtYWNyb3BoYWdlIG1lZGlhdG9ycyB3

aXRoIHBvdGVudCBhbnRpaW5mbGFtbWF0b3J5IGFuZCBwcm9yZXNvbHZpbmcgYWN0aW9uczwvdGl0

bGU+PHNlY29uZGFyeS10aXRsZT5KLkV4cC5NZWQuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+

PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+Si5FeHAuTWVkLjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjE1LTIzPC9wYWdlcz48dm9sdW1lPjIwNjwvdm9sdW1lPjxudW1iZXI+MTwvbnVt

YmVyPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29y

ZHM+PGtleXdvcmQ+QUNJRDwva2V5d29yZD48a2V5d29yZD5BQ1RJT048L2tleXdvcmQ+PGtleXdv

cmQ+QUNUSU9OUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+

QUNUSVZJVElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5B

Q1VURTwva2V5d29yZD48a2V5d29yZD5hbmFsb2dzICZhbXA7IGRlcml2YXRpdmVzPC9rZXl3b3Jk

PjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+YW50aS1pbmZsYW1tYXRvcnkgYWdl

bnRzLG5vbi1zdGVyb2lkYWw8L2tleXdvcmQ+PGtleXdvcmQ+QXV0YWNvaWRzPC9rZXl3b3JkPjxr

ZXl3b3JkPkJJT0xPR0lDQUw8L2tleXdvcmQ+PGtleXdvcmQ+Qmlvc3ludGhlc2lzPC9rZXl3b3Jk

PjxrZXl3b3JkPkJvc3Rvbjwva2V5d29yZD48a2V5d29yZD5DZWxsIE1vdmVtZW50PC9rZXl3b3Jk

PjxrZXl3b3JkPkNFTExVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPmNoYXJhY3Rlcml6YXRpb248L2tl

eXdvcmQ+PGtleXdvcmQ+Y2hlbWljYWxseSBpbmR1Y2VkPC9rZXl3b3JkPjxrZXl3b3JkPmNoZW1p

c3RyeTwva2V5d29yZD48a2V5d29yZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPmN5dG9sb2d5

PC9rZXl3b3JkPjxrZXl3b3JkPkRpbm9wcm9zdG9uZTwva2V5d29yZD48a2V5d29yZD5Eb2Nvc2Fo

ZXhhZW5vaWMgQWNpZHM8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1ZyBlZmZlY3RzPC9rZXl3b3JkPjxr

ZXl3b3JkPkVpY29zYXBlbnRhZW5vaWMgQWNpZDwva2V5d29yZD48a2V5d29yZD5FTkRPR0VOT1VT

PC9rZXl3b3JkPjxrZXl3b3JkPkVOSEFOQ0VTPC9rZXl3b3JkPjxrZXl3b3JkPkVYUEVSSU1FTlRB

TDwva2V5d29yZD48a2V5d29yZD5FWFVEQVRFUzwva2V5d29yZD48a2V5d29yZD5HRU5FVElDUzwv

a2V5d29yZD48a2V5d29yZD5Ib21lb3N0YXNpczwva2V5d29yZD48a2V5d29yZD5IT1NQSVRBTDwv

a2V5d29yZD48a2V5d29yZD5IT1NUPC9rZXl3b3JkPjxrZXl3b3JkPkhVTUFOUzwva2V5d29yZD48

a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRpb248L2tleXdvcmQ+PGtleXdv

cmQ+SW5mbGFtbWF0aW9uIE1lZGlhdG9yczwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8

L2tleXdvcmQ+PGtleXdvcmQ+aW5qdXJpZXM8L2tleXdvcmQ+PGtleXdvcmQ+SU5KVVJZPC9rZXl3

b3JkPjxrZXl3b3JkPmxldWtvY3l0ZXMsbW9ub251Y2xlYXI8L2tleXdvcmQ+PGtleXdvcmQ+TGlw

aWQgTWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5MSVBPWFlHRU5BU0U8L2tleXdvcmQ+PGtl

eXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNyb3BoYWdlczwva2V5d29yZD48

a2V5d29yZD5tYWNyb3BoYWdlcyxwZXJpdG9uZWFsPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklT

TTwva2V5d29yZD48a2V5d29yZD5NRUNIQU5JU01TPC9rZXl3b3JkPjxrZXl3b3JkPk1FRElBVE9S

PC9rZXl3b3JkPjxrZXl3b3JkPm1lZGlhdG9yczwva2V5d29yZD48a2V5d29yZD5NRURJQ0FMPC9r

ZXl3b3JkPjxrZXl3b3JkPk1FRElDSU5FPC9rZXl3b3JkPjxrZXl3b3JkPk1FVEFCT0xJU008L2tl

eXdvcmQ+PGtleXdvcmQ+TUlDRTwva2V5d29yZD48a2V5d29yZD5taWNlLGluYnJlZCBzdHJhaW5z

PC9rZXl3b3JkPjxrZXl3b3JkPk1PTEVDVUxBUjwva2V5d29yZD48a2V5d29yZD5tb2xlY3VsYXIg

c3RydWN0dXJlPC9rZXl3b3JkPjxrZXl3b3JkPk48L2tleXdvcmQ+PGtleXdvcmQ+TmV1dHJvcGhp

bHM8L2tleXdvcmQ+PGtleXdvcmQ+TkVXPC9rZXl3b3JkPjxrZXl3b3JkPk5PVkVMPC9rZXl3b3Jk

PjxrZXl3b3JkPlBBSU48L2tleXdvcmQ+PGtleXdvcmQ+UEFUSFdBWTwva2V5d29yZD48a2V5d29y

ZD5QZXJpdG9uaXRpczwva2V5d29yZD48a2V5d29yZD5QaGFnb2N5dG9zaXM8L2tleXdvcmQ+PGtl

eXdvcmQ+cGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlBPVEVOVDwva2V5d29yZD48a2V5

d29yZD5QUk9QRVJUSUVTPC9rZXl3b3JkPjxrZXl3b3JkPlJlcGVyZnVzaW9uIEluanVyeTwva2V5

d29yZD48a2V5d29yZD5TQ0hPT0w8L2tleXdvcmQ+PGtleXdvcmQ+U0VSSUVTPC9rZXl3b3JkPjxr

ZXl3b3JkPlNUQUJMRTwva2V5d29yZD48a2V5d29yZD5TdGVyZW9pc29tZXJpc208L2tleXdvcmQ+

PGtleXdvcmQ+U1VCU1RSQVRFPC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3Jk

PjxrZXl3b3JkPlRJU1NVRTwva2V5d29yZD48a2V5d29yZD5UT1hJQ0lUWTwva2V5d29yZD48a2V5

d29yZD5VU0E8L2tleXdvcmQ+PGtleXdvcmQ+V09NRU48L2tleXdvcmQ+PGtleXdvcmQ+V291bmQg

SGVhbGluZzwva2V5d29yZD48a2V5d29yZD5aWU1PU0FOPC9rZXl3b3JkPjwva2V5d29yZHM+PGRh

dGVzPjx5ZWFyPjIwMDk8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzE2LzIwMDk8L2RhdGU+PC9w

dWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+U0VSSEFOMjAwOTwvbGFiZWw+PHVybHM+PC91cmxzPjwv

cmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+

ADDIN EN.CITE.DATA [146]. Defective efferocytosis by macrophages in COPD may prevent resolution of inflammation and may be the same defect that reduces bacteria phagocytosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2RnZTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl

Y051bT44MzczPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls0NiwgMTQ3XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj44MzczPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5NTEiPjgzNzM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkhvZGdlLFMuPC9hdXRob3I+PGF1dGhvcj5Ib2RnZSxHLjwvYXV0aG9yPjxhdXRob3I+U2Np

Y2NoaXRhbm8sUi48L2F1dGhvcj48YXV0aG9yPlJleW5vbGRzLFAuTi48L2F1dGhvcj48YXV0aG9y

PkhvbG1lcyxNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRs

ZT5BbHZlb2xhciBtYWNyb3BoYWdlcyBmcm9tIHN1YmplY3RzIHdpdGggY2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZSBhcmUgZGVmaWNpZW50IGluIHRoZWlyIGFiaWxpdHkgdG8g

cGhhZ29jeXRvc2UgYXBvcHRvdGljIGFpcndheSBlcGl0aGVsaWFsIGNlbGxzPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkltbXVub2wuQ2VsbCBCaW9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkltbXVub2wuQ2VsbCBCaW9sLjwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjI4OS0yOTY8L3BhZ2VzPjx2b2x1bWU+ODE8L3ZvbHVtZT48bnVt

YmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPjIyNzM0MDk5PC9rZXl3b3JkPjxrZXl3b3JkPkFDQ1VNVUxB

VElPTjwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QUxWRU9MQVI8

L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9waGFnZTwva2V5d29yZD48a2V5d29yZD5B

TlRJPC9rZXl3b3JkPjxrZXl3b3JkPmFwb3B0b3Npczwva2V5d29yZD48a2V5d29yZD5BU1NBWTwv

a2V5d29yZD48a2V5d29yZD5CQVNJQzwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hPQUxWRU9MQVI8

L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFSIExBVkFHRTwva2V5d29yZD48a2V5d29y

ZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8

L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5D

aHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJ

R0FSRVRURTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEUgU01PS0U8L2tleXdvcmQ+PGtleXdv

cmQ+Q09NTVVOSVRZPC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBMRVhFUzwva2V5d29yZD48a2V5d29y

ZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNVTFRVUkVEPC9rZXl3b3JkPjxrZXl3b3JkPkRB

TUFHRTwva2V5d29yZD48a2V5d29yZD5ERUZFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPkRFRklDSUVO

Q1k8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FUElUSEVMSUFM

PC9rZXl3b3JkPjxrZXl3b3JkPmVwaXRoZWxpYWwgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+RVhU

UkFDRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5leHRyYWNlbGx1bGFyIG1hdHJpeDwva2V5d29y

ZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3Jk

PjxrZXl3b3JkPmdsb2JhbDwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5J

TkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5EVUNFRDwva2V5d29yZD48a2V5d29yZD5pbmZs

YW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SU5HRVNURUQ8L2tleXdvcmQ+PGtleXdvcmQ+TEFW

QUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9w

aGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFUUklYPC9rZXl3b3JkPjxrZXl3b3JkPk1PUkJJRElU

WTwva2V5d29yZD48a2V5d29yZD5NT1JUQUxJVFk8L2tleXdvcmQ+PGtleXdvcmQ+Tk88L2tleXdv

cmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9nZW5lc2lzPC9r

ZXl3b3JkPjxrZXl3b3JkPlBoYWdvY3l0b3Npczwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8

L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29y

ZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5d29yZD5zdGFpbmluZzwva2V5d29yZD48

a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3Jk

PlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5UUkVB

VE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5ERVJTVEFORElORzwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OC8yMDAzPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkhPREdFMjAwMzwvbGFiZWw+PHVybHM+PC91cmxzPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRvbm5lbGx5PC9BdXRob3I+PFllYXI+MjAxMjwv

WWVhcj48UmVjTnVtPjExNTkzPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTU5MzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVm

ZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxMzc4NDc5MDAzIj4xMTU5Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9y

PjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+RGVmZWN0aXZlIHBoYWdvY3l0b3NpcyBpbiBhaXJ3YXlzIGRpc2Vhc2U8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+Q2hlc3QuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3QuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MTA1NS0xMDYyPC9wYWdlcz48dm9sdW1lPjE0MTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVy

PjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdv

cmQ+QUxWRU9MQVI8L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9waGFnZTwva2V5d29y

ZD48a2V5d29yZD5hbnRpb3hpZGFudDwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+

PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5D

RUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNZU1RJQyBG

SUJST1NJUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VB

U0VTPC9rZXl3b3JkPjxrZXl3b3JkPkRZU0ZVTkNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVOR0xB

TkQ8L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0lP

Tjwva2V5d29yZD48a2V5d29yZD5GSUJST1NJUzwva2V5d29yZD48a2V5d29yZD5mdW5jdGlvbjwv

a2V5d29yZD48a2V5d29yZD5GVU5DVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+SEVBTFRIWTwva2V5

d29yZD48a2V5d29yZD5IRUFSVDwva2V5d29yZD48a2V5d29yZD5Ib21lb3N0YXNpczwva2V5d29y

ZD48a2V5d29yZD5JREVOVElGSUNBVElPTjwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdv

cmQ+PGtleXdvcmQ+SW1tdW5lIFN5c3RlbTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48

a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5JTkhBTEVEPC9rZXl3b3JkPjxr

ZXl3b3JkPktJTExJTkc8L2tleXdvcmQ+PGtleXdvcmQ+bG9uZG9uPC9rZXl3b3JkPjxrZXl3b3Jk

Pkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNy

b3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVD

SEFOSVNNUzwva2V5d29yZD48a2V5d29yZD5NT1JCSURJVFk8L2tleXdvcmQ+PGtleXdvcmQ+TU9S

VEFMSVRZPC9rZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRy

b3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+TmV1dHJvcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+Tk9W

RUw8L2tleXdvcmQ+PGtleXdvcmQ+T2JzZXJ2YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+T1hJREFU

SVZFPC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+

UEFSVElDTEVTPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPUEhZU0lPTE9HWTwva2V5d29yZD48a2V5

d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QaGFnb2N5dGVzPC9rZXl3b3JkPjxrZXl3

b3JkPlBoYWdvY3l0b3Npczwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5

d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+UkVDT0dOSVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRU1PVkFMPC9rZXl3b3JkPjxrZXl3b3Jk

PlJFUE9SVDwva2V5d29yZD48a2V5d29yZD5SRVZFUlNFRDwva2V5d29yZD48a2V5d29yZD5TUEVD

SUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUUkFURUdJRVM8L2tleXdvcmQ+PGtleXdvcmQ+c3RyZXNz

PC9rZXl3b3JkPjxrZXl3b3JkPlNVUkZBQ0U8L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNPC9rZXl3

b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPlRSRUFUTUVOVDwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

NC8yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkRPTk5FTExZMjAxMjwvbGFi

ZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2RnZTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl

Y051bT44MzczPC9SZWNOdW0+PERpc3BsYXlUZXh0Pls0NiwgMTQ3XTwvRGlzcGxheVRleHQ+PHJl

Y29yZD48cmVjLW51bWJlcj44MzczPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9

IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3Rh

bXA9IjEzNzg0Nzg5NTEiPjgzNzM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPkhvZGdlLFMuPC9hdXRob3I+PGF1dGhvcj5Ib2RnZSxHLjwvYXV0aG9yPjxhdXRob3I+U2Np

Y2NoaXRhbm8sUi48L2F1dGhvcj48YXV0aG9yPlJleW5vbGRzLFAuTi48L2F1dGhvcj48YXV0aG9y

PkhvbG1lcyxNLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRs

ZT5BbHZlb2xhciBtYWNyb3BoYWdlcyBmcm9tIHN1YmplY3RzIHdpdGggY2hyb25pYyBvYnN0cnVj

dGl2ZSBwdWxtb25hcnkgZGlzZWFzZSBhcmUgZGVmaWNpZW50IGluIHRoZWlyIGFiaWxpdHkgdG8g

cGhhZ29jeXRvc2UgYXBvcHRvdGljIGFpcndheSBlcGl0aGVsaWFsIGNlbGxzPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkltbXVub2wuQ2VsbCBCaW9sLjwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVz

PjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkltbXVub2wuQ2VsbCBCaW9sLjwvZnVsbC10aXRsZT48

L3BlcmlvZGljYWw+PHBhZ2VzPjI4OS0yOTY8L3BhZ2VzPjx2b2x1bWU+ODE8L3ZvbHVtZT48bnVt

YmVyPjQ8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRp

b24+PGtleXdvcmRzPjxrZXl3b3JkPjIyNzM0MDk5PC9rZXl3b3JkPjxrZXl3b3JkPkFDQ1VNVUxB

VElPTjwva2V5d29yZD48a2V5d29yZD5BSVJXQVk8L2tleXdvcmQ+PGtleXdvcmQ+QUxWRU9MQVI8

L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9waGFnZTwva2V5d29yZD48a2V5d29yZD5B

TlRJPC9rZXl3b3JkPjxrZXl3b3JkPmFwb3B0b3Npczwva2V5d29yZD48a2V5d29yZD5BU1NBWTwv

a2V5d29yZD48a2V5d29yZD5CQVNJQzwva2V5d29yZD48a2V5d29yZD5CUk9OQ0hPQUxWRU9MQVI8

L2tleXdvcmQ+PGtleXdvcmQ+QlJPTkNIT0FMVkVPTEFSIExBVkFHRTwva2V5d29yZD48a2V5d29y

ZD5DRUxMPC9rZXl3b3JkPjxrZXl3b3JkPkNFTExTPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUM8

L2tleXdvcmQ+PGtleXdvcmQ+Q0hST05JQyBPQlNUUlVDVElWRTwva2V5d29yZD48a2V5d29yZD5D

aHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkNJ

R0FSRVRURTwva2V5d29yZD48a2V5d29yZD5DSUdBUkVUVEUgU01PS0U8L2tleXdvcmQ+PGtleXdv

cmQ+Q09NTVVOSVRZPC9rZXl3b3JkPjxrZXl3b3JkPkNPTVBMRVhFUzwva2V5d29yZD48a2V5d29y

ZD5DT05UUk9MPC9rZXl3b3JkPjxrZXl3b3JkPkNVTFRVUkVEPC9rZXl3b3JkPjxrZXl3b3JkPkRB

TUFHRTwva2V5d29yZD48a2V5d29yZD5ERUZFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPkRFRklDSUVO

Q1k8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29yZD48a2V5d29yZD5FUElUSEVMSUFM

PC9rZXl3b3JkPjxrZXl3b3JkPmVwaXRoZWxpYWwgY2VsbHM8L2tleXdvcmQ+PGtleXdvcmQ+RVhU

UkFDRUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5leHRyYWNlbGx1bGFyIG1hdHJpeDwva2V5d29y

ZD48a2V5d29yZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkZsb3cgQ3l0b21ldHJ5PC9rZXl3b3Jk

PjxrZXl3b3JkPmdsb2JhbDwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5J

TkNSRUFTRUQ8L2tleXdvcmQ+PGtleXdvcmQ+SU5EVUNFRDwva2V5d29yZD48a2V5d29yZD5pbmZs

YW1tYXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SU5HRVNURUQ8L2tleXdvcmQ+PGtleXdvcmQ+TEFW

QUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1BQ1JPUEhBR0U8L2tleXdvcmQ+PGtleXdvcmQ+TWFjcm9w

aGFnZXM8L2tleXdvcmQ+PGtleXdvcmQ+TUFUUklYPC9rZXl3b3JkPjxrZXl3b3JkPk1PUkJJRElU

WTwva2V5d29yZD48a2V5d29yZD5NT1JUQUxJVFk8L2tleXdvcmQ+PGtleXdvcmQ+Tk88L2tleXdv

cmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+cGF0aG9nZW5lc2lzPC9r

ZXl3b3JkPjxrZXl3b3JkPlBoYWdvY3l0b3Npczwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8

L2tleXdvcmQ+PGtleXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5TTU9LRTwva2V5d29y

ZD48a2V5d29yZD5TUEVDSUZJQzwva2V5d29yZD48a2V5d29yZD5zdGFpbmluZzwva2V5d29yZD48

a2V5d29yZD5TVFVESUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURZPC9rZXl3b3JkPjxrZXl3b3Jk

PlNVQkpFQ1RTPC9rZXl3b3JkPjxrZXl3b3JkPlRBUkdFVDwva2V5d29yZD48a2V5d29yZD5UUkVB

VE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5ERVJTVEFORElORzwva2V5d29yZD48L2tleXdvcmRz

PjxkYXRlcz48eWVhcj4yMDAzPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+OC8yMDAzPC9kYXRlPjwv

cHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkhPREdFMjAwMzwvbGFiZWw+PHVybHM+PC91cmxzPjwv

cmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPkRvbm5lbGx5PC9BdXRob3I+PFllYXI+MjAxMjwv

WWVhcj48UmVjTnVtPjExNTkzPC9SZWNOdW0+PHJlY29yZD48cmVjLW51bWJlcj4xMTU5MzwvcmVj

LW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVm

ZXZycDd2emRza3N2cjV3d3plendlMCIgdGltZXN0YW1wPSIxMzc4NDc5MDAzIj4xMTU5Mzwva2V5

PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYt

dHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+RG9ubmVsbHksTC5FLjwvYXV0aG9y

PjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+RGVmZWN0aXZlIHBoYWdvY3l0b3NpcyBpbiBhaXJ3YXlzIGRpc2Vhc2U8L3Rp

dGxlPjxzZWNvbmRhcnktdGl0bGU+Q2hlc3QuPC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+Q2hlc3QuPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn

ZXM+MTA1NS0xMDYyPC9wYWdlcz48dm9sdW1lPjE0MTwvdm9sdW1lPjxudW1iZXI+NDwvbnVtYmVy

PjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5d29yZHM+

PGtleXdvcmQ+QUlSV0FZPC9rZXl3b3JkPjxrZXl3b3JkPkFpcndheXM8L2tleXdvcmQ+PGtleXdv

cmQ+QUxWRU9MQVI8L2tleXdvcmQ+PGtleXdvcmQ+QWx2ZW9sYXIgbWFjcm9waGFnZTwva2V5d29y

ZD48a2V5d29yZD5hbnRpb3hpZGFudDwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+

PGtleXdvcmQ+Q0VMTDwva2V5d29yZD48a2V5d29yZD5DRUxMUzwva2V5d29yZD48a2V5d29yZD5D

RUxMVUxBUjwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNZU1RJQyBG

SUJST1NJUzwva2V5d29yZD48a2V5d29yZD5ESVNFQVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRJU0VB

U0VTPC9rZXl3b3JkPjxrZXl3b3JkPkRZU0ZVTkNUSU9OPC9rZXl3b3JkPjxrZXl3b3JkPkVOR0xB

TkQ8L2tleXdvcmQ+PGtleXdvcmQ+RVZJREVOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+RVhQUkVTU0lP

Tjwva2V5d29yZD48a2V5d29yZD5GSUJST1NJUzwva2V5d29yZD48a2V5d29yZD5mdW5jdGlvbjwv

a2V5d29yZD48a2V5d29yZD5GVU5DVElPTlM8L2tleXdvcmQ+PGtleXdvcmQ+SEVBTFRIWTwva2V5

d29yZD48a2V5d29yZD5IRUFSVDwva2V5d29yZD48a2V5d29yZD5Ib21lb3N0YXNpczwva2V5d29y

ZD48a2V5d29yZD5JREVOVElGSUNBVElPTjwva2V5d29yZD48a2V5d29yZD5JTU1VTkU8L2tleXdv

cmQ+PGtleXdvcmQ+SW1tdW5lIFN5c3RlbTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48

a2V5d29yZD5JTkRJVklEVUFMUzwva2V5d29yZD48a2V5d29yZD5JTkhBTEVEPC9rZXl3b3JkPjxr

ZXl3b3JkPktJTExJTkc8L2tleXdvcmQ+PGtleXdvcmQ+bG9uZG9uPC9rZXl3b3JkPjxrZXl3b3Jk

Pkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+TUFDUk9QSEFHRTwva2V5d29yZD48a2V5d29yZD5NYWNy

b3BoYWdlczwva2V5d29yZD48a2V5d29yZD5NRUNIQU5JU008L2tleXdvcmQ+PGtleXdvcmQ+TUVD

SEFOSVNNUzwva2V5d29yZD48a2V5d29yZD5NT1JCSURJVFk8L2tleXdvcmQ+PGtleXdvcmQ+TU9S

VEFMSVRZPC9rZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3b3JkPm5ldXRy

b3BoaWw8L2tleXdvcmQ+PGtleXdvcmQ+TmV1dHJvcGhpbHM8L2tleXdvcmQ+PGtleXdvcmQ+Tk9W

RUw8L2tleXdvcmQ+PGtleXdvcmQ+T2JzZXJ2YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+T1hJREFU

SVZFPC9rZXl3b3JkPjxrZXl3b3JkPk94aWRhdGl2ZSBTdHJlc3M8L2tleXdvcmQ+PGtleXdvcmQ+

UEFSVElDTEVTPC9rZXl3b3JkPjxrZXl3b3JkPlBBVEhPUEhZU0lPTE9HWTwva2V5d29yZD48a2V5

d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QaGFnb2N5dGVzPC9rZXl3b3JkPjxrZXl3

b3JkPlBoYWdvY3l0b3Npczwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5

d29yZD5SZWNlcHRvcnM8L2tleXdvcmQ+PGtleXdvcmQ+UkVDT0dOSVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+UkVEVUNFRDwva2V5d29yZD48a2V5d29yZD5SRU1PVkFMPC9rZXl3b3JkPjxrZXl3b3Jk

PlJFUE9SVDwva2V5d29yZD48a2V5d29yZD5SRVZFUlNFRDwva2V5d29yZD48a2V5d29yZD5TUEVD

SUVTPC9rZXl3b3JkPjxrZXl3b3JkPlNUUkFURUdJRVM8L2tleXdvcmQ+PGtleXdvcmQ+c3RyZXNz

PC9rZXl3b3JkPjxrZXl3b3JkPlNVUkZBQ0U8L2tleXdvcmQ+PGtleXdvcmQ+U1lTVEVNPC9rZXl3

b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPlRSRUFUTUVOVDwva2V5

d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+

NC8yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkRPTk5FTExZMjAxMjwvbGFi

ZWw+PHVybHM+PC91cmxzPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+AG==

ADDIN EN.CITE.DATA [46, 147]. Indeed colonising bacteria, particularly Haemophilus influenzae may be an important mechanism driving persistent lower airway inflammation in COPD ADDIN EN.CITE <EndNote><Cite><Author>Singh</Author><Year>2014</Year><RecNum>12078</RecNum><DisplayText>[47]</DisplayText><record><rec-number>12078</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1412586608">12078</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Singh, R.</author><author>Mackay, A. J.</author><author>Patel, A.</author><author>Garcha, D. S.</author><author>Kowlessar, B. S.</author><author>Brill, S. E.</author><author>Donnelly, L. E.</author><author>Barnes, P. J.</author><author>Donaldson, G. C.</author><author>Wedzicha, J. A.</author></authors></contributors><titles><title>Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive pulmonary disease</title><secondary-title>Respir Res</secondary-title><alt-title>Respiratory research</alt-title></titles><periodical><full-title>Respir Res</full-title></periodical><pages>114</pages><volume>15</volume><number>1</number><edition>2014/09/15</edition><dates><year>2014</year><pub-dates><date>Sep 14</date></pub-dates></dates><isbn>1465-9921</isbn><accession-num>25218165</accession-num><urls></urls><custom2>Pmc4173051</custom2><electronic-resource-num>10.1186/s12931-014-0114-1</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>Eng</language></record></Cite></EndNote>[47].IMPLICATIONS FOR THERAPYBetter understanding of the cellular and molecular mechanisms of asthma and COPD is important for the more accurate phenotyping of patients and for the development of new and more effective therapies in the future. Most asthma patients respond well to ICS therapy providing they take it on a regular basis, but corticosteroids are a broad spectrum therapy that target many inflammatory mechanisms, so may be effective in many different phenotypes of asthma. Eosinophilic inflammation, found in the majority of patients with asthma, is usually responsive to corticosteroid therapy, but is also found in some patients with COPD, who may show a response to corticosteroid therapy, whereas most COPD patients do not ADDIN EN.CITE <EndNote><Cite><Author>Pavord</Author><Year>2016</Year><RecNum>12722</RecNum><DisplayText>[148]</DisplayText><record><rec-number>12722</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1458048996">12722</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pavord, I. D.</author><author>Lettis, S.</author><author>Locantore, N.</author><author>Pascoe, S.</author><author>Jones, P. W.</author><author>Wedzicha, J. A.</author><author>Barnes, N. C.</author></authors></contributors><auth-address>Respiratory Medicine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.&#xD;GSK, Uxbridge, UK.&#xD;Respiratory Medicine Development Center, GSK, Research Triangle Park, North Carolina, USA.&#xD;St George&apos;s, University of London, London, UK.&#xD;National Heart and Lung Institute, Royal Brompton Campus, Imperial College London, London, UK.&#xD;Respiratory Medical Franchise, GSK, Uxbridge, UK William Harvey Institute, Barts and The London School of Medicine and Dentistry, London, UK.</auth-address><titles><title>Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD</title><secondary-title>Thorax</secondary-title><alt-title>Thorax</alt-title></titles><periodical><full-title>Thorax</full-title></periodical><alt-periodical><full-title>Thorax</full-title></alt-periodical><pages>118-25</pages><volume>71</volume><number>2</number><edition>2015/11/21</edition><keywords><keyword>COPD Exacerbations</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0040-6376</isbn><accession-num>26585525</accession-num><urls></urls><custom2>Pmc4752631</custom2><electronic-resource-num>10.1136/thoraxjnl-2015-207021</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[148]. Around 5% of asthmatic patients have severe disease, which does not respond to optimal therapy and there appear to be distinct phenotypes, including those with predominant eosinophils, those with predominant neutrophils or those with no increase in inflammatory cells, suggesting the need for different treatment strategies ADDIN EN.CITE <EndNote><Cite><Author>Ray</Author><Year>2016</Year><RecNum>12908</RecNum><DisplayText>[11]</DisplayText><record><rec-number>12908</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1479483774">12908</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ray, A.</author><author>Raundhal, M.</author><author>Oriss, T. B.</author><author>Ray, P.</author><author>Wenzel, S. E.</author></authors></contributors><titles><title>Current concepts of severe asthma</title><secondary-title>J Clin Invest</secondary-title><alt-title>The Journal of clinical investigation</alt-title></titles><periodical><full-title>J Clin Invest</full-title></periodical><pages>2394-403</pages><volume>126</volume><number>7</number><edition>2016/07/02</edition><dates><year>2016</year><pub-dates><date>Jul 1</date></pub-dates></dates><isbn>0021-9738</isbn><accession-num>27367183</accession-num><urls></urls><custom2>PMC4922699</custom2><electronic-resource-num>10.1172/jci84144</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>Eng</language></record></Cite></EndNote>[11]. The patients with high eosinophils who do not respond to steroids may show a good clinical response to anti-IL-5 antibodies ADDIN EN.CITE <EndNote><Cite><Author>Chung</Author><Year>2015</Year><RecNum>12737</RecNum><DisplayText>[149]</DisplayText><record><rec-number>12737</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1458149358">12737</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chung, K. F.</author></authors></contributors><auth-address>Experimental Studies, Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, UK; National Institute for Health Research (NIHR), Respiratory Biomedical Research Unit, Royal Brompton &amp; Harefield NHS Trust and Imperial College London, London, UK. Electronic address: f.chung@imperial.ac.uk.</auth-address><titles><title>Targeting the interleukin pathway in the treatment of asthma</title><secondary-title>Lancet</secondary-title><alt-title>Lancet (London, England)</alt-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1086-96</pages><volume>386</volume><number>9998</number><edition>2015/09/19</edition><keywords><keyword>Anti-Asthmatic Agents/pharmacology/*therapeutic use</keyword><keyword>Asthma/*drug therapy/immunology</keyword><keyword>Humans</keyword><keyword>Interleukins/*antagonists &amp; inhibitors</keyword><keyword>Molecular Targeted Therapy/methods</keyword><keyword>Signal Transduction/drug effects</keyword><keyword>Th2 Cells/drug effects</keyword></keywords><dates><year>2015</year><pub-dates><date>Sep 12</date></pub-dates></dates><isbn>0140-6736</isbn><accession-num>26383000</accession-num><urls></urls><electronic-resource-num>10.1016/s0140-6736(15)00157-9</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[149], whereas those with increased neutrophils may respond to a macrolide PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcnVzc2VsbGU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

PjxSZWNOdW0+MTIyOTM8L1JlY051bT48RGlzcGxheVRleHQ+WzE1MF08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTIyOTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQyOTcxMTA5MCI+MTIyOTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkJydXNzZWxsZSwgRy4gRy48L2F1dGhvcj48YXV0aG9yPlZhbmRlcnN0aWNoZWxlLCBD

LjwvYXV0aG9yPjxhdXRob3I+Sm9yZGVucywgUC48L2F1dGhvcj48YXV0aG9yPkRlbWFuLCBSLjwv

YXV0aG9yPjxhdXRob3I+U2xhYmJ5bmNrLCBILjwvYXV0aG9yPjxhdXRob3I+UmluZ29ldCwgVi48

L2F1dGhvcj48YXV0aG9yPlZlcmxlZGVuLCBHLjwvYXV0aG9yPjxhdXRob3I+RGVtZWR0cywgSS4g

Sy48L2F1dGhvcj48YXV0aG9yPlZlcmhhbW1lLCBLLjwvYXV0aG9yPjxhdXRob3I+RGVscG9ydGUs

IEEuPC9hdXRob3I+PGF1dGhvcj5EZW1leWVyZSwgQi48L2F1dGhvcj48YXV0aG9yPkNsYWV5cywg

Ry48L2F1dGhvcj48YXV0aG9yPkJvZWxlbnMsIEouPC9hdXRob3I+PGF1dGhvcj5QYWRhbGtvLCBF

LjwvYXV0aG9yPjxhdXRob3I+VmVyc2NoYWtlbGVuLCBKLjwvYXV0aG9yPjxhdXRob3I+VmFuIE1h

ZWxlLCBHLjwvYXV0aG9yPjxhdXRob3I+RGVzY2hlcHBlciwgRS48L2F1dGhvcj48YXV0aG9yPkpv

b3MsIEcuIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgR2hlbnQsIEJlbGdpdW0uIGd1eS5icnVzc2VsbGVAdWdlbnQuYmU8L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5Beml0aHJvbXljaW4gZm9yIHByZXZlbnRpb24gb2YgZXhhY2VyYmF0

aW9ucyBpbiBzZXZlcmUgYXN0aG1hIChBWklTQVNUKTogYSBtdWx0aWNlbnRyZSByYW5kb21pc2Vk

IGRvdWJsZS1ibGluZCBwbGFjZWJvLWNvbnRyb2xsZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+VGhvcmF4PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaG9yYXg8L2FsdC10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+

PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MzIyLTk8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48

bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDEzLzAxLzA4PC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BbnRpLUJhY3RlcmlhbCBBZ2VudHMvYWRt

aW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+QXN0aG1hLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QXppdGhyb215Y2luL2Fk

bWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkRpc2Vhc2UgUHJvZ3Jlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1l

dGhvZDwva2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHksIENvbWJpbmF0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5U

cmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MDA0MC02Mzc2PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzMjkxMzQ5PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEzNi90aG9yYXhqbmwtMjAx

Mi0yMDI2OTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlk

ZXI+TmxtPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcnVzc2VsbGU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

PjxSZWNOdW0+MTIyOTM8L1JlY051bT48RGlzcGxheVRleHQ+WzE1MF08L0Rpc3BsYXlUZXh0Pjxy

ZWNvcmQ+PHJlYy1udW1iZXI+MTIyOTM8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFw

cD0iRU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVz

dGFtcD0iMTQyOTcxMTA5MCI+MTIyOTM8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFt

ZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48

YXV0aG9yPkJydXNzZWxsZSwgRy4gRy48L2F1dGhvcj48YXV0aG9yPlZhbmRlcnN0aWNoZWxlLCBD

LjwvYXV0aG9yPjxhdXRob3I+Sm9yZGVucywgUC48L2F1dGhvcj48YXV0aG9yPkRlbWFuLCBSLjwv

YXV0aG9yPjxhdXRob3I+U2xhYmJ5bmNrLCBILjwvYXV0aG9yPjxhdXRob3I+UmluZ29ldCwgVi48

L2F1dGhvcj48YXV0aG9yPlZlcmxlZGVuLCBHLjwvYXV0aG9yPjxhdXRob3I+RGVtZWR0cywgSS4g

Sy48L2F1dGhvcj48YXV0aG9yPlZlcmhhbW1lLCBLLjwvYXV0aG9yPjxhdXRob3I+RGVscG9ydGUs

IEEuPC9hdXRob3I+PGF1dGhvcj5EZW1leWVyZSwgQi48L2F1dGhvcj48YXV0aG9yPkNsYWV5cywg

Ry48L2F1dGhvcj48YXV0aG9yPkJvZWxlbnMsIEouPC9hdXRob3I+PGF1dGhvcj5QYWRhbGtvLCBF

LjwvYXV0aG9yPjxhdXRob3I+VmVyc2NoYWtlbGVuLCBKLjwvYXV0aG9yPjxhdXRob3I+VmFuIE1h

ZWxlLCBHLjwvYXV0aG9yPjxhdXRob3I+RGVzY2hlcHBlciwgRS48L2F1dGhvcj48YXV0aG9yPkpv

b3MsIEcuIEYuPC9hdXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+

RGVwYXJ0bWVudCBvZiBSZXNwaXJhdG9yeSBNZWRpY2luZSwgR2hlbnQgVW5pdmVyc2l0eSBIb3Nw

aXRhbCwgR2hlbnQsIEJlbGdpdW0uIGd1eS5icnVzc2VsbGVAdWdlbnQuYmU8L2F1dGgtYWRkcmVz

cz48dGl0bGVzPjx0aXRsZT5Beml0aHJvbXljaW4gZm9yIHByZXZlbnRpb24gb2YgZXhhY2VyYmF0

aW9ucyBpbiBzZXZlcmUgYXN0aG1hIChBWklTQVNUKTogYSBtdWx0aWNlbnRyZSByYW5kb21pc2Vk

IGRvdWJsZS1ibGluZCBwbGFjZWJvLWNvbnRyb2xsZWQgdHJpYWw8L3RpdGxlPjxzZWNvbmRhcnkt

dGl0bGU+VGhvcmF4PC9zZWNvbmRhcnktdGl0bGU+PGFsdC10aXRsZT5UaG9yYXg8L2FsdC10aXRs

ZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+PC9w

ZXJpb2RpY2FsPjxhbHQtcGVyaW9kaWNhbD48ZnVsbC10aXRsZT5UaG9yYXg8L2Z1bGwtdGl0bGU+

PC9hbHQtcGVyaW9kaWNhbD48cGFnZXM+MzIyLTk8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48

bnVtYmVyPjQ8L251bWJlcj48ZWRpdGlvbj4yMDEzLzAxLzA4PC9lZGl0aW9uPjxrZXl3b3Jkcz48

a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29yZD5BbnRpLUJhY3RlcmlhbCBBZ2VudHMvYWRt

aW5pc3RyYXRpb24gJmFtcDsgZG9zYWdlLyp0aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdv

cmQ+QXN0aG1hLypkcnVnIHRoZXJhcHk8L2tleXdvcmQ+PGtleXdvcmQ+QXppdGhyb215Y2luL2Fk

bWluaXN0cmF0aW9uICZhbXA7IGRvc2FnZS8qdGhlcmFwZXV0aWMgdXNlPC9rZXl3b3JkPjxrZXl3

b3JkPkRpc2Vhc2UgUHJvZ3Jlc3Npb248L2tleXdvcmQ+PGtleXdvcmQ+RG91YmxlLUJsaW5kIE1l

dGhvZDwva2V5d29yZD48a2V5d29yZD5EcnVnIFRoZXJhcHksIENvbWJpbmF0aW9uPC9rZXl3b3Jk

PjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5IdW1hbnM8L2tleXdvcmQ+PGtleXdv

cmQ+TWFsZTwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5U

cmVhdG1lbnQgT3V0Y29tZTwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEzPC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+QXByPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+

MDA0MC02Mzc2PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjIzMjkxMzQ5PC9hY2Nlc3Npb24tbnVtPjx1

cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTEzNi90aG9yYXhqbmwtMjAx

Mi0yMDI2OTg8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlk

ZXI+TmxtPC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+

PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=

ADDIN EN.CITE.DATA [150]. A major unmet need is to find safe and effective anti-inflammatory treatments for COPD, which has proved to be a major challenge as most drugs have either been ineffective or have had unacceptable toxicity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+MTE1OTk8L1JlY051bT48RGlzcGxheVRleHQ+WzE1MSwgMTUyXTwvRGlzcGxheVRleHQ+

PHJlY29yZD48cmVjLW51bWJlcj4xMTU5OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGlt

ZXN0YW1wPSIxMzc4NDc5MDA0Ij4xMTU5OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+TmV3IGFudGktaW5mbGFtbWF0b3J5IHRyZWF0bWVudHMgZm9yIGNocm9uaWMg

b2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0

IFJldiBEcnVnIERpc2Nvdi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OYXQgUmV2IERydWcgRGlzY292LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjU0My01NTk8L3BhZ2VzPjx2b2x1bWU+MTI8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9u

Pk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPk5FVzwva2V5

d29yZD48a2V5d29yZD5BTlRJLUlORkxBTU1BVE9SWTwva2V5d29yZD48a2V5d29yZD5DT1BEPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDEzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkJBUk5FUzIwMTNDPC9sYWJl

bD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+R3Jvc3M8L0F1dGhv

cj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MTI5Mzk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjEyOTM5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

dHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0ODM3MDc5

OTIiPjEyOTM5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0

aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Hcm9zcywg

Ti4gSi48L2F1dGhvcj48YXV0aG9yPkJhcm5lcywgUC4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IE1lZGljYWwgUmVzZWFyY2ggTExD

LCBTdCBGcmFuY2lzIEhvc3BpdGFsLCBIYXJ0Zm9yZCwgQ29ubmVjdGljdXQsIFVuaXRlZCBTdGF0

ZXMgOyBncm9zc25pY2hvbGFzMUBnbWFpbC5jb20uJiN4RDtOYXRpb25hbCBIZWFydCAmYW1wOyBM

dW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSBMb25kb24sIEFpcndheSBEaXNlYXNlIFNl

Y3Rpb24sIExvbmRvbiwgVW5pdGVkIEtpbmdkb20gb2YgR3JlYXQgQnJpdGFpbiBhbmQgTm9ydGhl

cm4gSXJlbGFuZCA7IHAuai5iYXJuZXNAaW1wZXJpYWwuYWMudWsuPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+TmV3IHRoZXJhcGllcyBmb3IgYXN0aG1hIGFuZCBjaHJvbmljIG9ic3RydWN0

aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGly

IENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkFtZXJpY2FuIGpvdXJu

YWwgb2YgcmVzcGlyYXRvcnkgYW5kIGNyaXRpY2FsIGNhcmUgbWVkaWNpbmU8L2FsdC10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVk

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTU5LTE2NjwvcGFnZXM+PHZvbHVtZT4x

OTU8L3ZvbHVtZT48ZWRpdGlvbj4yMDE2LzEyLzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5OZXcgYnJvbmNob2RpbGF0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPmtpbmFzZSBpbmhpYml0b3Jz

PC9rZXl3b3JkPjxrZXl3b3JkPm1lZGlhdG9yIGFudGFnb25pc3RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pm5ldyBjb3J0aWNvc3Rlcm9pZHM8L2tleXdvcmQ+PGtleXdvcmQ+cGhvc3Bob2RpZXN0ZXJhc2Ug

aW5oaWJpdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+RGVjIDA2PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA3

My00NDl4PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3OTIyNzUxPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE2NC9yY2NtLjIwMTYxMC0yMDc0

UFA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxN

PC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+MTE1OTk8L1JlY051bT48RGlzcGxheVRleHQ+WzE1MSwgMTUyXTwvRGlzcGxheVRleHQ+

PHJlY29yZD48cmVjLW51bWJlcj4xMTU5OTwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg

YXBwPSJFTiIgZGItaWQ9InRyMHJ6MHJmajUyZjVmZXZycDd2emRza3N2cjV3d3plendlMCIgdGlt

ZXN0YW1wPSIxMzc4NDc5MDA0Ij4xMTU5OTwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBu

YW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3Jz

PjxhdXRob3I+QmFybmVzLFAuSi48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRp

dGxlcz48dGl0bGU+TmV3IGFudGktaW5mbGFtbWF0b3J5IHRyZWF0bWVudHMgZm9yIGNocm9uaWMg

b2JzdHJ1Y3RpdmUgcHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+TmF0

IFJldiBEcnVnIERpc2Nvdi48L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48

ZnVsbC10aXRsZT5OYXQgUmV2IERydWcgRGlzY292LjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+

PHBhZ2VzPjU0My01NTk8L3BhZ2VzPjx2b2x1bWU+MTI8L3ZvbHVtZT48cmVwcmludC1lZGl0aW9u

Pk5vdCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPk5FVzwva2V5

d29yZD48a2V5d29yZD5BTlRJLUlORkxBTU1BVE9SWTwva2V5d29yZD48a2V5d29yZD5DT1BEPC9r

ZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0

ZT4yMDEzPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPkJBUk5FUzIwMTNDPC9sYWJl

bD48dXJscz48L3VybHM+PC9yZWNvcmQ+PC9DaXRlPjxDaXRlPjxBdXRob3I+R3Jvc3M8L0F1dGhv

cj48WWVhcj4yMDE3PC9ZZWFyPjxSZWNOdW0+MTI5Mzk8L1JlY051bT48cmVjb3JkPjxyZWMtbnVt

YmVyPjEyOTM5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0i

dHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0ODM3MDc5

OTIiPjEyOTM5PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0

aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5Hcm9zcywg

Ti4gSi48L2F1dGhvcj48YXV0aG9yPkJhcm5lcywgUC4gSi48L2F1dGhvcj48L2F1dGhvcnM+PC9j

b250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5Vbml2ZXJzaXR5IE1lZGljYWwgUmVzZWFyY2ggTExD

LCBTdCBGcmFuY2lzIEhvc3BpdGFsLCBIYXJ0Zm9yZCwgQ29ubmVjdGljdXQsIFVuaXRlZCBTdGF0

ZXMgOyBncm9zc25pY2hvbGFzMUBnbWFpbC5jb20uJiN4RDtOYXRpb25hbCBIZWFydCAmYW1wOyBM

dW5nIEluc3RpdHV0ZSwgSW1wZXJpYWwgQ29sbGVnZSBMb25kb24sIEFpcndheSBEaXNlYXNlIFNl

Y3Rpb24sIExvbmRvbiwgVW5pdGVkIEtpbmdkb20gb2YgR3JlYXQgQnJpdGFpbiBhbmQgTm9ydGhl

cm4gSXJlbGFuZCA7IHAuai5iYXJuZXNAaW1wZXJpYWwuYWMudWsuPC9hdXRoLWFkZHJlc3M+PHRp

dGxlcz48dGl0bGU+TmV3IHRoZXJhcGllcyBmb3IgYXN0aG1hIGFuZCBjaHJvbmljIG9ic3RydWN0

aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGly

IENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFyeS10aXRsZT48YWx0LXRpdGxlPkFtZXJpY2FuIGpvdXJu

YWwgb2YgcmVzcGlyYXRvcnkgYW5kIGNyaXRpY2FsIGNhcmUgbWVkaWNpbmU8L2FsdC10aXRsZT48

L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0IENhcmUgTWVk

PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTU5LTE2NjwvcGFnZXM+PHZvbHVtZT4x

OTU8L3ZvbHVtZT48ZWRpdGlvbj4yMDE2LzEyLzA3PC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29y

ZD5OZXcgYnJvbmNob2RpbGF0b3JzPC9rZXl3b3JkPjxrZXl3b3JkPmtpbmFzZSBpbmhpYml0b3Jz

PC9rZXl3b3JkPjxrZXl3b3JkPm1lZGlhdG9yIGFudGFnb25pc3RzPC9rZXl3b3JkPjxrZXl3b3Jk

Pm5ldyBjb3J0aWNvc3Rlcm9pZHM8L2tleXdvcmQ+PGtleXdvcmQ+cGhvc3Bob2RpZXN0ZXJhc2Ug

aW5oaWJpdG9yczwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxw

dWItZGF0ZXM+PGRhdGU+RGVjIDA2PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MTA3

My00NDl4PC9pc2JuPjxhY2Nlc3Npb24tbnVtPjI3OTIyNzUxPC9hY2Nlc3Npb24tbnVtPjx1cmxz

PjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTE2NC9yY2NtLjIwMTYxMC0yMDc0

UFA8L2VsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjxyZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+TkxN

PC9yZW1vdGUtZGF0YWJhc2UtcHJvdmlkZXI+PGxhbmd1YWdlPmVuZzwvbGFuZ3VhZ2U+PC9yZWNv

cmQ+PC9DaXRlPjwvRW5kTm90ZT4A

ADDIN EN.CITE.DATA [151, 152]. An additional challenge in COPD is the treatment of comorbidities, but the recent recognition that these comorbid diseases share common molecular mechanisms, such as cellular senescence, may lead to the development of drugs that may treat multimorbidity ADDIN EN.CITE <EndNote><Cite><Author>Barnes</Author><Year>2016</Year><RecNum>12843</RecNum><DisplayText>[128]</DisplayText><record><rec-number>12843</rec-number><foreign-keys><key app="EN" db-id="tr0rz0rfj52f5fevrp7vzdsksvr5wwzezwe0" timestamp="1468403360">12843</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnes, P.J.</author></authors></contributors><titles><title>Senescence in COPD and its comorbidities</title><secondary-title>Annu Rev Physiol</secondary-title></titles><periodical><full-title>Annu Rev Physiol</full-title></periodical><dates><year>2016</year></dates><urls></urls></record></Cite></EndNote>[128].Corticosteroid resistanceResistance to the anti-inflammatory effects of corticosteroids is one of the major barriers to effective treatment of severe asthma and COPD, prompting a search for alternative anti-inflammatory treatments, Several molecular mechanisms of corticosteroid resistance in asthma and COPD have been identified and include decreased HDAC2 activity and expression due to activation of PI3K signalling pathways in severe asthma and COPD, phosphorylation of the glucocorticoid receptor (GR) by MAP kinases, such as p38 and JNK, which reduce GR nuclear translocation and activation of mTOR, resulting in increased c-Jun and increased activation of transcription factor activator protein-1 (AP-1) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+MTE2OTQ8L1JlY051bT48RGlzcGxheVRleHQ+WzE1My0xNTVdPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjExNjk0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1l

c3RhbXA9IjEzNzg0NzkwMDUiPjExNjk0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5CYXJuZXMsUC5KLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0

bGVzPjx0aXRsZT5Db3J0aWNvc3Rlcm9pZCByZXNpc3RhbmNlIGluIHBhdGllbnRzIHdpdGggYXN0

aG1hIGFuZCBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVub2wuPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbGxlcmd5IENsaW4uSW1tdW5vbC48L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz42MzYtNjQ1PC9wYWdlcz48dm9sdW1lPjEzMTwv

dm9sdW1lPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPkFD

VElPTjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZB

VElPTjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUT1I8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJ

VElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BTFBIQTwv

a2V5d29yZD48a2V5d29yZD5BTlRJLUlORkxBTU1BVE9SWTwva2V5d29yZD48a2V5d29yZD5BUFBS

T0FDSEVTPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5hc3RobWF0

aWM8L2tleXdvcmQ+PGtleXdvcmQ+QklORElORzwva2V5d29yZD48a2V5d29yZD5DLUpVTjwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lE

PC9rZXl3b3JkPjxrZXl3b3JkPkNvcnRpY29zdGVyb2lkczwva2V5d29yZD48a2V5d29yZD5ESVNF

QVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRSVUc8L2tleXdvcmQ+PGtleXdvcmQ+RFJVR1M8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVFM8L2tleXdvcmQ+PGtl

eXdvcmQ+RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdv

cmQ+R0VORTwva2V5d29yZD48a2V5d29yZD5HRU5FUzwva2V5d29yZD48a2V5d29yZD5HTFVDT0NP

UlRJQ09JRDwva2V5d29yZD48a2V5d29yZD5nbHVjb2NvcnRpY29pZCByZWNlcHRvcjwva2V5d29y

ZD48a2V5d29yZD5IRUFSVDwva2V5d29yZD48a2V5d29yZD5oaXN0b25lPC9rZXl3b3JkPjxrZXl3

b3JkPkhpc3RvbmUgRGVhY2V0eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5DUkVBU0U8L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3

b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5JTkhJQklUPC9rZXl3b3JkPjxrZXl3

b3JkPklOSElCSVRPUjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1JTPC9rZXl3b3JkPjxrZXl3

b3JkPklOSElCSVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVFM8L2tleXdvcmQ+PGtleXdv

cmQ+S0lOQVNFPC9rZXl3b3JkPjxrZXl3b3JkPktJTkFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+TGVh

ZDwva2V5d29yZD48a2V5d29yZD5sb25kb248L2tleXdvcmQ+PGtleXdvcmQ+TE9ORyBBQ1RJTkc8

L2tleXdvcmQ+PGtleXdvcmQ+TE9ORy1BQ1RJTkc8L2tleXdvcmQ+PGtleXdvcmQ+THVuZzwva2V5

d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1BSk9SPC9rZXl3b3Jk

PjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUFOQUdJTkc8L2tleXdvcmQ+

PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tleXdvcmQ+

PGtleXdvcmQ+TUVESUFURTwva2V5d29yZD48a2V5d29yZD5NSUdSQVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3

b3JkPk5FVzwva2V5d29yZD48a2V5d29yZD5OT1ZFTDwva2V5d29yZD48a2V5d29yZD5OVUNMRUFS

PC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk9YSURBVElW

RTwva2V5d29yZD48a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPnAz

ODwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QSE9TUEhPSU5P

U0lUSURFPC9rZXl3b3JkPjxrZXl3b3JkPnBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29y

ZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4ga2luYXNlPC9rZXl3b3JkPjxrZXl3

b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5d29y

ZD5SRURVQ0VEPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0lTVEFOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

UkVTUE9OU0lWRU5FU1M8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPlNFVkVSRTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPnN0

ZXJvaWQgcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkczwva2V5d29yZD48a2V5

d29yZD5TVFJBVEVHSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnN0cmVzczwva2V5d29yZD48a2V5d29y

ZD5UQVJHRVQ8L2tleXdvcmQ+PGtleXdvcmQ+VGhlb3BoeWxsaW5lPC9rZXl3b3JkPjxrZXl3b3Jk

PlRIRVJBUElFUzwva2V5d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRS

QU5TQ1JJUFRJT048L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNsb2NhdGlvbjwva2V5d29yZD48a2V5

d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzI2LzIwMTM8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+QkFSTkVTMjAxMzwvbGFiZWw+PHVybHM+PC91

cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1pdGFuaTwvQXV0aG9yPjxZZWFyPjIw

MTY8L1llYXI+PFJlY051bT4xMjQxNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTI0MTQ8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1

MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTQ0MTg5MTU4MSI+MTI0MTQ8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1pdGFuaSxBLjwvYXV0aG9y

PjxhdXRob3I+SXRvLCBLLjwvYXV0aG9yPjxhdXRob3I+VnVwcHVzZXR0eSwgQy48L2F1dGhvcj48

YXV0aG9yPkJhcm5lcywgUC5KLjwvYXV0aG9yPjxhdXRob3I+TWVyY2FkbywgTi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+UmVzdG9yYXRpb24gb2YgY29y

dGljb3N0ZXJvaWQgc2Vuc2l0aXZpdHkgaW4gY2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkg

ZGlzZWFzZSBieSBpbmhpYml0aW9uIG9mIG1hbW1hbGlhbiB0YXJnZXQgb2YgcmFwYW15Y2luPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0

IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTQzLTE1MzwvcGFnZXM+

PHZvbHVtZT4xOTM8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48L2RhdGVzPjx1cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVh

cj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTI4MTM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEy

ODEzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnow

cmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NjI4OTI4MTQiPjEy

ODEzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5CYXJuZXMsIFAuSi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+S2luYXNlcyBh

cyBub3ZlbCB0aGVyYXBldXRpYyB0YXJnZXRzIGluIGFzdGhtYSBhbmQgQ09QRDwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5QaGFybWFjb2wgUmV2PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+UGhhcm1hY29sIFJldjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjc4OC04MTU8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48L2RhdGVzPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

ZWNOdW0+MTE2OTQ8L1JlY051bT48RGlzcGxheVRleHQ+WzE1My0xNTVdPC9EaXNwbGF5VGV4dD48

cmVjb3JkPjxyZWMtbnVtYmVyPjExNjk0PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBh

cHA9IkVOIiBkYi1pZD0idHIwcnowcmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1l

c3RhbXA9IjEzNzg0NzkwMDUiPjExNjk0PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5h

bWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+

PGF1dGhvcj5CYXJuZXMsUC5KLjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0

bGVzPjx0aXRsZT5Db3J0aWNvc3Rlcm9pZCByZXNpc3RhbmNlIGluIHBhdGllbnRzIHdpdGggYXN0

aG1hIGFuZCBjaHJvbmljIG9ic3RydWN0aXZlIHB1bG1vbmFyeSBkaXNlYXNlPC90aXRsZT48c2Vj

b25kYXJ5LXRpdGxlPkogQWxsZXJneSBDbGluLkltbXVub2wuPC9zZWNvbmRhcnktdGl0bGU+PC90

aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBBbGxlcmd5IENsaW4uSW1tdW5vbC48L2Z1

bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz42MzYtNjQ1PC9wYWdlcz48dm9sdW1lPjEzMTwv

dm9sdW1lPjxyZXByaW50LWVkaXRpb24+Tm90IGluIEZpbGU8L3JlcHJpbnQtZWRpdGlvbj48a2V5

d29yZHM+PGtleXdvcmQ+MTwva2V5d29yZD48a2V5d29yZD4yPC9rZXl3b3JkPjxrZXl3b3JkPkFD

VElPTjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFURUQ8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZB

VElPTjwva2V5d29yZD48a2V5d29yZD5BQ1RJVkFUT1I8L2tleXdvcmQ+PGtleXdvcmQ+QUNUSVZJ

VElFUzwva2V5d29yZD48a2V5d29yZD5BQ1RJVklUWTwva2V5d29yZD48a2V5d29yZD5BTFBIQTwv

a2V5d29yZD48a2V5d29yZD5BTlRJLUlORkxBTU1BVE9SWTwva2V5d29yZD48a2V5d29yZD5BUFBS

T0FDSEVTPC9rZXl3b3JkPjxrZXl3b3JkPkFzdGhtYTwva2V5d29yZD48a2V5d29yZD5hc3RobWF0

aWM8L2tleXdvcmQ+PGtleXdvcmQ+QklORElORzwva2V5d29yZD48a2V5d29yZD5DLUpVTjwva2V5

d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJVQ1RJ

VkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlzZWFz

ZTwva2V5d29yZD48a2V5d29yZD5DT1BEPC9rZXl3b3JkPjxrZXl3b3JkPkNPUlRJQ09TVEVST0lE

PC9rZXl3b3JkPjxrZXl3b3JkPkNvcnRpY29zdGVyb2lkczwva2V5d29yZD48a2V5d29yZD5ESVNF

QVNFPC9rZXl3b3JkPjxrZXl3b3JkPkRSVUc8L2tleXdvcmQ+PGtleXdvcmQ+RFJVR1M8L2tleXdv

cmQ+PGtleXdvcmQ+RUZGRUNUPC9rZXl3b3JkPjxrZXl3b3JkPkVGRkVDVFM8L2tleXdvcmQ+PGtl

eXdvcmQ+RVhQUkVTU0lPTjwva2V5d29yZD48a2V5d29yZD5GQUNUT1I8L2tleXdvcmQ+PGtleXdv

cmQ+R0VORTwva2V5d29yZD48a2V5d29yZD5HRU5FUzwva2V5d29yZD48a2V5d29yZD5HTFVDT0NP

UlRJQ09JRDwva2V5d29yZD48a2V5d29yZD5nbHVjb2NvcnRpY29pZCByZWNlcHRvcjwva2V5d29y

ZD48a2V5d29yZD5IRUFSVDwva2V5d29yZD48a2V5d29yZD5oaXN0b25lPC9rZXl3b3JkPjxrZXl3

b3JkPkhpc3RvbmUgRGVhY2V0eWxhc2U8L2tleXdvcmQ+PGtleXdvcmQ+SU48L2tleXdvcmQ+PGtl

eXdvcmQ+SU5DUkVBU0U8L2tleXdvcmQ+PGtleXdvcmQ+SU5DUkVBU0VEPC9rZXl3b3JkPjxrZXl3

b3JkPmluZmxhbW1hdG9yeTwva2V5d29yZD48a2V5d29yZD5JTkhJQklUPC9rZXl3b3JkPjxrZXl3

b3JkPklOSElCSVRPUjwva2V5d29yZD48a2V5d29yZD5JTkhJQklUT1JTPC9rZXl3b3JkPjxrZXl3

b3JkPklOSElCSVRPUlk8L2tleXdvcmQ+PGtleXdvcmQ+SU5ISUJJVFM8L2tleXdvcmQ+PGtleXdv

cmQ+S0lOQVNFPC9rZXl3b3JkPjxrZXl3b3JkPktJTkFTRVM8L2tleXdvcmQ+PGtleXdvcmQ+TGVh

ZDwva2V5d29yZD48a2V5d29yZD5sb25kb248L2tleXdvcmQ+PGtleXdvcmQ+TE9ORyBBQ1RJTkc8

L2tleXdvcmQ+PGtleXdvcmQ+TE9ORy1BQ1RJTkc8L2tleXdvcmQ+PGtleXdvcmQ+THVuZzwva2V5

d29yZD48a2V5d29yZD5NQUNST1BIQUdFPC9rZXl3b3JkPjxrZXl3b3JkPk1BSk9SPC9rZXl3b3Jk

PjxrZXl3b3JkPk1BTkFHRU1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+TUFOQUdJTkc8L2tleXdvcmQ+

PGtleXdvcmQ+TUVDSEFOSVNNPC9rZXl3b3JkPjxrZXl3b3JkPk1FQ0hBTklTTVM8L2tleXdvcmQ+

PGtleXdvcmQ+TUVESUFURTwva2V5d29yZD48a2V5d29yZD5NSUdSQVRJT048L2tleXdvcmQ+PGtl

eXdvcmQ+TU9MRUNVTEFSPC9rZXl3b3JkPjxrZXl3b3JkPk5BVElPTkFMPC9rZXl3b3JkPjxrZXl3

b3JkPk5FVzwva2V5d29yZD48a2V5d29yZD5OT1ZFTDwva2V5d29yZD48a2V5d29yZD5OVUNMRUFS

PC9rZXl3b3JkPjxrZXl3b3JkPk9CU1RSVUNUSVZFPC9rZXl3b3JkPjxrZXl3b3JkPk9YSURBVElW

RTwva2V5d29yZD48a2V5d29yZD5PeGlkYXRpdmUgU3RyZXNzPC9rZXl3b3JkPjxrZXl3b3JkPnAz

ODwva2V5d29yZD48a2V5d29yZD5QQVRJRU5UUzwva2V5d29yZD48a2V5d29yZD5QSE9TUEhPSU5P

U0lUSURFPC9rZXl3b3JkPjxrZXl3b3JkPnBob3NwaG9yeWxhdGlvbjwva2V5d29yZD48a2V5d29y

ZD5QUk9URUlOPC9rZXl3b3JkPjxrZXl3b3JkPlByb3RlaW4ga2luYXNlPC9rZXl3b3JkPjxrZXl3

b3JkPlBVTE1PTkFSWTwva2V5d29yZD48a2V5d29yZD5yZWNlcHRvcjwva2V5d29yZD48a2V5d29y

ZD5SRURVQ0VEPC9rZXl3b3JkPjxrZXl3b3JkPlJFU0lTVEFOQ0U8L2tleXdvcmQ+PGtleXdvcmQ+

UkVTUE9OU0lWRU5FU1M8L2tleXdvcmQ+PGtleXdvcmQ+U0VDUkVUSU9OPC9rZXl3b3JkPjxrZXl3

b3JkPlNFVkVSRTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkPC9rZXl3b3JkPjxrZXl3b3JkPnN0

ZXJvaWQgcmVzaXN0YW5jZTwva2V5d29yZD48a2V5d29yZD5zdGVyb2lkczwva2V5d29yZD48a2V5

d29yZD5TVFJBVEVHSUVTPC9rZXl3b3JkPjxrZXl3b3JkPnN0cmVzczwva2V5d29yZD48a2V5d29y

ZD5UQVJHRVQ8L2tleXdvcmQ+PGtleXdvcmQ+VGhlb3BoeWxsaW5lPC9rZXl3b3JkPjxrZXl3b3Jk

PlRIRVJBUElFUzwva2V5d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRS

QU5TQ1JJUFRJT048L2tleXdvcmQ+PGtleXdvcmQ+VHJhbnNsb2NhdGlvbjwva2V5d29yZD48a2V5

d29yZD5UUkVBVE1FTlQ8L2tleXdvcmQ+PGtleXdvcmQ+VU5JVEVEPC9rZXl3b3JkPjwva2V5d29y

ZHM+PGRhdGVzPjx5ZWFyPjIwMTM8L3llYXI+PHB1Yi1kYXRlcz48ZGF0ZT4xLzI2LzIwMTM8L2Rh

dGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48bGFiZWw+QkFSTkVTMjAxMzwvbGFiZWw+PHVybHM+PC91

cmxzPjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPk1pdGFuaTwvQXV0aG9yPjxZZWFyPjIw

MTY8L1llYXI+PFJlY051bT4xMjQxNDwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+MTI0MTQ8

L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ0cjByejByZmo1

MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFtcD0iMTQ0MTg5MTU4MSI+MTI0MTQ8

L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4xNzwv

cmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPk1pdGFuaSxBLjwvYXV0aG9y

PjxhdXRob3I+SXRvLCBLLjwvYXV0aG9yPjxhdXRob3I+VnVwcHVzZXR0eSwgQy48L2F1dGhvcj48

YXV0aG9yPkJhcm5lcywgUC5KLjwvYXV0aG9yPjxhdXRob3I+TWVyY2FkbywgTi48L2F1dGhvcj48

L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+UmVzdG9yYXRpb24gb2YgY29y

dGljb3N0ZXJvaWQgc2Vuc2l0aXZpdHkgaW4gY2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkg

ZGlzZWFzZSBieSBpbmhpYml0aW9uIG9mIG1hbW1hbGlhbiB0YXJnZXQgb2YgcmFwYW15Y2luPC90

aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkFtIEogUmVzcGlyIENyaXQgQ2FyZSBNZWQ8L3NlY29uZGFy

eS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5BbSBKIFJlc3BpciBDcml0

IENhcmUgTWVkPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+MTQzLTE1MzwvcGFnZXM+

PHZvbHVtZT4xOTM8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+MjAxNjwveWVhcj48L2RhdGVzPjx1cmxz

PjwvdXJscz48L3JlY29yZD48L0NpdGU+PENpdGU+PEF1dGhvcj5CYXJuZXM8L0F1dGhvcj48WWVh

cj4yMDE2PC9ZZWFyPjxSZWNOdW0+MTI4MTM8L1JlY051bT48cmVjb3JkPjxyZWMtbnVtYmVyPjEy

ODEzPC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0idHIwcnow

cmZqNTJmNWZldnJwN3Z6ZHNrc3ZyNXd3emV6d2UwIiB0aW1lc3RhbXA9IjE0NjI4OTI4MTQiPjEy

ODEzPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+

MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5CYXJuZXMsIFAuSi48

L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PHRpdGxlcz48dGl0bGU+S2luYXNlcyBh

cyBub3ZlbCB0aGVyYXBldXRpYyB0YXJnZXRzIGluIGFzdGhtYSBhbmQgQ09QRDwvdGl0bGU+PHNl

Y29uZGFyeS10aXRsZT5QaGFybWFjb2wgUmV2PC9zZWNvbmRhcnktdGl0bGU+PC90aXRsZXM+PHBl

cmlvZGljYWw+PGZ1bGwtdGl0bGU+UGhhcm1hY29sIFJldjwvZnVsbC10aXRsZT48L3BlcmlvZGlj

YWw+PHBhZ2VzPjc4OC04MTU8L3BhZ2VzPjx2b2x1bWU+Njg8L3ZvbHVtZT48ZGF0ZXM+PHllYXI+

MjAxNjwveWVhcj48L2RhdGVzPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl

PgB=

ADDIN EN.CITE.DATA [153-155]. Identification of the molecular mechanisms of corticosteroid resistance suggests that treatments may be directed to reversing corticosteroid resistance., For example, theophylline is a potent inhibitor of PI3K-δ and is able to reverse corticosteroid resistance in COPD and severe asthma cells, whereas LABA, such as formoterol, and p38 inhibitors may reverse GR phosphorylation and enhance GR nuclear translocation and thus anti-inflammatory effects.Drug deliveryMore effective drug delivery is an important area of research. Inhaled therapies that directly target lung cells has been an effective strategy for reducing side effects, but current inhaler devices are often inefficient. Better delivery of inhaled drugs to peripheral airways is particularly important in treating severe asthma and COPD and new aerosols with smaller particle size have been developed PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Vc21hbmk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE1NDk8L1JlY051bT48RGlzcGxheVRleHQ+WzE1Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE1NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMyI+MTE1NDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlVzbWFuaSxPLlMuPC9hdXRob3I+PGF1dGhvcj5CYXJuZXMsUC5KLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Bc3Nlc3NpbmcgYW5kIHRyZWF0aW5n

IHNtYWxsIGFpcndheXMgZGlzZWFzZSBpbiBhc3RobWEgYW5kIGNocm9uaWMgb2JzdHJ1Y3RpdmUg

cHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW5uLk1lZC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Bbm4uTWVkLjwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE0Ni0xNTY8L3BhZ2VzPjx2b2x1bWU+NDQ8L3Zv

bHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFCTk9STUFMSVRJRVM8L2tleXdvcmQ+PGtl

eXdvcmQ+YWJzdHJhY3Q8L2tleXdvcmQ+PGtleXdvcmQ+QURWQU5DRVM8L2tleXdvcmQ+PGtleXdv

cmQ+QUVST1NPTDwva2V5d29yZD48a2V5d29yZD5BRVJPU09MSVpFRDwva2V5d29yZD48a2V5d29y

ZD5BSVJGTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3

YXlzPC9rZXl3b3JkPjxrZXl3b3JkPkFQUFJPQUNIRVM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNT

TUVOVDwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+Q0hBTkdFUzwv

a2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJV

Q1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlz

ZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9r

ZXl3b3JkPjxrZXl3b3JkPkRFVklDRVM8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29y

ZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5ESVNPUkRFUlM8L2tleXdvcmQ+

PGtleXdvcmQ+RFJVRzwva2V5d29yZD48a2V5d29yZD5FRkZJQ0FDWTwva2V5d29yZD48a2V5d29y

ZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkhFQVJU

PC9rZXl3b3JkPjxrZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT1BBVEhP

TE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8

L2tleXdvcmQ+PGtleXdvcmQ+SU5IQUxBVElPTjwva2V5d29yZD48a2V5d29yZD5JTkhBTEVSPC9r

ZXl3b3JkPjxrZXl3b3JkPkxBUkdFPC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+bG9uZG9uPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+bW9y

cGhvbG9neTwva2V5d29yZD48a2V5d29yZD5OQVRJT05BTDwva2V5d29yZD48a2V5d29yZD5ORVc8

L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UGFydGljbGUg

U2l6ZTwva2V5d29yZD48a2V5d29yZD5QQVRIT1BIWVNJT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+

UEhZU0lPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UkVDRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlJFR0lPTjwva2V5d29yZD48a2V5d29yZD5SRVNQ

SVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFDVDwva2V5d29yZD48a2V5

d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5T

VFJVQ1RVUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RV

RFk8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VUPC9rZXl3b3JkPjxrZXl3b3JkPlRFU1RTPC9rZXl3

b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUElFUzwva2V5

d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRSQUNUPC9rZXl3b3JkPjxr

ZXl3b3JkPlRSRUFUTUVOVDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+My8yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxh

YmVsPlVTTUFOSTIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Vc21hbmk8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

ZWNOdW0+MTE1NDk8L1JlY051bT48RGlzcGxheVRleHQ+WzE1Nl08L0Rpc3BsYXlUZXh0PjxyZWNv

cmQ+PHJlYy1udW1iZXI+MTE1NDk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0i

RU4iIGRiLWlkPSJ0cjByejByZmo1MmY1ZmV2cnA3dnpkc2tzdnI1d3d6ZXp3ZTAiIHRpbWVzdGFt

cD0iMTM3ODQ3OTAwMyI+MTE1NDk8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i

Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0

aG9yPlVzbWFuaSxPLlMuPC9hdXRob3I+PGF1dGhvcj5CYXJuZXMsUC5KLjwvYXV0aG9yPjwvYXV0

aG9ycz48L2NvbnRyaWJ1dG9ycz48dGl0bGVzPjx0aXRsZT5Bc3Nlc3NpbmcgYW5kIHRyZWF0aW5n

IHNtYWxsIGFpcndheXMgZGlzZWFzZSBpbiBhc3RobWEgYW5kIGNocm9uaWMgb2JzdHJ1Y3RpdmUg

cHVsbW9uYXJ5IGRpc2Vhc2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0bGU+QW5uLk1lZC48L3NlY29u

ZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48ZnVsbC10aXRsZT5Bbm4uTWVkLjwvZnVs

bC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE0Ni0xNTY8L3BhZ2VzPjx2b2x1bWU+NDQ8L3Zv

bHVtZT48bnVtYmVyPjI8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxlPC9yZXBy

aW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFCTk9STUFMSVRJRVM8L2tleXdvcmQ+PGtl

eXdvcmQ+YWJzdHJhY3Q8L2tleXdvcmQ+PGtleXdvcmQ+QURWQU5DRVM8L2tleXdvcmQ+PGtleXdv

cmQ+QUVST1NPTDwva2V5d29yZD48a2V5d29yZD5BRVJPU09MSVpFRDwva2V5d29yZD48a2V5d29y

ZD5BSVJGTE9XPC9rZXl3b3JkPjxrZXl3b3JkPkFJUldBWTwva2V5d29yZD48a2V5d29yZD5BaXJ3

YXlzPC9rZXl3b3JkPjxrZXl3b3JkPkFQUFJPQUNIRVM8L2tleXdvcmQ+PGtleXdvcmQ+QVNTRVNT

TUVOVDwva2V5d29yZD48a2V5d29yZD5Bc3RobWE8L2tleXdvcmQ+PGtleXdvcmQ+Q0hBTkdFUzwv

a2V5d29yZD48a2V5d29yZD5DSFJPTklDPC9rZXl3b3JkPjxrZXl3b3JkPkNIUk9OSUMgT0JTVFJV

Q1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBvYnN0cnVjdGl2ZSBwdWxtb25hcnkgZGlz

ZWFzZTwva2V5d29yZD48a2V5d29yZD5jbGluaWNhbDwva2V5d29yZD48a2V5d29yZD5DT1BEPC9r

ZXl3b3JkPjxrZXl3b3JkPkRFVklDRVM8L2tleXdvcmQ+PGtleXdvcmQ+RElTRUFTRTwva2V5d29y

ZD48a2V5d29yZD5ESVNFQVNFUzwva2V5d29yZD48a2V5d29yZD5ESVNPUkRFUlM8L2tleXdvcmQ+

PGtleXdvcmQ+RFJVRzwva2V5d29yZD48a2V5d29yZD5FRkZJQ0FDWTwva2V5d29yZD48a2V5d29y

ZD5GTE9XPC9rZXl3b3JkPjxrZXl3b3JkPmZ1bmN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPkhFQVJU

PC9rZXl3b3JkPjxrZXl3b3JkPkhPU1BJVEFMPC9rZXl3b3JkPjxrZXl3b3JkPklNTVVOT1BBVEhP

TE9HWTwva2V5d29yZD48a2V5d29yZD5JTjwva2V5d29yZD48a2V5d29yZD5pbmZsYW1tYXRvcnk8

L2tleXdvcmQ+PGtleXdvcmQ+SU5IQUxBVElPTjwva2V5d29yZD48a2V5d29yZD5JTkhBTEVSPC9r

ZXl3b3JkPjxrZXl3b3JkPkxBUkdFPC9rZXl3b3JkPjxrZXl3b3JkPkxlYWQ8L2tleXdvcmQ+PGtl

eXdvcmQ+bG9uZG9uPC9rZXl3b3JkPjxrZXl3b3JkPkx1bmc8L2tleXdvcmQ+PGtleXdvcmQ+bW9y

cGhvbG9neTwva2V5d29yZD48a2V5d29yZD5OQVRJT05BTDwva2V5d29yZD48a2V5d29yZD5ORVc8

L2tleXdvcmQ+PGtleXdvcmQ+T0JTVFJVQ1RJVkU8L2tleXdvcmQ+PGtleXdvcmQ+UGFydGljbGUg

U2l6ZTwva2V5d29yZD48a2V5d29yZD5QQVRIT1BIWVNJT0xPR1k8L2tleXdvcmQ+PGtleXdvcmQ+

UEhZU0lPTE9HSUNBTDwva2V5d29yZD48a2V5d29yZD5QVUxNT05BUlk8L2tleXdvcmQ+PGtleXdv

cmQ+UkVDRU5UPC9rZXl3b3JkPjxrZXl3b3JkPlJFR0lPTjwva2V5d29yZD48a2V5d29yZD5SRVNQ

SVJBVE9SWTwva2V5d29yZD48a2V5d29yZD5SRVNQSVJBVE9SWSBUUkFDVDwva2V5d29yZD48a2V5

d29yZD5SRVNQT05TRTwva2V5d29yZD48a2V5d29yZD5TTUFMTDwva2V5d29yZD48a2V5d29yZD5T

VFJVQ1RVUkFMPC9rZXl3b3JkPjxrZXl3b3JkPlNUVURJRVM8L2tleXdvcmQ+PGtleXdvcmQ+U1RV

RFk8L2tleXdvcmQ+PGtleXdvcmQ+VEFSR0VUPC9rZXl3b3JkPjxrZXl3b3JkPlRFU1RTPC9rZXl3

b3JkPjxrZXl3b3JkPlRIRVJBUEVVVElDPC9rZXl3b3JkPjxrZXl3b3JkPlRIRVJBUElFUzwva2V5

d29yZD48a2V5d29yZD50aGVyYXB5PC9rZXl3b3JkPjxrZXl3b3JkPlRSQUNUPC9rZXl3b3JkPjxr

ZXl3b3JkPlRSRUFUTUVOVDwva2V5d29yZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDEyPC95

ZWFyPjxwdWItZGF0ZXM+PGRhdGU+My8yMDEyPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxh

YmVsPlVTTUFOSTIwMTI8L2xhYmVsPjx1cmxzPjwvdXJscz48L3JlY29yZD48L0NpdGU+PC9FbmRO

b3RlPgB=

ADDIN EN.CITE.DATA [156]. Targeting specific cell types, such as macrophages, may be developed in the future as a more selective approach. COPD is a systemic disease so it may be important to develop systemic therapies, although this poses a high risk of side effects, so may necessitate specific cell delivery mechanisms. REFERENCES ADDIN EN.REFLIST 1Postma, D. S. and Rabe, K. F. (2015) The Asthma-COPD Overlap Syndrome. N Engl J Med. 373, 1241-12492Bateman, E. D., Reddel, H. K., van Zyl-Smit, R. N. and Agusti, A. (2015) The asthma-COPD overlap syndrome: towards a revised taxonomy of chronic airways diseases? The lancet. Respiratory medicine. 3, 719-7283Barnes, P. J. (2016) Asthma-COPD Overlap. Chest. 149, 7-84Price, D., Fletcher, M. and van der Molen, T. (2014) Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ primary care respiratory medicine. 24, 140095Barnes, P. J. (2011) Pathophysiology of allergic inflammation. Immunol Rev. 242, 31-506Wenzel, S. E. (2016) Emergence of biomolecular pathways to define novel asthma phenotypes. Type-2 immunity and beyond. Am J Respir Cell Mol Biol. 55, 1-47Lotvall, J., Akdis, C. A., Bacharier, L. B., Bjermer, L., Casale, T. B., Custovic, A., Lemanske, R. F., Jr., Wardlaw, A. J., Wenzel, S. E. and Greenberger, P. A. (2011) Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin.Immunol. 127, 355-3608Hirota, N. and Martin, J. G. (2013) Mechanisms of airway remodeling. Chest. 144, 1026-10329Harvey, B. C. and Lutchen, K. R. (2013) Factors determining airway caliber in asthma. Critical reviews in biomedical engineering. 41, 515-53210Hekking, P. P., Wener, R. R., Amelink, M., Zwinderman, A. H., Bouvy, M. L. and Bel, E. H. (2015) The prevalence of severe refractory asthma. J Allergy Clin Immunol. 135, 896-90211Ray, A., Raundhal, M., Oriss, T. B., Ray, P. and Wenzel, S. E. (2016) Current concepts of severe asthma. J Clin Invest. 126, 2394-240312Barnes, P. J., Burney, P. G. J., Silverman, E. K., Celli, B. R., Vestbo, J., Wedzicha, J. A. and Wouters, E. F. M. (2015) Chronic obstructive pulmonary disease. Nature Rev Primers. 1, 1-2113Lozano, R., Naghavi, M., Foreman, K.,et al. (2012) Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 380, 2095-212814Salvi, S. S. and Barnes, P. J. (2009) Chronic obstructive pulmonary disease in non-smokers. Lancet. 374, 733-74315Castaldi, P. J., Dy, J., Ross, J., et al. (2014) Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema. Thorax. 69, 415-42216Burgel, P. R., Paillasseur, J. L., Caillaud, D., Tillie-Leblond, I., Chanez, P., Escamilla, R., Court-Fortune, I., Perez, T., Carre, P. and Roche, N. (2010) Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur Respir J. 36, 531-53917Barnes, P. J. (2016) Inflammatory mechanisms in COPD. J Allergy Clin Immunol. 138, 16-2718Barnes, P. J. (2014) Cellular and molecular mechanisms of Chronic Obstructive Pulmonary Disease. Clin Chest Med. 35, 71-8619McDonough, J. E., Yuan, R., Suzuki, M., Seyednejad, N., Elliott, W. M., Sanchez, P. G., Wright, A. C., Gefter, W. B., Litzky, L., Coxson, H. O., Pare, P. D., Sin, D. D., Pierce, R. A., Woods, J. C., McWilliams, A. M., Mayo, J. R., Lam, S. C., Cooper, J. D. and Hogg, J. C. (2011) Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N.Engl.J Med. 365, 1567-157520Galban, C. J., Han, M. K., Boes, J. L., Chughtai, K. A., Meyer, C. R., Johnson, T. D., Galban, S., Rehemtulla, A., Kazerooni, E. A., Martinez, F. J. and Ross, B. D. (2012) Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med. 18, 1711-171521Lange, P., Celli, B., Agusti, A., Boje Jensen, G., Divo, M., Faner, R., Guerra, S., Marott, J. L., Martinez, F. D., Martinez-Camblor, P., Meek, P., Owen, C. A., Petersen, H., Pinto-Plata, V., Schnohr, P., Sood, A., Soriano, J. B., Tesfaigzi, Y. and Vestbo, J. (2015) Lung-function trajectories leading to chronic obstructive pulmonary disease. N Engl J Med. 373, 111-12222Martinez, F. D. (2016) Early-life origins of chronic obstructive pulmonary disease. N Engl J Med. 375, 871-87823Barnes, P. J. (2008) Immunology of asthma and chronic obstructive pulmonary disease. Nat Immunol Rev. 8, 183-19224Brusselle, G. G., Joos, G. F. and Bracke, K. R. (2011) New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 378, 1015-102625Hogg, J. C., Chu, F., Utokaparch, S., Woods, R., Elliott, W. M., Buzatu, L., Cherniack, R. M., Rogers, R. M., Sciurba, F. C., Coxson, H. O. and Pare, P. D. (2004) The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 350, 2645-265326Givi, M. E., Redegeld, F. A., Folkerts, G. and Mortaz, E. (2012) Dendritic cells in pathogenesis of COPD. Curr Pharm Design. 18, 2329-233527Arthur, G. and Bradding, P. (2016) New developments in mast cell biology: clinical Implications. Chest. 150, 680-69328Galli, S. J. and Tsai, M. (2012) IgE and mast cells in allergic disease. Nat Med. 18, 693-70429Reber, L., Da Silva, C. A. and Frossard, N. (2006) Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharmacol. 533, 327-34030Brightling, C. E., Bradding, P., Symon, F. A., Holgate, S. T., Wardlaw, A. J. and Pavord, I. D. (2002) Mast-cell infiltration of airway smooth muscle in asthma. N.Engl.J Med. 346, 1699-170531Caughey, G. H. (2016) Mast cell proteases as pharmacological targets. Eur J Pharmacol. 778, 44-5532Ballarin, A., Bazzan, E., Zenteno, R. H., Turato, G., Baraldo, S., Zanovello, D., Mutti, E., Hogg, J. C., Saetta, M. and Cosio, M. G. (2012) Mast cell infiltration discriminates between histopathological phenotypes of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 186, 233-23933Morales-Nebreda, L., Misharin, A. V., Perlman, H. and Budinger, G. R. (2015) The heterogeneity of lung macrophages in the susceptibility to disease. Eur Respir Rev. 24, 505-50934Chana, K. K., Fenwick, P. S., Nicholson, A. G., Barnes, P. J. and Donnelly, L. E. (2014) Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 133, 207-21635Tomita, K., Lim, S., Hanazawa, T., Usmani, O., Stirling, R., Chung, K. F., Barnes, P. J. and Adcock, I. M. (2002) Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma. Clin Immunol. 102, 258-26636Barnes, P. J. (2004) Macrophages as orchestrators of COPD. J COPD. 1, 59-7037Traves, S. L., Culpitt, S., Russell, R. E. K., Barnes, P. J. and Donnelly, L. E. (2002) Elevated levels of the chemokines GRO-a and MCP-1 in sputum samples from COPD patients. Thorax. 57, 590-59538Traves, S. L., Smith, S. J., Barnes, P. J. and Donnelly, L. E. (2004) Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2. J Leukoc.Biol. 76, 441-45039Vlahos, R. and Bozinovski, S. (2014) Role of alveolar macrophages in chronic obstructive pulmonary disease. Frontiers Immunol. 5, 43540Culpitt, S. V., Rogers, D. F., Shah, P., de Matos, C., Russell, R. E., Donnelly, L. E. and Barnes, P. J. (2003) Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 167, 24-3141Russell, R. E., Thorley, A., Culpitt, S. V., Dodd, S., Donnelly, L. E., Demattos, C., Fitzgerald, M. and Barnes, P. J. (2002) Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases. Am J Physiol Lung Cell Mol Physiol. 283, L867-L87342Caramori, G., Romagnoli, M., Casolari, P., Bellettato, C., Casoni, G., Boschetto, P., Fan, C. K., Barnes, P. J., Adcock, I. M., Ciaccia, A., Fabbri, L. M. and Papi, A. (2003) Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. Thorax. 58, 348-35143Renda, T., Baraldo, S., Pelaia, G., Bazzan, E., Turato, G., Papi, A., Maestrelli, P., Maselli, R., Vatrella, A., Fabbri, L. M., Zuin, R., Marsico, S. A. and Saetta, M. (2008) Increased activation of p38 MAPK in COPD. Eur Respir J. 31, 62-6944Grumelli, S., Corry, D. B., Song, L.-X., Song, L., Green, L., Huh, J., Haccken, J., Espada, R., Bag, R., Lewis, D. E. and Kheradmand, F. (2004) An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med. 1, 75-8345Taylor, A. E., Finney-Hayward, T. K., Quint, J. K., Thomas, C. M., Tudhope, S. J., Wedzicha, J. A., Barnes, P. J. and Donnelly, L. E. (2010) Defective macrophage phagocytosis of bacteria in COPD. Eur Respir J. 35, 1039-104746Hodge, S., Hodge, G., Scicchitano, R., Reynolds, P. N. and Holmes, M. (2003) Alveolar macrophages from subjects with chronic obstructive pulmonary disease are deficient in their ability to phagocytose apoptotic airway epithelial cells. Immunol.Cell Biol. 81, 289-29647Singh, R., Mackay, A. J., Patel, A., Garcha, D. S., Kowlessar, B. S., Brill, S. E., Donnelly, L. E., Barnes, P. J., Donaldson, G. C. and Wedzicha, J. A. (2014) Inflammatory thresholds and the species-specific effects of colonising bacteria in stable chronic obstructive pulmonary disease. Respir Res. 15, 11448Liang, Z., Zhang, Q., Thomas, C. M., Chana, K. K., Gibeon, D., Barnes, P. J., Chung, K. F., Bhavsar, P. K. and Donnelly, L. E. (2014) Impaired macrophage phagocytosis of bacteria in severe asthma. Respir Res. 15, 7249Upham, J. W. and Xi, Y. (2016) Dendritic cells in human lung disease: recent advances. Chest50Hammad, H. and Lambrecht, B. N. (2015) Barrier epithelial cells and the control of type 2 immunity. Immunity. 43, 29-4051Van Pottelberge, G. R., Bracke, K. R., Demedts, I. K., De Rijck, K., Reinartz, S. M., van Drunen, C. M., Verleden, G. M., Vermassen, F. E., Joos, G. F. and Brusselle, G. G. (2010) Selective accumulation of langerhans-type dendritic cells in small airways of patients with COPD. Respir.Res. 11:35., 3552Freeman, C. M., Martinez, F. J., Han, M. K., Ames, T. M., Chensue, S. W., Todt, J. C., Arenberg, D. A., Meldrum, C. A., Getty, C., McCloskey, L. and Curtis, J. L. (2009) Lung dendritic cell expression of maturation molecules increases with worsening chronic obstructive pulmonary disease. Am.J Respir.Crit Care Med. 180, 1179-118853Rosenberg, H. F., Dyer, K. D. and Foster, P. S. (2013) Eosinophils: changing perspectives in health and disease. Nat Rev Immunol. 13, 9-2254Scanlon, S. T. and McKenzie, A. N. (2012) Type 2 innate lymphoid cells: new players in asthma and allergy. Curr.Opin.Immunol. 24, 707-71255Leckie, M. J., ten Brincke, A., Khan, J., Diamant, Z., O'Connor, B. J., Walls, C. M., Mathur, M., Cowley, H., Chung, K. F., Djukanovic, R. J., Hansel, T. T., Holgate, S. T., Sterk, P. J. and Barnes, P. J. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet. 356, 2144-214856Ortega, H. G., Liu, M. C., Pavord, I. D., Brusselle, G. G., FitzGerald, J. M., Chetta, A., Humbert, M., Katz, L. E., Keene, O. N., Yancey, S. W. and Chanez, P. (2014) Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 371, 1198-120757Byers, D. E., Alexander-Brett, J., Patel, A. C., Agapov, E., Dang-Vu, G., Jin, X., Wu, K., You, Y., Alevy, Y., Girard, J. P., Stappenbeck, T. S., Patterson, G. A., Pierce, R. A., Brody, S. L. and Holtzman, M. J. (2013) Long-term IL-33-producing epithelial progenitor cells in chronic obstructive lung disease. J Clin Invest. 123, 3967-398258Bafadhel, M., Saha, S., Siva, R., McCormick, M., Monteiro, W., Rugman, P., Dodson, P., Pavord, I. D., Newbold, P. and Brightling, C. E. (2009) Sputum IL-5 concentration is associated with a sputum eosinophilia and attenuated by corticosteroid therapy in COPD. Respiration. 78, 256-26259Trejo Bittar, H. E., Yousem, S. A. and Wenzel, S. E. (2015) Pathobiology of severe asthma. Annual review of pathology. 10, 511-54560Barnes, P. J. (2015) Therapeutic approaches to asthma-chronic obstructive pulmonary disease overlap syndromes. J Allergy Clin Immunol. 136, 531-54561Al-Ramli, W., Prefontaine, D., Chouiali, F., Martin, J. G., Olivenstein, R., Lemiere, C. and Hamid, Q. (2009) T(H)17-associated cytokines (IL-17A and IL-17F) in severe asthma. J Allergy Clin Immunol. 123, 1185-118762Vlahos, R., Bozinovski, S., Chan, S. P., Ivanov, S., Linden, A., Hamilton, J. A. and Anderson, G. P. (2010) Neutralizing granulocyte/macrophage colony-stimulating factor inhibits cigarette smoke-induced lung inflammation. Am.J.Respir.Crit Care Med. 182, 34-4063Di Stefano, A., Maestrelli, P., Roggeri, A., Turato, G., Calabro, S., Potena, A., Mapp, C. E., Ciaccia, A., Covacev, L. and Fabbri, L. M. (1994) Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am.J.Respir.Crit.Care Med. 149, 803-81064Keatings, V. M. and Barnes, P. J. (1997) Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma and normal subjects. Am J Respir Crit Care Med. 155, 449-45365Fahy, J. V. and Dickey, B. F. (2010) Airway mucus function and dysfunction. N.Engl.J Med. 363, 2233-224766Sapey, E., Stockley, J. A., Greenwood, H., Ahmad, A., Bayley, D., Lord, J. M., Insall, R. H. and Stockley, R. A. (2011) Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease. Am.J.Respir.Crit Care Med. 183, 1176-118667Lambrecht, B. N. and Hammad, H. (2015) The immunology of asthma. Nature immunology. 16, 45-5668Smith, S. G., Chen, R., Kjarsgaard, M., Huang, C., Oliveria, J. P., O'Byrne, P. M., Gauvreau, G. M., Boulet, L. P., Lemiere, C., Martin, J., Nair, P. and Sehmi, R. (2015) Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 137, 75-8669Halwani, R., Al-Muhsen, S. and Hamid, Q. (2013) T helper 17 cells in airway diseases: from laboratory bench to bedside. Chest. 143, 494-50170Koch, S., Sopel, N. and Finotto, S. (2016) Th9 and other IL-9-producing cells in allergic asthma. Seminars in immunopathology71Takhar, P., Corrigan, C. J., Smurthwaite, L., O'Connor, B. J., Durham, S. R., Lee, T. H. and Gould, H. J. (2007) Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma. J Allergy Clin.Immunol. 119, 213-21872Kato, A., Xiao, H., Chustz, R. T., Liu, M. C. and Schleimer, R. P. (2009) Local release of B cell-activating factor of the TNF family after segmental allergen challenge of allergic subjects. J Allergy Clin.Immunol. 123, 369-37573Seys, L. J., Verhamme, F. M., Schinwald, A., Hammad, H., Cunoosamy, D. M., Bantsimba-Malanda, C., Sabirsh, A., McCall, E., Flavell, L., Herbst, R., Provoost, S., Lambrecht, B. N., Joos, G. F., Brusselle, G. G. and Bracke, K. R. (2015) Role of B cell-activating factor in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 192, 706-71874Saetta, M., Di Stefano, A., Turato, G., Facchini, F. M., Corbino, L., Mapp, C. E., Maestrelli, P., Ciaccia, A. and Fabbri, L. M. (1998) CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am.J.Respir.Crit.Care Med. 157, 822-82675Di Stefano, A., Caramori, G., Capelli, A., Gnemmi, I., Ricciardolo, F., Oates, T., Donner, C. F., Chung, K. F., Barnes, P. J. and Adcock, I. M. (2004) STAT4 activation in smokers and patients with chronic obstructive pulmonary disease. Eur Resp J. 24, 78-8576Di Stefano, A., Caramori, G., Gnemmi, I., Contoli, M., Vicari, C., Capelli, A., Magno, F., D'Anna, S. E., Zanini, A., Brun, P., Casolari, P., Chung, K. F., Barnes, P. J., Papi, A., Adcock, I. and Balbi, B. (2009) T helper type 17-related cytokine expression is increased in the bronchial mucosa of stable chronic obstructive pulmonary disease patients. Clin Exp Immunol. 157, 316-32477Pridgeon, C., Bugeon, L., Donnelly, L., Straschil, U., Tudhope, S. J., Fenwick, P., Lamb, J. R., Barnes, P. J. and Dallman, M. J. (2011) Regulation of IL-17 in chronic inflammation in the human lung. Clin.Sci.(Lond). 120, 515-52478Costa, C., Rufino, R., Traves, S. L., JR, L. E. S., Barnes, P. J. and Donnelly, L. E. (2008) CXCR3 and CCR5 chemokines in the induced sputum from patients with COPD. Chest. 133, 26-3379Saetta, M., Mariani, M., Panina-Bordignon, P., Turato, G., Buonsanti, C., Baraldo, S., Bellettato, C. M., Papi, A., Corbetta, L., Zuin, R., Sinigaglia, F. and Fabbri, L. M. (2002) Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 165, 1404-140980Majo, J., Ghezzo, H. and Cosio, M. G. (2001) Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J. 17, 946-95381Lambers, C., Hacker, S., Posch, M., Hoetzenecker, K., Pollreisz, A., Lichtenauer, M., Klepetko, W. and Ankersmit, H. J. (2009) T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease. Clin.Exp.Immunol. 155, 466-47582Hodge, G., Mukaro, V., Reynolds, P. N. and Hodge, S. (2011) Role of increased CD8/CD28(null) T cells and alternative co-stimulatory molecules in chronic obstructive pulmonary disease. Clin.Exp.Immunol. 166, 94-10283Artis, D. and Spits, H. (2015) The biology of innate lymphoid cells. Nature. 517, 293-30184De Grove, K. C., Provoost, S., Verhamme, F. M., Bracke, K. R., Joos, G. F., Maes, T. and Brusselle, G. G. (2016) Characterization and quantification of innate lymphoid cell subsets in human lung. PloS one. 11, e014596185Nahm, D. H., Lee, Y. E., Yim, E. J., Park, H. S., Yim, H., Kang, Y. and Kim, J. K. (2002) Identification of cytokeratin 18 as a bronchial epithelial autoantigen associated with nonallergic asthma. Am J Respir Crit Care Med. 165, 1536-153986Kirkham, P. A., Caramori, G., Casolari, P., Papi, A., Edwards, M., Shamji, B., Triantaphyllopoulos, K., Hussain, F., Pinart, M., Khan, Y., Heinemann, L., Stevens, L., Yeadon, M., Barnes, P. J., Chung, K. F. and Adcock, I. M. (2011) Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of COPD. Am J Respir Crit Care Med. 184, 796-80287Karayama, M., Inui, N., Suda, T., Nakamura, Y., Nakamura, H. and Chida, K. (2010) Antiendothelial Cell Antibodies in Patients With COPD. Chest. 138, 1303-130888Klareskog, L. and Catrina, A. I. (2015) Autoimmunity: lungs and citrullination. Nature reviews. Rheumatology. 11, 261-26289Gao, W., Li, L., Wang, Y., Zhang, S., Adcock, I. M., Barnes, P. J., Huang, M. and Yao, X. (2015) Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease? Respirology (Carlton, Vic.). 20, 722-72990Pettipher, R., Hansel, T. T. and Armer, R. (2007) Antagonism of the prostaglandin D2 receptors DP1 and CRTH2 as an approach to treat allergic diseases. Nat Rev Drug Discov. 6, 313-32591Gonem, S., Berair, R., Singapuri, A., Hartley, R., Laurencin, M. F., Bacher, G., Holzhauer, B., Bourne, M., Mistry, V., Pavord, I. D., Mansur, A. H., Wardlaw, A. J., Siddiqui, S. H., Kay, R. A. and Brightling, C. E. (2016) Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. The lancet. Respiratory medicine, 699-70792Montuschi, P., Kharitonov, S. A., Ciabattoni, G. and Barnes, P. J. (2003) Exhaled leukotrienes and prostaglandins in COPD. Thorax. 58, 585-58893Beeh, K. M., Kornmann, O., Buhl, R., Culpitt, S. V., Giembycz, M. A. and Barnes, P. J. (2003) Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest. 123, 1240-124794Biernacki, W. A., Kharitonov, S. A. and Barnes, P. J. (2003) Increased leukotriene B4 and 8-isoprostane in exhaled breath condensate of patients with exacerbations of COPD. Thorax. 58, 294-29895Barnes, P. J. (2008) Cytokine networks in asthma and chronic obstructive pulmonary disease. J Clin Invest. 118, 3546-355696Barnes, P. J. (2009) The cytokine network in COPD. Am J Respir Cell Mol Biol. 41, 631-63897Parulekar, A. D., Diamant, Z. and Hanania, N. A. (2017) Role of biologics targeting type 2 airway inflammation in asthma: what have we learned so far? Curr Opin Pulm Med. 23, 3-1198Mitchell, P. D. and O'Byrne, P. M. (2016) Biologics and the lung: TSLP and other epithelial cell-derived cytokines in asthma. Pharmacol Ther99Aaron, S. D., Angel, J. B., Lunau, M., Wright, K., Fex, C., Le Saux, N. and Dales, R. E. (2001) Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 163, 349-355100Rennard, S. I., Fogarty, C., Kelsen, S., Long, W., Ramsdell, J., Allison, J., Mahler, D., Saadeh, C., Siler, T., Snell, P., Korenblat, P., Smith, W., Kaye, M., Mandel, M., Andrews, C., Prabhu, R., Donohoue, J. F., Watt, R., Hung, K. L., Schlenker-Herceg, R., Barnathan, E. S. and Murray, E. S. (2007) The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 175., 926-934101Xia, J., Zhao, J., Shang, J., Li, M., Zeng, Z., Zhao, J., Wang, J., Xu, Y. and Xie, J. (2015) Increased IL-33 expression in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 308, L619-627102Ying, S., O'Connor, B., Ratoff, J., Meng, Q., Fang, C., Cousins, D., Zhang, G., Gu, S., Gao, Z., Shamji, B., Edwards, M. J., Lee, T. H. and Corrigan, C. J. (2008) Expression and cellular provenance of thymic stromal lymphopoietin and chemokines in patients with severe asthma and chronic obstructive pulmonary disease. J Immunol. 181, 2790-2798103Rennard, S. I., Dale, D. C., Donohue, J. F., Kanniess, F., Magnussen, H., Sutherland, E. R., Watz, H., Lu, S., Stryszak, P., Rosenberg, E. and Staudinger, H. (2015) CXCR2 antagonist MK-7123- a phase 2 proof-of-concept trial for chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 191, 1001-1011104Costa, C., Traves, S. L., Tudhope, S. J., Fenwick, P. S., Belchamber, K. B., Russell, R. E., Barnes, P. J. and Donnelly, L. E. (2016) Enhanced monocyte migration to CXCR3 and CCR5 chemokines in COPD. Eur Respir J. 47, 1093-1102105Jo, E. K., Kim, J. K., Shin, D. M. and Sasakawa, C. (2016) Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 13, 148-159106Lee, S., Suh, G. Y., Ryter, S. W. and Choi, A. M. (2016) Regulation and Function of the Nucleotide Binding Domain Leucine-Rich Repeat-Containing Receptor, Pyrin Domain-Containing-3 Inflammasome in Lung Disease. Am J Respir Cell Mol Biol. 54, 151-160107Kim, R. Y., Pinkerton, J. W., Gibson, P. G., Cooper, M. A., Horvat, J. C. and Hansbro, P. M. (2015) Inflammasomes in COPD and neutrophilic asthma. Thorax. 70, 1199-1201108Bruchard, M., Rebe, C., Derangere, V., Togbe, D., Ryffel, B., Boidot, R., Humblin, E., Hamman, A., Chalmin, F., Berger, H., Chevriaux, A., Limagne, E., Apetoh, L., Vegran, F. and Ghiringhelli, F. (2015) The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nature immunol. 16, 859-870109Franklin, B. S., Bossaller, L., De Nardo, D., Ratter, J. M., Stutz, A., Engels, G., Brenker, C., Nordhoff, M., Mirandola, S. R., Al-Amoudi, A., Mangan, M. S., Zimmer, S., Monks, B. G., Fricke, M., Schmidt, R. E., Espevik, T., Jones, B., Jarnicki, A. G., Hansbro, P. M., Busto, P., Marshak-Rothstein, A., Hornemann, S., Aguzzi, A., Kastenmuller, W. and Latz, E. (2014) The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nature Immunol. 15, 727-737110Di Stefano, A., Caramori, G., Barczyk, A., Vicari, C., Brun, P., Zanini, A., Cappello, F., Garofano, E., Padovani, A., Contoli, M., Casolari, P., Durham, A. L., Chung, K. F., Barnes, P. J., Papi, A., Adcock, I. and Balbi, B. (2014) Innate immunity but not NLRP3 inflammasome activation correlates with severity of stable COPD. Thorax. 69, 516-524111Rogliani, P., Calzetta, L., Ora, J. and Matera, M. G. (2015) Canakinumab for the treatment of chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 31, 15-27112Montuschi, P., Ciabattoni, G., Corradi, M., Nightingale, J. A., Collins, J. V., Kharitonov, S. A. and Barnes, P. J. (1999) Increased 8-Isoprostane, a marker of oxidative stress, in exhaled condensates of asthmatic patients. Am J Respir Crit Care Med. 160, 216-220113Paredi, P., Kharitonov, S. A. and Barnes, P. J. (2000) Elevation of exhaled ethane concentration in asthma. Am J Respir Crit Care Med. 162, 1450-1454114Polosa, R. and Thomson, N. C. (2012) Smoking and asthma: dangerous liaisons. Eur.Respir.J.115Kirkham, P. A. and Barnes, P. J. (2013) Oxidative stress in COPD. Chest. 144, 266-273116Montuschi, P., Collins, J. V., Ciabattoni, G., Lazzeri, N., Corradi, M., Kharitonov, S. A. and Barnes, P. J. (2000) Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers. Am J Respir Crit Care Med. 162, 1175-1177117Malhotra, D., Thimmulappa, R., Navas-Acien, A., Sandford, A., Elliott, M., Singh, A., Chen, L., Zhuang, X., Hogg, J., Pare, P., Tuder, R. M. and Biswal, S. (2008) Decline in NRF2 regulated antioxidants in COPD lungs due to loss of its positive regulator DJ-1. Am J Respir Crit Care Med. 178, 592-604118Mercado, N., Thimmulappa, R., Thomas, C. M., Fenwick, P. S., Chana, K. K., Donnelly, L. E., Biswal, S., Ito, K. and Barnes, P. J. (2011) Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress. Biochem.Biophys.mun. 406, 292-298119Barnes, P. J. (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol. 71, 451-464120Nakamaru, Y., Vuppusetty, C., Wada, H., Milne, J. C., Ito, M., Rossios, C., Elliot, M., Hogg, J., Kharitonov, S., Goto, H., Bemis, J. E., Elliott, P., Barnes, P. J. and Ito, K. (2009) A protein deacetylase SIRT1 is a negative regulator of metalloproteinase-9. FASEB J. 23, 2810-2819121Mercado, N., Ito, K. and Barnes, P. J. (2015) Accelerated ageing in chronic obstructive pulmonary disease: new concepts. Thorax. 70, 482-489122Gaggar, A., Jackson, P. L., Noerager, B. D., O'Reilly, P. J., McQuaid, D. B., Rowe, S. M., Clancy, J. P. and Blalock, J. E. (2008) A novel proteolytic cascade generates an extracellular matrix-derived chemoattractant in chronic neutrophilic inflammation. J Immunol. 180, 5662-5669123Xu, X., Jackson, P. L., Tanner, S., Hardison, M. T., Abdul, R. M., Blalock, J. E. and Gaggar, A. (2011) A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation. PLoS.One. 6, e15781124Takeyama, K., Fahy, J. V. and Nadel, J. A. (2001) Relationship of epidermal growth factor receptors to goblet cell production in human bronchi. Am J Respir Crit Care Med. 163, 511-516125Russell, R. E., Culpitt, S. V., DeMatos, C., Donnelly, L., Smith, M., Wiggins, J. and Barnes, P. J. (2002) Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 26, 602-609126Pelleg, A., Schulman, E. S. and Barnes, P. J. (2016) Extracellular adenosine 5'-triphosphate in obstructive airway diseases. Chest. 150, 908-915127Abdulqawi, R., Dockry, R., Holt, K., Layton, G., McCarthy, B. G., Ford, A. P. and Smith, J. A. (2015) P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet. 385, 1198-1205128Barnes, P. J. (2017) Senescence in COPD and its comorbidities. Annu Rev Physiol 79, 517-539.129Salama, R., Sadaie, M., Hoare, M. and Narita, M. (2014) Cellular senescence and its effector programs. Genes Dev. 28, 99-114130Sideleva, O. and Dixon, A. E. (2014) The many faces of asthma in obesity. J Cell Biochem. 115, 421-426131Shore, S. A. and Cho, Y. (2016) Obesity and asthma: microbiome-metabolome interactions. Am J Respir Cell Mol Biol. 54, 609-617132Gan, W. Q., Man, S. F., Senthilselvan, A. and Sin, D. D. (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 59, 574-580133Agusti, A., Edwards, L. D., Rennard, S. I., Macnee, W., Tal-Singer, R., Miller, B. E., Vestbo, J., Lomas, D. A., Calverley, P. M., Wouters, E., Crim, C., Yates, J. C., Silverman, E. K., Coxson, H. O., Bakke, P., Mayer, R. J. and Celli, B. (2012) Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS.One. 7, e37483134Thomsen, M., Dahl, M., Lange, P., Vestbo, J. and Nordestgaard, B. G. (2012) Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am.J.Respir.Crit Care Med. 186, 982-988135Hurst, J. R., Donaldson, G. C., Perea, W. R., Wilkinson, T. M., Bilello, J. A., Hagan, G. W., Vessey, R. S. and Wedzicha, J. A. (2006) Utility of plasma biomarkers at exacerbation of chronic obstructive pulmonary disease. Am J Respir.Crit Care Med. 174, 867-874136Black, J. L., Panettieri, R. A., Jr., Banerjee, A. and Berger, P. (2012) Airway smooth muscle in asthma: just a target for bronchodilation? Clin.Chest Med. 33, 543-558137Dombret, M. C., Alagha, K., Boulet, L. P., Brillet, P. Y., Joos, G., Laviolette, M., Louis, R., Rochat, T., Soccal, P., Aubier, M. and Chanez, P. (2014) Bronchial thermoplasty: a new therapeutic option for the treatment of severe, uncontrolled asthma in adults. Eur Respir Rev. 23, 510-518138Paredi, P. and Barnes, P. J. (2009) The airway vasculature: recent advances and clinical implications. Thorax. 64, 444-450139Kanazawa, H. T., Y.; Asai, K.; Hirata, K. (2014) Simultaneous assessment of HGF and VEGF in epithelial lining fluid from patients with COPD. Chest. 146, 1159-1165140Burgel, P. R. and Nadel, J. A. (2004) Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax. 59, 992-996141Bateman, E. D., Rennard, S., Barnes, P. J., Dicpinigaitis, P. V., Gosens, R., Gross, N. J., Nadel, J. A., Pfeifer, M., Racke, K., Rabe, K. F., Rubin, B. K., Welte, T. and Wessler, I. (2009) Alternative mechanisms for tiotropium. Pulm.Pharmacol Ther. 22, 533-542142Grace, M. S., Baxter, M., Dubuis, E., Birrell, M. A. and Belvisi, M. G. (2014) Transient receptor potential (TRP) channels in the airway: role in airway disease. Br J Pharmacol. 171, 2593-2607143Nassenstein, C., Schulte-Herbruggen, O., Renz, H. and Braun, A. (2006) Nerve growth factor: the central hub in the development of allergic asthma? Eur.J.Pharmacol. 533, 195-206144de Boer, W. I., van Schadewijk, A., Sont, J. K., Sharma, H. S., Stolk, J., Hiemstra, P. S. and van Krieken, J. H. (1998) Transforming growth factor beta1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 158, 1951-1957145Serhan, C. N. (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature. 510, 92-101146Serhan, C. N., Yang, R., Martinod, K., Kasuga, K., Pillai, P. S., Porter, T. F., Oh, S. F. and Spite, M. (2009) Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. J.Exp.Med. 206, 15-23147Donnelly, L. E. and Barnes, P. J. (2012) Defective phagocytosis in airways disease. Chest. 141, 1055-1062148Pavord, I. D., Lettis, S., Locantore, N., Pascoe, S., Jones, P. W., Wedzicha, J. A. and Barnes, N. C. (2016) Blood eosinophils and inhaled corticosteroid/long-acting beta-2 agonist efficacy in COPD. Thorax. 71, 118-125149Chung, K. F. (2015) Targeting the interleukin pathway in the treatment of asthma. Lancet. 386, 1086-1096150Brusselle, G. G., Vanderstichele, C., Jordens, P., Deman, R., Slabbynck, H., Ringoet, V., Verleden, G., Demedts, I. K., Verhamme, K., Delporte, A., Demeyere, B., Claeys, G., Boelens, J., Padalko, E., Verschakelen, J., Van Maele, G., Deschepper, E. and Joos, G. F. (2013) Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 68, 322-329151Barnes, P. J. (2013) New anti-inflammatory treatments for chronic obstructive pulmonary disease. Nat Rev Drug Discov. 12, 543-559152Gross, N. J. and Barnes, P. J. (2017) New therapies for asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 195, 159-166153Barnes, P. J. (2013) Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin.Immunol. 131, 636-645154Mitani, A., Ito, K., Vuppusetty, C., Barnes, P. J. and Mercado, N. (2016) Restoration of corticosteroid sensitivity in chronic obstructive pulmonary disease by inhibition of mammalian target of rapamycin. Am J Respir Crit Care Med. 193, 143-153155Barnes, P. J. (2016) Kinases as novel therapeutic targets in asthma and COPD. Pharmacol Rev. 68, 788-815156Usmani, O. S. and Barnes, P. J. (2012) Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease. Ann.Med. 44, 146-156FIGURE LEGENDSFig. 1. Asthma-COPD overlap. Asthma and COPD have distinct features, with different cells, mediators and consequences of inflammation as well as different response to treatment with corticosteroids. Approximately 15% of COPD patients have features of asthma, whereas a similar proportion of asthma patients have features of COPD.Fig. 2. Pathology of asthma and COPD. Left panel shows a small airway from a patient who died of a severe asthma attack and the right panel is a small airway from a patient with severe COPD. Although there is an increase in inflammatory cells in the airway wall in both diseases, there are marked structural differences and while there is alveolar wall destruction in COPD this is not seen in asthma. A mucus plug (MP), comprised on inflammatory cells, mucus glycoproteins and plasma proteins fills the lumen of the asthma patient.[Both slides are courtesy of Dr James Hogg, University of British Columbia]Fig. 3. Inflammation in COPD. Inhaled irritants such as cigarette and biomass smoke activate epithelia cells and macrophages to release several chemotactic factors that attract inflammatory cells to the lungs, including CCL2, which acts on CC-chemokine receptor 2 (CCR2) to attract monocytes, CXC-chemokine ligand 1 (CXCL1) and CXCL8, which act on CXCR2 to attract neutrophils and monocytes (which differentiate into macrophages in the lungs) and CXCL9, CXCL10 and CXCL11, which act on CXCR3 to attract T helper 1 (Th1) cells and type 1 cytotoxic T cells (Tc1 cells). Macrophages release IL-23 to attract Th17 cells that release IL-17, which promotes neutrophilic inflammation. These inflammatory cells together with macrophages and epithelial cells release proteases, such as matrix metalloproteinase-9 (MMP9), which cause elastin degradation and emphysema. Neutrophil elastase also causes mucus hypersecretion. Epithelial cells and macrophages also release transforming growth factor-? (TGF?), which stimulates fibroblast proliferation, and the release of connective tissue growth factor (CTGF), which results in fibrosis around the small airways. Fig. 4. Eosinophilic inflammation. Allergens are taken up by dendritic cells (DC), which attract T helper-2 (Th2) lymphocytes that secrete T2 cytokines that are involved in mast cell and eosinophil recruitment and survival. Mast cells also attract Th2 cells and eosinophils through the release of prostaglandin(PG)D2 through chemotactic receptors of Th2 cells (CRTh2). Epithelial cells release alarmins (IL-25 and IL-33) to recruit type 2 innate lymphoid cells (ILC2), which also attract eosinophils through release of IL-5 and CCL11 (eotaxin) and CCL5 (RANTES) which are chemotactic for eosinophils through binding to CCR3 expressed on these cells.Fig. 5. Neutrophilic inflammation. Airway epithelial cells and macrophages may be activated by infections, reactive oxygen species (ROS) and allergens via the activation of nuclear factor-κB (NF-κB) and p38 MAP kinase to release chemokines (CXCL1, CXCL8), which attract neutrophils via CXCR2. Epithelial cells also release leukotriene-B4 (LTB4) which is chemotactic for neutrophils via BLT1-receptors. Both epithelial cells and macrophages may release tumour necrosis factor-α (TNF-α), interleukin(IL)-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), which promotes neutrophil survival. Macrophages release IL-23, which acts on Th17 cells and type 3 innate lymphoid cells (ILC3) that release IL-17 that releases CXCL1 and CXCL8 from epithelial cells. Neutrophils may amplify inflammation through releasing ROS, as well as neutrophil elastase and the elastolytic enzymes matrix metalloproteinase(MMP)-8 and -9. ................
................