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On the role of neutrophils and NETosis in acute pancreatitis(De neutrophilis NETosique ad pancreatitim acutam pertinentibus)Johan Linderscenter349948500DOCTORAL DISSERTATIONby due permission of the Faculty of Medicine, Lund University, Sweden.To be defended at Prof Thorlacius office (room 3050) 3rd floor, Carl Bertil Laurells gata 9 Malm?. Date 2020 11 06 at 09.00 am.Faculty opponentProf. Norbert Nemeth Faculty of Medicine, Department of Surgery, University of Debrecen, HungaryOrganizationLUND UNIVERSITY, Faculty of MedicineDocument nameDoctoral DissertationDepartment of SurgeryInstitution of Clinical Sciences, Malm?Date of issue 2020-10-01Author(s) Johan LindersSponsoring organizationTitle and subtitle On the role of neutrophils and NETosis in acute pancreatitisAbstractBackground and aims Acute pancreatitis (AP) is a common and potentially life threatening condition to which there is no targeted treatment. This is partly due to insufficient knowledge of the pathophysiology. What is generally accepted is that the development of AP starts with preemptive activation of trypsinogen into trypsin followed by an inflammatory respons and massive infiltration of neutrophils into the inflammed pancreatic tissue. The latter is generally considered to be the rate limiting step in the course of the disease and hence the step were therapies to target the disease has the best possibillities. In this thesis some of the pathophysilogical mechanisms of AP were investigated using well established murine models. The aim was to investigate specific mechanisms behind neutrophil recruitment and formation of neutrophil extracellular traps (NETs) and their role in regulating inflammation and tissue damage in AP.Results In paper I it was found that the chemokine CXCL4 secreted from the platelets play an imortant role in neutrophil recruitment, probably via another chemokine, CXCL2. The role of platelets was further studied in paper II where their close interplay with neutrophils was underlined by the fact that neutrophils and platelets formed complexes together and that these complexes promoted NETs formation. It was also found that the expelled NETs formed complexes with microparticles in a platelet dependent process, that furter promoted the NETosis. In paper II the role in the NETs formation of the platelet derived enzyme IP6K1in AP was also adressed. Paper III demonstrated that the nuclear protein eCIRP was elevated in AP and also that inhibiting eCIRP with the specific inhibitor C23 reduced NETosis and hence inflammation. In Paper IV it was shown that complement component 3 (C3) is directly involved in NETs formation and inflamation in AP.Conclusion This thesis provides new insights in some of the crucial mechanisms in the recruitment of neutrophils and the regulation of NETs formation in the inflamed pancreas. Targeting the examined substances, namely CXCL4, IP6K1, eCIRP and/or C3 are all possible strategies for ameliorating the inflammation in APKey words Acute pancreatitis, neutrophils, platelets, CXCL4, microparticles, IP6K1, platelet-neutrophil aggregation, eCIRP, neutrophil extracellular traps (NETs), complement C3Classification system and/or index terms (if any)Supplementary bibliographical information Lund University, Faculty of Medicine Doctoral Dissertation Series 2020:118LanguageEnglishISSN and key title 1652-8220ISBN 978-91-7619-981-7Recipient’s notesNumber of pages 145PriceSecurity classificationI, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation.Signature Date 2020-09-30On the role of neutrophils and NETosis in acute pancreatitis(De neutrophilis NETosique ad pancreatitim acutam pertinentibus)Johan Linderscenter349948500Cover by Anna AxelssonCopyright pp 1-?? Johan LindersPaper 1 ? Elsivier health Paper 2 ? American Society for Clinical InvestigationPaper 3 ? Springer Nature Paper 4 ? by the Authors (Manuscript unpublished) Faculty of medicineDepartment of clinical sciences, Malm?, surgeryISBN 978-91-7619-981-7ISSN 1652-8220Printed in Sweden by Media-Tryck, Lund University, Lund 2020 Till Min familj Table of Contents TOC \o "1-3" \u List of papers PAGEREF _Toc51926269 \h 8Abbreviations PAGEREF _Toc51926270 \h 9Background PAGEREF _Toc51926271 \h 13The Pancreas PAGEREF _Toc51926272 \h 13History PAGEREF _Toc51926273 \h 13Anatomy and physiology of the pancreas PAGEREF _Toc51926274 \h 14Acute pancreatitis PAGEREF _Toc51926275 \h 17Epidemiology and aetiology PAGEREF _Toc51926276 \h 17Diagnostics and classification PAGEREF _Toc51926277 \h 18Management of the patient PAGEREF _Toc51926278 \h 20Pathogenesis PAGEREF _Toc51926279 \h 21Proteas activation and initial cellular damage PAGEREF _Toc51926280 \h 21Local and systemic inflammation PAGEREF _Toc51926281 \h 24Leukocytes PAGEREF _Toc51926282 \h 26Neutrophil recruitment and extravasation PAGEREF _Toc51926283 \h 28Neutrophil extracellular traps -NETs PAGEREF _Toc51926284 \h 31Microparticles PAGEREF _Toc51926285 \h 33Platelets PAGEREF _Toc51926286 \h 34Complement system PAGEREF _Toc51926287 \h 36Cytokines, Chemokines PAGEREF _Toc51926288 \h 39Chromatin changes and Nuclear proteins PAGEREF _Toc51926289 \h 40Aims PAGEREF _Toc51926290 \h 43Paper I PAGEREF _Toc51926291 \h 43Paper II PAGEREF _Toc51926292 \h 43Paper III PAGEREF _Toc51926293 \h 43Paper IV PAGEREF _Toc51926294 \h 44Material and methods: PAGEREF _Toc51926295 \h 45Animals PAGEREF _Toc51926296 \h 45Study design PAGEREF _Toc51926297 \h 45Experimental models of induction of pancreatitis. PAGEREF _Toc51926298 \h 46Taurocholate induced pancreatitis PAGEREF _Toc51926299 \h 46L-arginine induced pancreatitis PAGEREF _Toc51926300 \h 47Amylase levels PAGEREF _Toc51926301 \h 48Preparation of Neutrophils and Platelets PAGEREF _Toc51926302 \h 48NETs generation in vitro PAGEREF _Toc51926303 \h 48Pancreatic Acinar Cells PAGEREF _Toc51926304 \h 48Chemotaxis assay PAGEREF _Toc51926305 \h 49Myeloperoxidase levels PAGEREF _Toc51926306 \h 49Flow cytometry PAGEREF _Toc51926307 \h 50Histology PAGEREF _Toc51926308 \h 52Electron microscopy PAGEREF _Toc51926309 \h 54Confocal imaging PAGEREF _Toc51926310 \h 54Enzyme-linked immunosorbent assay (ELISA) PAGEREF _Toc51926311 \h 55Western blot PAGEREF _Toc51926312 \h 56Quantitative Reverse Transcription-polymerase chain reaction (qRT-PCR) PAGEREF _Toc51926313 \h 57Genotyping by polymerase chain reaction (PCR) PAGEREF _Toc51926314 \h 58Patients Samples PAGEREF _Toc51926315 \h 58Statistical analysis. PAGEREF _Toc51926316 \h 59Results and Discussions PAGEREF _Toc51926317 \h 61Paper 1 PAGEREF _Toc51926318 \h 61Paper II PAGEREF _Toc51926319 \h 72Paper III PAGEREF _Toc51926320 \h 84Paper IV PAGEREF _Toc51926321 \h 93Considerations, concluding remarks, and future perspectives PAGEREF _Toc51926322 \h 103Conclusions PAGEREF _Toc51926323 \h 109Acknowledgment – Tack PAGEREF _Toc51926324 \h 111Popul?rvetenskaplig sammanfattning p? svenska PAGEREF _Toc51926325 \h 115Bakgrund PAGEREF _Toc51926326 \h 115Metod PAGEREF _Toc51926327 \h 117Resultat PAGEREF _Toc51926328 \h 117Studie 1. PAGEREF _Toc51926329 \h 117Studie 2 PAGEREF _Toc51926330 \h 117Studie 3 PAGEREF _Toc51926331 \h 118Studie 4 PAGEREF _Toc51926332 \h 119Konklusioner PAGEREF _Toc51926333 \h 120References PAGEREF _Toc51926334 \h 121List of papersPaper I. Erik Wetterholm 1 , Johan Linders 1 , Mohammed Merza, Sara Regner , Henrik Thorlacius. Platelet-derived CXCL4 Regulates Neutrophil Infiltration and Tissue Damage in Severe Acute Pancreatitis. Transl Res, 2016;76:105-118.Paper II. Raed Madhi, Milladur Rahman, Dler Taha, Johan Linders, Mohammed Merza, Yongzhi Wang, Matthias M?rgelin, Henrik Thorlacius. Platelet IP6K1 Regulates Neutrophil Extracellular Trap-Microparticle Complex Formation in Acute Pancreatitis. JCI Insight doi:10.1172/jci.insight.129270 (2019).Paper III. Johan Linders, Raed Madhi, Milladur Rahman, Matthias M?rgelin, Sara Regner, Max Brenner, Ping Wang, and Henrik Thorlacius. Extracellular cold-inducible RNA-binding protein regulates neutrophil extracellular trap formation and tissue damage in acute pancreatitis. Lab Invest. doi: 10.1038/s41374-020-0469-5 (2020).Paper IV. Johan Linders, Raed Madhi, Matthias M?rgelin, Ben King, Anna M. Blom, Milladur Rahman. Complement component 3 is required for tissue damage, neutrophil infiltration and ensuring NETs formation in acute pancreatitis. Submitted manuscript, European?Surgical Research1 Equal contributorsAbbreviationsACAtlanta classificationADAnno DominiANCAcute necrotic collectionsAPAcute PancreatitisAPCAllophycocyaninAPFCAcute Pancreatic fluid collectionsARDSAcute Respiratory Distress syndromeATPaseAdenosine triphosphataseBCBefore Christbpmbeats per minuteCAMscell adhesion moleculesCCK CholesystokininCECTContrast enhanced Computer tomographycfDNAcell free Deoxyribonucleic acidCGDchronic granulomatosis diseaseCIRPcold-inducible RNA-binding proteinCOXCyclooxygenasesCRegscomplement regulatory proteinsCTComputer TomographyCXCLChemokine (C-X-C motif) ligandDAMPSDamage Associated Molecule PatternsDBCDeterminant-based classificationELISAEnzyme-linked immunosorbent assayEREndoplasmic ReticulumERCPEndoscopic retrograde cholangiopancreatographyESAMendothelia cell-selective adhesion moleculeEUSEndoscopic Ultra SoundH3, H4Histone 3, Histone 4HAThistone acetylaseHDAChistone deacetylaseHMBG 1high-mobility group box 1ICAMsIntra cellular adhesion moleculesIEPIntestinal edematous pancreatitisILInterleukinei.p.intra peritonealIP3RInositol 1,4,5-triphoste receptorIP6K1inositol hexakisphosphate kinase 1JAK-2Janus Kinase-2JAMsjunction adhesion moleculesLFA-1Lymphocyte function antigen-1LPSLipopolysacharidesMACMembrane Attack Complexmac-1membrane activated complex-1MAP-kinasemitogen-activated protein?kinaseMAPKsmitogen-activated protein kinasesMASPMBL-associated proteasesMBLmannose-binding lectinMCP-1Monocyte chemotactic protein-1MIP-2Macrophage inflammatory protein-2MMP-9Matrix metalloproteinase-9MODSMultiple organ dysfunction syndromeMPmicroparticlesMPOMyeloperoxidaseMRCPMagnetic resonance cholangiopancreatographyMRIMagnetic Resonance ImaginingmTORmammalian target of RapamycinNADPHnicotinamide adenine dinucleotide phosphataseNEneutrophil elastaseNETs Neutrophil extracellular trapsNF-κBnuclear factor kappa-light-chain-enhancer of activated B cellsPAD-4protein-arginine deiminase type 4PAMPSPathogen-Associated Molecular PatternsPCphosphatidylcholinePCRpolymerase chain reactionPEphosphatidyl-ethanolaminePECAM-1platelet endothelial cell adhesion molecule-1PKCprotein kinase CPMAphorbol 12-myristate 13-acetatePMNLspolymorphonuclear leukocytesPMPplatelet microbicidal proteinsPNAPlatelet-Neutrophil AggregatesPolyPsPolyphosphatesPRRPattern Recognition ReceptorsPSphosphatidylserinePSGL-1 P-selectin glycoprotein ligand-1PSTIPancreatic Secretory Trypsin InhibitorQT-PCRQuantitative Reverse Transcription-polymerase chain reactionRACRevised Atlanta classificationRAGEreceptor for advanced glycation end productsRNAribonucleic acidROSreactive oxygen speciesRyRRyadin ReceptorSIRSSystemic Inflammatory reaction syndromeSLESystemic Lupus ErythematosusSMSphingomyelinSOFA-scoreSepsis Related Organ Failure assessment scoreSPINK-1Serine Protease Inhibitor Kazal type 1STAT-3Signal Transducer and Activator of Transcription-3TAPTrypsinogen Activation PeptideTFTissue factorTGFβ1Transforming growth factor beta 1TIRToll-IL-1 receptorTIRFTIR-domain-containing adapter-inducing interferon-βTLRsToll-like ReceptorsTNFαTumor Necrotic Factor αTNP2N-(m-Trifluorobenzyl), N6-(p-nitrobenzyl) purineWONWalled off necrosis Mitt ?ga fl?g fr?n blad till blad, Jag velat kyssa varje rad…… …. De tala n?gra enkla ord, Tag mot dem, dyra fosterjord! //Johan Ludvig RunebergBackgroundThe PancreasHistoryThe organ was first described by the Greek anatomist and surgeon Herophilus (335-280 BC). The name “pancreas” was given to the organ four centuries later by another Greek anatomist, Rufus of Ephesus (c70-c110 AD). It was constructed by the two words “pan” meaning whole, and “creas” meaning flesh, the name presumably implying it?s fleshy consistence ADDIN EN.CITE <EndNote><Cite><Author>Tsuchiya</Author><Year>1997</Year><RecNum>372</RecNum><DisplayText>(1)</DisplayText><record><rec-number>372</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582931969">372</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tsuchiya, R.</author><author>Fujisawa, N.</author></authors></contributors><auth-address>Tagami Hospital, Nagasaki, Japan.</auth-address><titles><title>On the etymology of &quot;pancreas&quot;</title><secondary-title>Int J Pancreatol</secondary-title></titles><periodical><full-title>Int J Pancreatol</full-title></periodical><pages>269-72</pages><volume>21</volume><number>3</number><edition>1997/06/01</edition><keywords><keyword>*History, Ancient</keyword><keyword>*Pancreas</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0169-4197 (Print)&#xD;0169-4197 (Linking)</isbn><accession-num>9322128</accession-num><urls><related-urls><url>;(1). The roman anatomist Galenius (138-201 AD) made the wrong assumption that the task of the pancreas was to function as a padding, protecting the large vessels just behind the organ. This inaccuracy stood then as the truth for more than a thousand years ADDIN EN.CITE <EndNote><Cite><Author>Tsuchiya</Author><Year>2015</Year><RecNum>371</RecNum><DisplayText>(2)</DisplayText><record><rec-number>371</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582931700">371</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tsuchiya, R.</author><author>Kuroki, T.</author><author>Eguchi, S.</author></authors></contributors><auth-address>Surgical Section, Tagami Hospital, Nagaski, Japan; Department of Surgery, Nagasaki University Hospital, Nagasaki, Japan. Electronic address: roytschy@sound.ocn.ne.jp.&#xD;Department of Surgery, Nagasaki University Hospital, Nagasaki, Japan.</auth-address><titles><title>The pancreas from Aristotle to Galen</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>2-7</pages><volume>15</volume><number>1</number><edition>2014/12/04</edition><keywords><keyword>Anatomy, Comparative/*history</keyword><keyword>Animals</keyword><keyword>Birds/anatomy &amp; histology</keyword><keyword>Famous Persons</keyword><keyword>Greece, Ancient</keyword><keyword>History, Ancient</keyword><keyword>Humans</keyword><keyword>Indonesia</keyword><keyword>Mammals/anatomy &amp; histology</keyword><keyword>Pancreas/*anatomy &amp; histology</keyword><keyword>Aristotle</keyword><keyword>Comparative anatomy</keyword><keyword>Galen</keyword><keyword>Kaloumenon pancreas</keyword><keyword>Rufus</keyword><keyword>Theophrastus</keyword></keywords><dates><year>2015</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>1424-3911 (Electronic)&#xD;1424-3903 (Linking)</isbn><accession-num>25465799</accession-num><urls><related-urls><url>;(2). The main pancreas duct was first described by Johann George Wirsüng (1589-1643) in 1642, but he never understood the function of the duct that now bears his name. Wirsüng was later murdered by his student Giacomo Cambier, according to the legend, over an argument on whom of them that actually had discovered the duct. The basic histology of the pancreas was probably first described in 1852 by the French student D. Moyse who in his thesis draw a rough sketch of the acini. Seventeen years later the German student Paul Langerhans (1847-1888) made the first good histological description of the organ, including the endocrine islets that later was to be named the Islets of Langerhans. The hormone Insulin produced by the islets was later found in 1921 by Banting (1891-1941) and Best (1899-1978). The digestive enzymes of the pancreas were on the other hand all described in the second half of the 19th century by several scientists. In 1908 Julius Wohlgemuth discovered a way to measure Amylase, and thus made diagnostics of pancreatitis possible ADDIN EN.CITE <EndNote><Cite><Author>Busnardo</Author><Year>1983</Year><RecNum>345</RecNum><DisplayText>(3)</DisplayText><record><rec-number>345</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582756831">345</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Busnardo, A. C.</author><author>DiDio, L. J.</author><author>Tidrick, R. T.</author><author>Thomford, N. R.</author></authors></contributors><titles><title>History of the pancreas</title><secondary-title>Am J Surg</secondary-title></titles><periodical><full-title>Am J Surg</full-title></periodical><pages>539-50</pages><volume>146</volume><number>5</number><edition>1983/11/01</edition><keywords><keyword>Animals</keyword><keyword>Canada</keyword><keyword>Dogs</keyword><keyword>Europe</keyword><keyword>History, 16th Century</keyword><keyword>History, 17th Century</keyword><keyword>History, 18th Century</keyword><keyword>History, 19th Century</keyword><keyword>History, 20th Century</keyword><keyword>History, Ancient</keyword><keyword>Humans</keyword><keyword>*Pancreas/anatomy &amp; histology/physiology</keyword><keyword>Pancreas Transplantation</keyword><keyword>Pancreatic Diseases/history</keyword><keyword>Rats</keyword><keyword>Ussr</keyword><keyword>United States</keyword></keywords><dates><year>1983</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0002-9610 (Print)&#xD;0002-9610 (Linking)</isbn><accession-num>6356946</accession-num><urls><related-urls><url>(83)90286-6</electronic-resource-num></record></Cite></EndNote>(3). The first historic reference in the literature to pancreatitis is however from as early as 1652 when the Dutch physician Nicolas Tulp (1593-1674) described the disease. In 1889 Reginald Fitz (1843-1913) a pathologist and internist in Boston presented what is consider to be the first more thorough work on AP in which he described both clinical symptoms and pathological findings such as pus and necrosis, both local and disseminated and haemorrhage ADDIN EN.CITE <EndNote><Cite><Author>Leach</Author><Year>1990</Year><RecNum>446</RecNum><DisplayText>(4)</DisplayText><record><rec-number>446</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1587159549">446</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leach, S. D.</author><author>Gorelick, F. S.</author><author>Modlin, I. M.</author></authors></contributors><auth-address>Department of Surgery, Yale University School of Medicine, New Haven, CT 06510.</auth-address><titles><title>Acute pancreatitis at its centenary. The contribution of Reginald Fitz</title><secondary-title>Ann Surg</secondary-title></titles><periodical><full-title>Ann Surg</full-title></periodical><pages>109-13</pages><volume>212</volume><number>1</number><edition>1990/07/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Austria</keyword><keyword>Berlin</keyword><keyword>History, 19th Century</keyword><keyword>History, 20th Century</keyword><keyword>Humans</keyword><keyword>Massachusetts</keyword><keyword>Pancreatitis/*history</keyword></keywords><dates><year>1990</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0003-4932 (Print)&#xD;0003-4932 (Linking)</isbn><accession-num>2194439</accession-num><urls><related-urls><url>;(4). The first suggestion that gallstones could be involved in the pathogenesis was made in 1901 by Eugene Opie (1873-1971) ADDIN EN.CITE <EndNote><Cite><Author>Opie</Author><Year>1901</Year><RecNum>447</RecNum><DisplayText>(5)</DisplayText><record><rec-number>447</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1587160791">447</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Opie, E. L.</author></authors></contributors><auth-address>Johns Hopkins Univ, Baltimore, MD USA</auth-address><titles><title>The relation of cholelithiasis to disease of the pancreas and to fat necrosis.</title><secondary-title>American Journal of the Medical Sciences</secondary-title><alt-title>Am J Med Sci</alt-title></titles><periodical><full-title>American Journal of the Medical Sciences</full-title><abbr-1>Am J Med Sci</abbr-1></periodical><alt-periodical><full-title>American Journal of the Medical Sciences</full-title><abbr-1>Am J Med Sci</abbr-1></alt-periodical><pages>27-43</pages><volume>121</volume><dates><year>1901</year></dates><isbn>0002-9629</isbn><accession-num>WOS:000202655900002</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000202655900002</url></related-urls></urls><electronic-resource-num>Doi 10.1097/00000441-190101000-00002</electronic-resource-num><language>English</language></record></Cite></EndNote>(5), and the role of alcohol in development of AP was established by WSC Symmers in 1917 ADDIN EN.CITE <EndNote><Cite><Author>Symmers</Author><Year>1917</Year><RecNum>446</RecNum><DisplayText>(6)</DisplayText><record><rec-number>446</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1587160958">446</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Symmers, William St C</author></authors></contributors><titles><title>Acute alcoholic pancreatitis</title><secondary-title>Dublin Journal of Medical Science (1872-1920)</secondary-title></titles><periodical><full-title>Dublin Journal of Medical Science (1872-1920)</full-title></periodical><pages>244-247</pages><volume>143</volume><number>4</number><dates><year>1917</year></dates><isbn>0790-231X</isbn><urls></urls></record></Cite></EndNote>(6).Anatomy and physiology of the pancreasThe pancreas is the second biggest glandular organ of the body, measuring around 15 cm in length, weighting 75-110 g in an adult. It is located retroperitoneal in the upper abdomen, just ventral of the second lumbar vertebra in parallel with, and beneath the stomach. The organ is anatomically divided into the head (Caput) the neck (Colum), the body (Corpus) and the tail (Cauda). The head is framed by the duodenum, filling out its entire concavity. On the head of the pancreas is a small outgrowth, called the uncinate process, defined by a small incision named incisura pancreatitis. This process of the organ extends to the left, behind the superior mesenteric artery and superior mesenteric vein. Since the corpus runs in front of these vessels the pancreas encircles them on three out of four sides. The head is connected to the body of the pancreas by the neck, which is a slightly constricted part of the gland located just in front of the beginning of Vena Porta and the origin of the superior mesenteric artery. The tail finally is extending towards and not seldom into, or just below the hilum of the spleen. This very central location of the pancreas in the abdominal cavity, with proximity to large vessels and other organs (duodenum, stomach, spleen and colon transversus) is important since it plays a crucial role for the development of possible complications if the organ gets inflamed or in other ways affected by disease. The pancreatic duct runs through the organ from tail to head, where it merges with the common bile duct and enter the duodenum through the papilla Vateri. If an accessory duct is present, which is sometimes the case it will enter the duodenum through the papilla Santorini.Embryologically the pancreas develops from two endodermal diverticulae, the ventral and the dorsal, that buds from the duodenum around the 4th fetal week ADDIN EN.CITE <EndNote><Cite><Author>Edlund</Author><Year>2001</Year><RecNum>2</RecNum><DisplayText>(7)</DisplayText><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579095003">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Edlund, H.</author></authors></contributors><auth-address>Department of Microbiology, University of Umea, Sweden. helena.edlund@micro.umu.se</auth-address><titles><title>Developmental biology of the pancreas</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>S5-9</pages><volume>50 Suppl 1</volume><edition>2001/03/29</edition><keywords><keyword>Animals</keyword><keyword>Cell Differentiation</keyword><keyword>Cell Division</keyword><keyword>*Developmental Biology</keyword><keyword>Humans</keyword><keyword>Islets of Langerhans/cytology/physiology</keyword><keyword>Models, Biological</keyword><keyword>Pancreas/embryology/growth &amp; development/*physiology</keyword></keywords><dates><year>2001</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0012-1797 (Print)&#xD;0012-1797 (Linking)</isbn><accession-num>11272202</accession-num><urls><related-urls><url>;(7). The ventral pancreatic bud shares origin with the liver and the gallbladder and it will give rise to the uncinate process. Around the 5th week it will migrate posteriorly of the duodenum and merge with the dorsal bud which will give rise to the head, neck, body and tail ADDIN EN.CITE <EndNote><Cite><Author>Couzin</Author><Year>2007</Year><RecNum>11</RecNum><DisplayText>(8)</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579268924">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Couzin, J.</author></authors></contributors><titles><title>Developmental biology. In embryos, pancreas and liver reach full size in different ways</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title></periodical><pages>587</pages><volume>315</volume><number>5812</number><edition>2007/02/03</edition><keywords><keyword>Animals</keyword><keyword>Genetic Engineering</keyword><keyword>Homeodomain Proteins/genetics/physiology</keyword><keyword>Liver/cytology/*embryology</keyword><keyword>Mice</keyword><keyword>Organ Size</keyword><keyword>Pancreas/cytology/*embryology</keyword><keyword>Stem Cells/*physiology</keyword><keyword>Trans-Activators/genetics/physiology</keyword></keywords><dates><year>2007</year><pub-dates><date>Feb 2</date></pub-dates></dates><isbn>1095-9203 (Electronic)&#xD;0036-8075 (Linking)</isbn><accession-num>17272695</accession-num><urls><related-urls><url>;(8). The duct of the ventral bud will become the main pancreatic duct (ductus Wirsungii) were as the duct of the dorsal bud, if it persists will give rise to the accessory duct (ductus Santorini). The head of the pancreas gets it blood supply from an arterial arcade formed by the ventral and dorsal superior pancreaticoduodenal arteries, that branches from the gastroduodenal artery and the ventral and dorsal inferior pancreaticoduodenal arteries that comes from the superior mesenteric artery. The body and tail of the pancreas gets most of its blood supply from the splenic artery. The corresponding veins are drained in the portal systemThe pancreas holds both endocrine and exocrine function, where the endocrine role of maintaining a proper glucose homeostasis by producing and secreting peptides (mainly insulin and glucagon) is probably the most well-known. However, these endocrine cells, gathered together in the islets of Langerhans, constitutes only around 2% of the cells of the pancreas whereas the exocrine cells (i.e. acinar and ductal cells) make up around 80% of the gross weight ADDIN EN.CITE <EndNote><Cite><Author>Pandol</Author><Year>2010</Year><RecNum>4</RecNum><DisplayText>(9)</DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579172649">4</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Pandol, S. J.</author></authors></contributors><titles><secondary-title>The Exocrine Pancreas</secondary-title><tertiary-title>Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease</tertiary-title></titles><dates><year>2010</year></dates><pub-location>San Rafael (CA)</pub-location><accession-num>21634067</accession-num><urls><related-urls><url>;(9). The exocrine cells are organized in so called acinis which is spherical clusters containing several hundreds of acinar cells gathered around a small ductules. These ductules are lined with ductal cell called centro-acinar cells. Several acinis grouped together composes lobules, and a number of lobules constitutes a pancreatic lobe. The acinar cells work as the functional units of the exocrine pancreas producing, storing and secreting different proteins, of which around 90% in the form of digestive enzymes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYW1pc2F3YTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+

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ADDIN EN.CITE.DATA (10). The ductal cells make up the ductal system, which starts in the acinis and then drains the pancreatic secretions into larger and larger ducts to the main pancreatic duct and finally into the duodenum. Beside this function the ductal cells also secrete large amount of bicarbonate, that transports digestive enzymes from the acinis to the duodenum and in that way clearing the pancreatic ducts from harmful substances. The bicarbonate also neutralizes the acidic chyme in the duodenum, and in that way, both protecting the intestinal mucosa and creating an optimal pH for the function of the digestive enzymes.Both types of exocrine cells are regulated by both neural (vagal) stimulation and hormonal input in response to food, but under basal conditions the secretion rate is low. The gastrointestinal proteins responsible for inducing secretion of proteins from acinar cells are mainly cholecystokinin (CCK) whereas secretion of bicarbonate from ductal cells is a response of secretin. The hormone somatostatin has an opposing effect acting as an inhibitor of exocrine pancreas secretion ADDIN EN.CITE <EndNote><Cite><Author>Konturek</Author><Year>2003</Year><RecNum>34</RecNum><DisplayText>(11)</DisplayText><record><rec-number>34</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579390825">34</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Konturek, S. J.</author><author>Pepera, J.</author><author>Zabielski, K.</author><author>Konturek, P. C.</author><author>Pawlik, T.</author><author>Szlachcic, A.</author><author>Hahn, E. G.</author></authors></contributors><auth-address>Department of Physiology, Jagiellonian University School of Medicine, Krakow, Poland. mpkontur@cyf-kr.edu.pl</auth-address><titles><title>Brain-gut axis in pancreatic secretion and appetite control</title><secondary-title>J Physiol Pharmacol</secondary-title></titles><periodical><full-title>J Physiol Pharmacol</full-title></periodical><pages>293-317</pages><volume>54</volume><number>3</number><edition>2003/10/21</edition><keywords><keyword>Appetite Regulation/*physiology</keyword><keyword>Brain/*physiology</keyword><keyword>*Digestive System Physiological Phenomena</keyword><keyword>Humans</keyword><keyword>Models, Biological</keyword><keyword>Pancreas/*metabolism</keyword></keywords><dates><year>2003</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0867-5910 (Print)&#xD;0867-5910 (Linking)</isbn><accession-num>14566070</accession-num><urls><related-urls><url>;(11). Pancreatic secretion could be divided into three different phases ADDIN EN.CITE <EndNote><Cite><Author>Harper</Author><Year>1972</Year><RecNum>349</RecNum><DisplayText>(12)</DisplayText><record><rec-number>349</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582795718">349</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Harper, A. A.</author></authors></contributors><titles><title>The control of pancreatic secretion</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>308-17</pages><volume>13</volume><number>4</number><edition>1972/04/01</edition><keywords><keyword>Acids/pharmacology</keyword><keyword>Animals</keyword><keyword>Cholecystokinin/metabolism/pharmacology</keyword><keyword>Depression, Chemical</keyword><keyword>Dogs</keyword><keyword>Drug Synergism</keyword><keyword>Gastric Juice/metabolism</keyword><keyword>Glucose/pharmacology</keyword><keyword>Humans</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Hypertonic Solutions/pharmacology</keyword><keyword>Intestinal Secretions</keyword><keyword>Neurons, Afferent/physiology</keyword><keyword>Pancreas/drug effects/*metabolism</keyword><keyword>Pancreatic Juice/*metabolism</keyword><keyword>Phenylalanine/pharmacology</keyword><keyword>Reflex</keyword><keyword>Secretin/metabolism/pharmacology</keyword><keyword>Secretory Rate/drug effects</keyword><keyword>Stomach/physiology</keyword><keyword>Vagus Nerve/physiology</keyword></keywords><dates><year>1972</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0017-5749 (Print)&#xD;0017-5749 (Linking)</isbn><accession-num>4556019</accession-num><urls><related-urls><url>;(12); the cephalic phase (before food actually reaches the stomach, but when thinking of, smelling, tasting and swallowing food affects the system), the gastric phase (when food enters the stomach) and the intestinal phase when food (or rather chyme) enters the duodenum and intestinal tract. In the cephalic phase the Vagus nerve (cranial nerve X) sends signals that releases acetylcholine which then stimulate the acinar cells to secrete proteins, this initial stimulation will result in approximately 20 % of the total protein release. In the gastric phase the food will provoke additional nervous impulses from the Vagus nerve that will result in an extra 5-10% of the total protein secretion. The food (or now chyme) then passes further into the duodenum initiating the intestinal phase. Here the cells of the duodenal and upper jejunal mucosa will respond by producing CCK, that will give the final additional stimulus to the acinar cells. At the same time the pH of the duodenum will be lowered as the acidic chyme enters the bowel. This will trigger production of secretin which will stimulate secretion of bicarbonate from the ductal cells. This will flush out the secreted proteins from the pancreas into the duodenum, and in this way the proteins produced during the cephalic and gastric phase will not reach the duodenum until the intestinal phase, i.e. when their action is needed. Furthermore, the bicarbonate will neutralize the acid in the duodenum. Each day around 2,5 litres of pancreatic juices is secreted into the duodenum.The enzymes produced in the acinar cells could roughly be divided into three categories namely; proteases that degrades proteins (also called peptidases or proteinases), amylase that hydrolyses carbohydrates and lipases that degrades fat into fatty acids. Of these, the proteases, including trypsin, chymotrypsin and carboxypolypeptidase are by far the most bountiful. Since these proteases (from the combination of the Greek words “protelos” meaning “first rank” and diastasis meaning “cleavage” ADDIN EN.CITE <EndNote><Cite><Author>Vickery</Author><Year>1950</Year><RecNum>291</RecNum><DisplayText>(13)</DisplayText><record><rec-number>291</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581780265">291</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vickery, H. B.</author></authors></contributors><titles><title>The origin of the word protein</title><secondary-title>Yale J Biol Med</secondary-title></titles><periodical><full-title>Yale J Biol Med</full-title></periodical><pages>387-93</pages><volume>22</volume><number>5</number><edition>1950/05/01</edition><keywords><keyword>Aged</keyword><keyword>Humans</keyword><keyword>*Proteins</keyword><keyword>*Semantics</keyword><keyword>*protein</keyword></keywords><dates><year>1950</year><pub-dates><date>May</date></pub-dates></dates><isbn>0044-0086 (Print)&#xD;0044-0086 (Linking)</isbn><accession-num>15413335</accession-num><urls><related-urls><url>;(13)) has the aggressive non wanted ability of autodigestion of the organ itself, they are stored and secreted as inactive pro-enzymes (zymogens). These pro-enzymes are produced in the ribosomes of the rough endoplasmatic reticulum in the acinar cells, and from there they are transported to the Golgi apparatus where they are packed in condensing vacuoles, that matures into zymogen granules that also contains secretory trypsin inhibitors ADDIN EN.CITE <EndNote><Cite><Author>Marchbank</Author><Year>1998</Year><RecNum>67</RecNum><DisplayText>(14)</DisplayText><record><rec-number>67</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579709185">67</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marchbank, T.</author><author>Freeman, T. C.</author><author>Playford, R. J.</author></authors></contributors><auth-address>University Division of Gastroenterology, Leicester General Hospital NHS Trust, UK.</auth-address><titles><title>Human pancreatic secretory trypsin inhibitor. Distribution, actions and possible role in mucosal integrity and repair</title><secondary-title>Digestion</secondary-title></titles><periodical><full-title>Digestion</full-title></periodical><pages>167-74</pages><volume>59</volume><number>3</number><edition>1998/06/27</edition><keywords><keyword>Animals</keyword><keyword>ErbB Receptors/drug effects</keyword><keyword>Gastric Mucosa/metabolism</keyword><keyword>Humans</keyword><keyword>Intestinal Mucosa/metabolism</keyword><keyword>*Trypsin Inhibitor, Kazal Pancreatic/metabolism/pharmacology</keyword></keywords><dates><year>1998</year></dates><isbn>0012-2823 (Print)&#xD;0012-2823 (Linking)</isbn><accession-num>9643675</accession-num><urls><related-urls><url>;(14). Through exocytosis from the apical side of the acinar cells these membrane-bound compartments then release their content into the lumen of the pancreatic ductules. The exocytosis is very well regulated and controlled by rapid influx of Ca2+ into the acinar cells. A sudden elevation of the otherwise rather low intracellular Ca2+ levels will lead to release of the zymogens content into the ducts, and this is triggered by several mechanisms including acetylcholine ADDIN EN.CITE <EndNote><Cite><Author>Thorn</Author><Year>1993</Year><RecNum>50</RecNum><DisplayText>(15)</DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579688632">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thorn, P.</author><author>Lawrie, A. M.</author><author>Smith, P. M.</author><author>Gallacher, D. V.</author><author>Petersen, O. H.</author></authors></contributors><auth-address>Physiological Laboratory University of Liverpool, England.</auth-address><titles><title>Local and global cytosolic Ca2+ oscillations in exocrine cells evoked by agonists and inositol trisphosphate</title><secondary-title>Cell</secondary-title></titles><periodical><full-title>Cell</full-title></periodical><pages>661-8</pages><volume>74</volume><number>4</number><edition>1993/08/27</edition><keywords><keyword>Acetylcholine/*pharmacology</keyword><keyword>Animals</keyword><keyword>Calcium/*metabolism</keyword><keyword>*Calcium Channels</keyword><keyword>Cell Membrane/metabolism</keyword><keyword>Cholecystokinin/pharmacology</keyword><keyword>Cytosol/drug effects/metabolism</keyword><keyword>Fura-2</keyword><keyword>In Vitro Techniques</keyword><keyword>Inositol 1,4,5-Trisphosphate/*pharmacology</keyword><keyword>Inositol 1,4,5-Trisphosphate Receptors</keyword><keyword>Kinetics</keyword><keyword>Membrane Potentials/drug effects</keyword><keyword>Mice</keyword><keyword>Pancreas/drug effects/metabolism/*physiology</keyword><keyword>Receptors, Cell Surface/drug effects/metabolism</keyword><keyword>*Receptors, Cytoplasmic and Nuclear</keyword></keywords><dates><year>1993</year><pub-dates><date>Aug 27</date></pub-dates></dates><isbn>0092-8674 (Print)&#xD;0092-8674 (Linking)</isbn><accession-num>8395347</accession-num><urls><related-urls><url>(93)90513-p</electronic-resource-num></record></Cite></EndNote>(15) and CCK. It is of importance that the Ca2+not constantly remains elevated since high intracellular Ca2+ levels itself are toxic ADDIN EN.CITE <EndNote><Cite><Author>Rizzuto</Author><Year>2003</Year><RecNum>438</RecNum><DisplayText>(16)</DisplayText><record><rec-number>438</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1585173568">438</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rizzuto, R.</author><author>Pinton, P.</author><author>Ferrari, D.</author><author>Chami, M.</author><author>Szabadkai, G.</author><author>Magalhaes, P. J.</author><author>Di Virgilio, F.</author><author>Pozzan, T.</author></authors></contributors><auth-address>Department of Experimental and Diagnostic Medicine and Center for the Study of Inflammation, University of Ferrara, Italy. r.rizzuto@unife.it</auth-address><titles><title>Calcium and apoptosis: facts and hypotheses</title><secondary-title>Oncogene</secondary-title></titles><periodical><full-title>Oncogene</full-title></periodical><pages>8619-27</pages><volume>22</volume><number>53</number><edition>2003/11/25</edition><keywords><keyword>Animals</keyword><keyword>*Apoptosis</keyword><keyword>Calcium/*metabolism</keyword><keyword>Calcium-Transporting ATPases/physiology</keyword><keyword>Cation Transport Proteins</keyword><keyword>Endopeptidases/physiology</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Mitochondria/physiology</keyword><keyword>Plasma Membrane Calcium-Transporting ATPases</keyword><keyword>Protein Kinase C/physiology</keyword><keyword>Proto-Oncogene Proteins c-bcl-2/physiology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2003</year><pub-dates><date>Nov 24</date></pub-dates></dates><isbn>0950-9232 (Print)&#xD;0950-9232 (Linking)</isbn><accession-num>14634623</accession-num><urls><related-urls><url>;(16), but also since the normally low intracellular Ca2+ has a protective property in that it promotes degradation of trypsin rather than activation. The acidic milieu inside the zymogen granulaes also act as a protective mechanism against premature activation of pro-enzymes. Of the proteases Trypsin is the most abundant, and alone accounts for 40% of all secretion from the pancreas. It is secreted as the inactive proenzyme Trypsinogen that will be activated to Trypsin when the Trypsinogen Activation Peptide (TAP) is cleave from its N-terminal end by the brush border enzyme enterokinase. This is a process that occurs in the duodenum and this sets of an activation- cascade of other proenzymes, such as activation of chymotrypsinogen into chymotrypsin and proelastase into elastase. 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ADDIN EN.CITE.DATA (17).Acute pancreatitisEpidemiology and aetiologyAcute pancreatitis (AP) is a sudden inflammation and auto destruction of the pancreas. It is characterized by an early intracellular activation of proteases within the acinar cells, followed by an inflammatory response that could be both local or systemic, affecting remote organs ADDIN EN.CITE <EndNote><Cite><Author>Frossard</Author><Year>2008</Year><RecNum>5</RecNum><DisplayText>(18)</DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579254851">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Frossard, J. L.</author><author>Steer, M. L.</author><author>Pastor, C. M.</author></authors></contributors><auth-address>Division de Gastroenterologie, Hopitaux Universitaires de Geneve, Geneva, Switzerland. jean-louis.frossard@hcuge.ch</auth-address><titles><title>Acute pancreatitis</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>143-52</pages><volume>371</volume><number>9607</number><edition>2008/01/15</edition><keywords><keyword>Acute Disease</keyword><keyword>Amylases/*blood</keyword><keyword>Anti-Bacterial Agents/therapeutic use</keyword><keyword>Birnaviridae Infections/classification/metabolism/*physiopathology</keyword><keyword>Cholecystectomy</keyword><keyword>Gallstones/complications/drug therapy</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Infectious pancreatic necrosis virus/*pathogenicity</keyword><keyword>Lipase/*blood</keyword><keyword>*Pancreatitis/diagnosis/physiopathology/therapy</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2008</year><pub-dates><date>Jan 12</date></pub-dates></dates><isbn>1474-547X (Electronic)&#xD;0140-6736 (Linking)</isbn><accession-num>18191686</accession-num><urls><related-urls><url>(08)60107-5</electronic-resource-num></record></Cite></EndNote>(18). Worldwide the annual incidence of the disease ranges from 13-75 per 100?000 inhabitants depending on demographic variations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYWRhdjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (19), with a global average of 34 per 100?000 inhabitants ADDIN EN.CITE <EndNote><Cite><Author>Petrov</Author><Year>2019</Year><RecNum>8</RecNum><DisplayText>(20)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579255828">8</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petrov, M. S.</author><author>Yadav, D.</author></authors></contributors><auth-address>School of Medicine, University of Auckland, Auckland, New Zealand.&#xD;Division of Gastroenterology &amp; Hepatology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. yadavd@upmc.edu.</auth-address><titles><title>Global epidemiology and holistic prevention of pancreatitis</title><secondary-title>Nat Rev Gastroenterol Hepatol</secondary-title></titles><periodical><full-title>Nat Rev Gastroenterol Hepatol</full-title></periodical><pages>175-184</pages><volume>16</volume><number>3</number><edition>2018/11/30</edition><keywords><keyword>Acute Disease</keyword><keyword>Chronic Disease</keyword><keyword>Global Health/statistics &amp; numerical data</keyword><keyword>*Holistic Health</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Pancreatitis/complications/*epidemiology/mortality/prevention &amp; control</keyword><keyword>Prevalence</keyword></keywords><dates><year>2019</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1759-5053 (Electronic)&#xD;1759-5045 (Linking)</isbn><accession-num>30482911</accession-num><urls><related-urls><url>;(20), and the trend seems to be increasing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5ka3Zpc3Q8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE.DATA (21, 22) In total there is no significant difference in the incidence between men and women ADDIN EN.CITE <EndNote><Cite><Author>Xiao</Author><Year>2016</Year><RecNum>9</RecNum><DisplayText>(23)</DisplayText><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579256138">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Xiao, A. Y.</author><author>Tan, M. L.</author><author>Wu, L. M.</author><author>Asrani, V. M.</author><author>Windsor, J. A.</author><author>Yadav, D.</author><author>Petrov, M. S.</author></authors></contributors><auth-address>Department of Surgery, University of Auckland, Auckland, New Zealand.&#xD;Division of Gastroenterology, Hepatology &amp; Nutrition, University of Pittsburgh Medical Center, Pittsburgh, USA.&#xD;Department of Surgery, University of Auckland, Auckland, New Zealand. Electronic address: max.petrov@.</auth-address><titles><title>Global incidence and mortality of pancreatic diseases: a systematic review, meta-analysis, and meta-regression of population-based cohort studies</title><secondary-title>Lancet Gastroenterol Hepatol</secondary-title></titles><periodical><full-title>Lancet Gastroenterol Hepatol</full-title></periodical><pages>45-55</pages><volume>1</volume><number>1</number><edition>2017/04/14</edition><keywords><keyword>Cohort Studies</keyword><keyword>Global Health/*statistics &amp; numerical data</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Pancreatic Diseases/*epidemiology/mortality</keyword><keyword>Regression Analysis</keyword></keywords><dates><year>2016</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>2468-1253 (Electronic)</isbn><accession-num>28404111</accession-num><urls><related-urls><url>(16)30004-8</electronic-resource-num></record></Cite></EndNote>(23), but the different etiological causes of pancreatitis varies between the sexes, gallstones being more common in females, while alcohol is the more common cause in males. The disease predominantly affects middle-age and older persons PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZW5kaGFya2FyPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh

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ADDIN EN.CITE.DATA (27). Higher age and obesity increases this risk ADDIN EN.CITE <EndNote><Cite><Author>Shin</Author><Year>2011</Year><RecNum>16</RecNum><DisplayText>(28)</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579354803">16</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shin, K. Y.</author><author>Lee, W. S.</author><author>Chung, D. W.</author><author>Heo, J.</author><author>Jung, M. K.</author><author>Tak, W. Y.</author><author>Kweon, Y. O.</author><author>Cho, C. M.</author></authors></contributors><auth-address>Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Korea.</auth-address><titles><title>Influence of obesity on the severity and clinical outcome of acute pancreatitis</title><secondary-title>Gut Liver</secondary-title></titles><periodical><full-title>Gut Liver</full-title></periodical><pages>335-9</pages><volume>5</volume><number>3</number><edition>2011/09/20</edition><keywords><keyword>Acute pancreatitis</keyword><keyword>Obesity</keyword><keyword>Overweight</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>2005-1212 (Electronic)&#xD;1976-2283 (Linking)</isbn><accession-num>21927663</accession-num><urls><related-urls><url>;(28). Cause of death in acute pancreatitis is usually SIRS or MOD in the first two weeks after onset, while later deaths are often due to sepsis or other complications ADDIN EN.CITE <EndNote><Cite><Author>Olah</Author><Year>2007</Year><RecNum>32</RecNum><DisplayText>(29)</DisplayText><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579389847">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Olah, A.</author><author>Pardavi, G.</author><author>Belagyi, T.</author><author>Romics, L., Jr.</author></authors></contributors><auth-address>Department of Surgery, Petz Aladar Teaching Hospital, Gyor, Hungary. olaha@petz.gyor.hu</auth-address><titles><title>Preventive strategies for septic complications of acute pancreatitis</title><secondary-title>Chirurgia (Bucur)</secondary-title></titles><periodical><full-title>Chirurgia (Bucur)</full-title></periodical><pages>383-8</pages><volume>102</volume><number>4</number><edition>2007/10/31</edition><keywords><keyword>Acute Disease</keyword><keyword>Anti-Bacterial Agents/*therapeutic use</keyword><keyword>Bacterial Infections/*prevention &amp; control</keyword><keyword>Evidence-Based Medicine</keyword><keyword>Humans</keyword><keyword>Pancreatectomy/methods</keyword><keyword>Pancreatitis/complications</keyword><keyword>Pancreatitis, Acute Necrotizing/*complications/*drug</keyword><keyword>therapy/microbiology/mortality</keyword><keyword>Sepsis/complications/*prevention &amp; control</keyword><keyword>Survival Analysis</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1221-9118 (Print)&#xD;1221-9118 (Linking)</isbn><accession-num>17966933</accession-num><urls><related-urls><url>;(29).Around 80 % of all cases of pancreatitis are mild and the disease is self-limiting, whereas the remaining 20% consequently has a moderate to severe pancreatitis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNzb248L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE.DATA (30), featuring a systemic inflammatory response and organ dysfunction. More about the classification will be outlined in a later section. There are several known etiological factors for AP and most of them could be summarized with the English mnemonic “I GET SMASHED” (I: idiopathic, G: gallstones and genetic (predominantly cystic fibrosis), E: ethanol, T: trauma, S: steroids, M: mumps and malignancy, A: autoimmune, S: scorpion stings/spider bites, H: hyperlipidemia, hypercalcemia, hyperparathyroidism, E: ERCP-induced, D: drugs). The most common cause being gallstones contributing to roughly 40% of all cases ADDIN EN.CITE <EndNote><Cite><Author>Weiss</Author><Year>2019</Year><RecNum>19</RecNum><DisplayText>(31)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579363504">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weiss, F. U.</author><author>Laemmerhirt, F.</author><author>Lerch, M. M.</author></authors></contributors><auth-address>Department of Medicine A, Greifswald Medical School, Greifswald, Germany.</auth-address><titles><title>Etiology and Risk Factors of Acute and Chronic Pancreatitis</title><secondary-title>Visc Med</secondary-title></titles><periodical><full-title>Visc Med</full-title></periodical><pages>73-81</pages><volume>35</volume><number>2</number><edition>2019/06/14</edition><keywords><keyword>Alcohol abuse</keyword><keyword>Etiologic factors</keyword><keyword>Genetic risk</keyword><keyword>Pancreatitis</keyword></keywords><dates><year>2019</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2297-4725 (Print)&#xD;2297-4725 (Linking)</isbn><accession-num>31192240</accession-num><urls><related-urls><url>;(31). Gallstones will induce pancreatitis when they get stuck into the papilla of Vater and in that way obstructing the outflow of juices from the pancreatic duct. This will lead to an increased pressure in the pancreas that will induce acinar injury and onset of the disease ADDIN EN.CITE <EndNote><Cite><Author>Runzi</Author><Year>1993</Year><RecNum>21</RecNum><DisplayText>(32)</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579365180">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Runzi, M.</author><author>Saluja, A.</author><author>Lerch, M. M.</author><author>Dawra, R.</author><author>Nishino, H.</author><author>Steer, M. L.</author></authors></contributors><auth-address>Department of Surgery, Beth Israel Hospital, Boston, Massachusetts.</auth-address><titles><title>Early ductal decompression prevents the progression of biliary pancreatitis: an experimental study in the opossum</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>157-64</pages><volume>105</volume><number>1</number><edition>1993/07/01</edition><keywords><keyword>Animals</keyword><keyword>Bile Duct Diseases/complications</keyword><keyword>Bile Ducts/pathology</keyword><keyword>Cholelithiasis/*complications/surgery</keyword><keyword>Cholestasis/*complications/pathology</keyword><keyword>Female</keyword><keyword>L-Lactate Dehydrogenase/metabolism</keyword><keyword>Male</keyword><keyword>Opossums</keyword><keyword>Pancreatitis/*etiology</keyword></keywords><dates><year>1993</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>8514033</accession-num><urls><related-urls><url>(93)90021-4</electronic-resource-num></record></Cite></EndNote>(32). Regurgitation of bile salt could theoretically also be a possible explanatory mechanism. After gallstones, immoderate alcohol consumption are the second most common reason for AP, responsible for around 30% of the cases ADDIN EN.CITE <EndNote><Cite><Author>Weiss</Author><Year>2019</Year><RecNum>19</RecNum><DisplayText>(31)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579363504">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weiss, F. U.</author><author>Laemmerhirt, F.</author><author>Lerch, M. M.</author></authors></contributors><auth-address>Department of Medicine A, Greifswald Medical School, Greifswald, Germany.</auth-address><titles><title>Etiology and Risk Factors of Acute and Chronic Pancreatitis</title><secondary-title>Visc Med</secondary-title></titles><periodical><full-title>Visc Med</full-title></periodical><pages>73-81</pages><volume>35</volume><number>2</number><edition>2019/06/14</edition><keywords><keyword>Alcohol abuse</keyword><keyword>Etiologic factors</keyword><keyword>Genetic risk</keyword><keyword>Pancreatitis</keyword></keywords><dates><year>2019</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2297-4725 (Print)&#xD;2297-4725 (Linking)</isbn><accession-num>31192240</accession-num><urls><related-urls><url>;(31). For more than a century ethanol has been known to be a risk factor for AP and the epidemiological connection is evident. However only a minority of alcoholics ever experience AP. This indicate that alcohol itself is not responsible for developing the disease but rather for sensitizing the organ for other risk factors. However, due to developmental relations the pancreas shares the ability to metabolize alcohol with the liver, and when this is done several substances that has a known adverse effect to the pancreas is generated. In the pancreas massive alcohol intake will induce both oxidative and non-oxidative processes. The oxidative pathways that uses cytochrome P450 and pancreatic alcohol dehydrogenase, will form acetaldehyde and reactive oxygen species while the non-oxidative metabolism will yield fatty acid ethyl esters. These metabolites will cause oxidative stress and could cause several changes in the homeostasis of the acinar cells, including increased intracellular Ca2+, impaired autophagy and activation of digestive enzymes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWFuZzwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl

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Tm90ZT5=

ADDIN EN.CITE.DATA (33-35). AP generated by alcohol often has a more aggressive course than gallstone induced AP. In summary, gallstones and alcohol together account for 70-80% of the cases. In around 10-30% the aetiology remains unknown, making idiopathic the third most common cause. The other mentioned factors together make up for a few per cents of the total amount of AP, and here different pathomechanisms are at play, such as: sphincter spasm, localized angioedema, hypertensive reaction, toxicity of free fatty acids and other cytotoxic and metabolic effects PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hlcmVyPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA (40) and as a scarce complication to some infectious disease ADDIN EN.CITE <EndNote><Cite><Author>Parenti</Author><Year>1996</Year><RecNum>31</RecNum><DisplayText>(41)</DisplayText><record><rec-number>31</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579388151">31</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parenti, D. M.</author><author>Steinberg, W.</author><author>Kang, P.</author></authors></contributors><auth-address>Division of Infectious Diseases, George Washington University Medical Center, Washington, DC 20037, USA.</auth-address><titles><title>Infectious causes of acute pancreatitis</title><secondary-title>Pancreas</secondary-title></titles><periodical><full-title>Pancreas</full-title></periodical><pages>356-71</pages><volume>13</volume><number>4</number><edition>1996/11/01</edition><keywords><keyword>*Bacterial Infections</keyword><keyword>Humans</keyword><keyword>Mycoses</keyword><keyword>Pancreatitis/*microbiology/*parasitology/virology</keyword><keyword>*Parasitic Diseases</keyword><keyword>*Virus Diseases</keyword></keywords><dates><year>1996</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0885-3177 (Print)&#xD;0885-3177 (Linking)</isbn><accession-num>8899796</accession-num><urls><related-urls><url>;(41). Beside of this, pregnancy holds a slight inherent risk for AP ADDIN EN.CITE <EndNote><Cite><Author>Jin</Author><Year>2015</Year><RecNum>28</RecNum><DisplayText>(42)</DisplayText><record><rec-number>28</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579387125">28</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jin, J.</author><author>Yu, Y. H.</author><author>Zhong, M.</author><author>Zhang, G. W.</author></authors></contributors><auth-address>Department of Gynaecology and Obstetrics and.</auth-address><titles><title>Analyzing and identifying risk factors for acute pancreatitis with different etiologies in pregnancy</title><secondary-title>J Matern Fetal Neonatal Med</secondary-title></titles><periodical><full-title>J Matern Fetal Neonatal Med</full-title></periodical><pages>267-71</pages><volume>28</volume><number>3</number><edition>2014/04/11</edition><keywords><keyword>Adult</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Pancreatitis/*epidemiology</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications/*epidemiology</keyword><keyword>Retrospective Studies</keyword><keyword>Risk Factors</keyword><keyword>Young Adult</keyword><keyword>Biliary acute pancreatitis</keyword><keyword>hyperglyceridemic-induced pancreatitis</keyword><keyword>risk</keyword></keywords><dates><year>2015</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1476-4954 (Electronic)&#xD;1476-4954 (Linking)</isbn><accession-num>24716806</accession-num><urls><related-urls><url>;(42).Diagnostics and classificationThe diagnosis of AP is made if a patient shows at least two out of three cardinal signs, namely: 1: sudden onset of upper abdominal pain, 2: Serum Amylase that are elevated at least three times the normal, this could also be applied on lipase, or 3: classical pancreatitis signs on computer tomography (CT) ADDIN EN.CITE <EndNote><Cite><Author>Working Group</Author><Year>2013</Year><RecNum>314</RecNum><DisplayText>(43)</DisplayText><record><rec-number>314</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582473026">314</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Working Group, I. A. P. A. P. A. Acute Pancreatitis Guidelines</author></authors></contributors><auth-address>International Association of Pancreatology, UNSW Clinical School Locked Bag 7103, Liverpool, BC NSW 1871, Australia; American Pancreatic Association, PO Box 14906, Minneapolis, MN 55414, USA.</auth-address><titles><title>IAP/APA evidence-based guidelines for the management of acute pancreatitis</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>e1-15</pages><volume>13</volume><number>4 Suppl 2</number><edition>2013/09/27</edition><keywords><keyword>Acute Disease</keyword><keyword>Cholecystectomy</keyword><keyword>Disease Management</keyword><keyword>Fluid Therapy</keyword><keyword>Humans</keyword><keyword>Pancreas/surgery</keyword><keyword>Pancreatitis/*therapy</keyword><keyword>Pancreatitis, Acute Necrotizing/diagnosis/surgery/*therapy</keyword><keyword>Acute pancreatitis</keyword><keyword>Diagnosis</keyword><keyword>Gastroenterology</keyword><keyword>Guidelines</keyword><keyword>Intervention</keyword><keyword>Nutrition</keyword><keyword>Pancreas</keyword><keyword>Prediction</keyword><keyword>Prevention</keyword><keyword>Radiology</keyword><keyword>Surgery</keyword><keyword>Treatment</keyword></keywords><dates><year>2013</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1424-3911 (Electronic)&#xD;1424-3903 (Linking)</isbn><accession-num>24054878</accession-num><urls><related-urls><url>;(43). The clinical spectrum of the disease ranges from very mild to life threatening, and several attempts to classify AP have been made. Since 1992 the Atlanta classification (AC) has been the prevailing system ADDIN EN.CITE <EndNote><Cite><Author>Bradley</Author><Year>1993</Year><RecNum>315</RecNum><DisplayText>(44)</DisplayText><record><rec-number>315</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582487183">315</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bradley, E. L., 3rd</author></authors></contributors><auth-address>Department of Surgery, Emory University, Atlanta, Ga.</auth-address><titles><title>A clinically based classification system for acute pancreatitis. Summary of the International Symposium on Acute Pancreatitis, Atlanta, Ga, September 11 through 13, 1992</title><secondary-title>Arch Surg</secondary-title></titles><periodical><full-title>Arch Surg</full-title></periodical><pages>586-90</pages><volume>128</volume><number>5</number><edition>1993/05/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Humans</keyword><keyword>Necrosis</keyword><keyword>Pancreatitis/*classification/pathology/physiopathology</keyword><keyword>Terminology as Topic</keyword></keywords><dates><year>1993</year><pub-dates><date>May</date></pub-dates></dates><isbn>0004-0010 (Print)&#xD;0004-0010 (Linking)</isbn><accession-num>8489394</accession-num><urls><related-urls><url>;(44). After twenty years of assessment and further research in the field of AP, several limitations in the AC was identified PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2xsZW48L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (47, 48). The RAC is the system that best correlates to the recommendations given by the IAP/APA (International Association of Pancreatology/ American Pancreatic Association) ADDIN EN.CITE <EndNote><Cite><Author>Working Group</Author><Year>2013</Year><RecNum>314</RecNum><DisplayText>(43)</DisplayText><record><rec-number>314</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582473026">314</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Working Group, I. A. P. A. P. A. Acute Pancreatitis Guidelines</author></authors></contributors><auth-address>International Association of Pancreatology, UNSW Clinical School Locked Bag 7103, Liverpool, BC NSW 1871, Australia; American Pancreatic Association, PO Box 14906, Minneapolis, MN 55414, USA.</auth-address><titles><title>IAP/APA evidence-based guidelines for the management of acute pancreatitis</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>e1-15</pages><volume>13</volume><number>4 Suppl 2</number><edition>2013/09/27</edition><keywords><keyword>Acute Disease</keyword><keyword>Cholecystectomy</keyword><keyword>Disease Management</keyword><keyword>Fluid Therapy</keyword><keyword>Humans</keyword><keyword>Pancreas/surgery</keyword><keyword>Pancreatitis/*therapy</keyword><keyword>Pancreatitis, Acute Necrotizing/diagnosis/surgery/*therapy</keyword><keyword>Acute pancreatitis</keyword><keyword>Diagnosis</keyword><keyword>Gastroenterology</keyword><keyword>Guidelines</keyword><keyword>Intervention</keyword><keyword>Nutrition</keyword><keyword>Pancreas</keyword><keyword>Prediction</keyword><keyword>Prevention</keyword><keyword>Radiology</keyword><keyword>Surgery</keyword><keyword>Treatment</keyword></keywords><dates><year>2013</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1424-3911 (Electronic)&#xD;1424-3903 (Linking)</isbn><accession-num>24054878</accession-num><urls><related-urls><url>;(43) and it is also the system used in the Swedish guidelines. The classification is based on imaging, mainly contrast-enhanced CT (CECT), and organ failure according to the Marshall scoring system ADDIN EN.CITE <EndNote><Cite><Author>Marshall</Author><Year>1995</Year><RecNum>320</RecNum><DisplayText>(49)</DisplayText><record><rec-number>320</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582630673">320</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marshall, J. C.</author><author>Cook, D. J.</author><author>Christou, N. V.</author><author>Bernard, G. R.</author><author>Sprung, C. L.</author><author>Sibbald, W. J.</author></authors></contributors><auth-address>Department of Surgery, University of Toronto, ON, Canada.</auth-address><titles><title>Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome</title><secondary-title>Crit Care Med</secondary-title></titles><periodical><full-title>Crit Care Med</full-title></periodical><pages>1638-52</pages><volume>23</volume><number>10</number><edition>1995/10/01</edition><keywords><keyword>Humans</keyword><keyword>Intensive Care Units</keyword><keyword>Multiple Organ Failure/*classification/epidemiology/mortality</keyword><keyword>*Outcome Assessment, Health Care</keyword><keyword>Predictive Value of Tests</keyword><keyword>Prognosis</keyword><keyword>Prospective Studies</keyword><keyword>Reproducibility of Results</keyword><keyword>*Severity of Illness Index</keyword></keywords><dates><year>1995</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0090-3493 (Print)&#xD;0090-3493 (Linking)</isbn><accession-num>7587228</accession-num><urls><related-urls><url>;(49). CECT is the imaging modality that is considered to be the golden standard of assessing AP ADDIN EN.CITE <EndNote><Cite><Author>Lankisch</Author><Year>2015</Year><RecNum>321</RecNum><DisplayText>(50)</DisplayText><record><rec-number>321</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582635834">321</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lankisch, P. G.</author><author>Apte, M.</author><author>Banks, P. A.</author></authors></contributors><auth-address>Department of General Internal Medicine and Gastroenterology, Clinical Centre of Luneburg, Luneburg, Germany. Electronic address: paulgeorg.lankisch@t-online.de.&#xD;Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Ingham Institute for Applied Medical Research, Liverpool Hospital, Liverpool, NSW, Australia.&#xD;Division of Gastroenterology, Hepatology, and Endoscopy, Harvard Medical School, and Brigham and Women&apos;s Hospital, Boston, MA, USA.</auth-address><titles><title>Acute pancreatitis</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>85-96</pages><volume>386</volume><number>9988</number><edition>2015/01/27</edition><keywords><keyword>Acute Disease</keyword><keyword>Diagnosis, Differential</keyword><keyword>Gallstones/complications</keyword><keyword>Humans</keyword><keyword>Pancreatitis/*diagnosis/etiology/therapy</keyword><keyword>Pancreatitis, Alcoholic/diagnosis/therapy</keyword><keyword>Prognosis</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2015</year><pub-dates><date>Jul 4</date></pub-dates></dates><isbn>1474-547X (Electronic)&#xD;0140-6736 (Linking)</isbn><accession-num>25616312</accession-num><urls><related-urls><url>(14)60649-8</electronic-resource-num></record></Cite></EndNote>(50), and out of the findings AP could according to the RAC be classified as: interstitial edematous pancreatitis (IEP) or necrotizing pancreatitis. Associated with IEP are the findings that indicate local complications namely; acute pancreatic fluid collection (APFC) and pancreatic pseudocysts that both could be found on CECT. In necrotizing pancreatitis, the local complications are divided into acute necrotic collection (ANC) that could be found both intra and extra pancreatic and walled-off necrosis (WON) also both intra or extra pancreatic. They are also found on CECT, and the difference between them is how well developed the wall around the necrosis actually is ADDIN EN.CITE <EndNote><Cite><Author>Thoeni</Author><Year>2012</Year><RecNum>325</RecNum><DisplayText>(51)</DisplayText><record><rec-number>325</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582641772">325</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thoeni, R. F.</author></authors></contributors><auth-address>University of California San Francisco Medical School, Department of Radiology and Biomedical Imaging, PO Box 1325, San Francisco, CA 94143-1325, USA. ruedi.thoeni@radiology.ucsf.edu</auth-address><titles><title>The revised Atlanta classification of acute pancreatitis: its importance for the radiologist and its effect on treatment</title><secondary-title>Radiology</secondary-title></titles><periodical><full-title>Radiology</full-title></periodical><pages>751-64</pages><volume>262</volume><number>3</number><edition>2012/02/24</edition><keywords><keyword>Acute Disease</keyword><keyword>Disease Progression</keyword><keyword>Edema/classification/diagnosis/therapy</keyword><keyword>Humans</keyword><keyword>*Magnetic Resonance Imaging</keyword><keyword>Multiple Organ Failure/prevention &amp; control</keyword><keyword>Pancreatitis/*classification/*diagnosis/therapy</keyword><keyword>Pancreatitis, Acute Necrotizing/classification/diagnosis/therapy</keyword><keyword>Risk Factors</keyword><keyword>Systemic Inflammatory Response Syndrome/prevention &amp; control</keyword><keyword>*Tomography, X-Ray Computed</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1527-1315 (Electronic)&#xD;0033-8419 (Linking)</isbn><accession-num>22357880</accession-num><urls><related-urls><url>;(51). These necroses could then further be classified as sterile or infected, if there is gas bubbles in necrotic areas on the CECT. This is seen 2-4 weeks after onset of AP ADDIN EN.CITE <EndNote><Cite><Author>Bollen</Author><Year>2016</Year><RecNum>323</RecNum><DisplayText>(52)</DisplayText><record><rec-number>323</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582637899">323</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bollen, T. L.</author></authors></contributors><auth-address>Department of Radiology, St Antonius Hospital, Nieuwegein, The Netherlands. Electronic address: t.bollen@antoniusziekenhuis.nl.</auth-address><titles><title>Acute pancreatitis: international classification and nomenclature</title><secondary-title>Clin Radiol</secondary-title></titles><periodical><full-title>Clin Radiol</full-title></periodical><pages>121-33</pages><volume>71</volume><number>2</number><edition>2015/11/26</edition><keywords><keyword>Acute Disease</keyword><keyword>Contrast Media</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging</keyword><keyword>Pancreas/diagnostic imaging/pathology</keyword><keyword>Pancreatitis/*classification/*diagnosis</keyword><keyword>Radiographic Image Enhancement</keyword><keyword>*Terminology as Topic</keyword><keyword>Tomography, X-Ray Computed</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1365-229X (Electronic)&#xD;0009-9260 (Linking)</isbn><accession-num>26602933</accession-num><urls><related-urls><url>;(52). To the local determinants are also included, thrombosis of the portal or splenic vein, gastric outlet syndrome and colon necrosis, However, it must be stated that spite decades of technical refinement and constant progress of the interpretation CECT cannot evaluate the severity of AP the first days after onset, and thus has limited value and is not recommended as routine procedure ADDIN EN.CITE <EndNote><Cite><Author>Balthazar</Author><Year>2002</Year><RecNum>324</RecNum><DisplayText>(53)</DisplayText><record><rec-number>324</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582641177">324</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Balthazar, E. J.</author></authors></contributors><auth-address>Department of Radiology, New Bellevue Hospital, 462 First Ave, 3rd Fl, Rm 3W37-3W42, New York, NY 10016, USA. emiljmd@</auth-address><titles><title>Acute pancreatitis: assessment of severity with clinical and CT evaluation</title><secondary-title>Radiology</secondary-title></titles><periodical><full-title>Radiology</full-title></periodical><pages>603-13</pages><volume>223</volume><number>3</number><edition>2002/05/30</edition><keywords><keyword>Acute Disease</keyword><keyword>Contrast Media</keyword><keyword>Humans</keyword><keyword>Necrosis</keyword><keyword>Pancreatitis/complications/*diagnostic imaging/physiopathology</keyword><keyword>Prognosis</keyword><keyword>Severity of Illness Index</keyword><keyword>*Tomography, X-Ray Computed</keyword></keywords><dates><year>2002</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0033-8419 (Print)&#xD;0033-8419 (Linking)</isbn><accession-num>12034923</accession-num><urls><related-urls><url>;(53). The presence of organ failure is defined as two points or more in the Marshall Score. If it remains after 48 h it is classified as persisting, otherwise it is a transient organ failure. Systemic complications arise when there is an aggravation of other conditions such as heart or lung failure due to the AP.In the RAC a description of two different clinical phases have been made, namely: early phase (1st week after onset) in which severity is based on the presence or absence of systemic organ failure, and late (>1st week after onset):?in which severity is based on the presence of local complication or persistent systemic organ failure. Based on these three grades of AP could be defined: Mild AP: no organ failure, no local or systemic complications Moderate severe AP: transient organ failure, and/or local complications and/or systemic complicationsSevere AP: persisting organ failure, with or without local or systemic complicationsThe determinant-based classification (DBC) is built on the use of determinants of both local and systemic severity and not on clinical descriptions s the RAC ADDIN EN.CITE <EndNote><Cite><Author>Dellinger</Author><Year>2012</Year><RecNum>319</RecNum><DisplayText>(48)</DisplayText><record><rec-number>319</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582629879">319</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dellinger, E. P.</author><author>Forsmark, C. E.</author><author>Layer, P.</author><author>Levy, P.</author><author>Maravi-Poma, E.</author><author>Petrov, M. S.</author><author>Shimosegawa, T.</author><author>Siriwardena, A. K.</author><author>Uomo, G.</author><author>Whitcomb, D. C.</author><author>Windsor, J. A.</author><author>Pancreatitis Across Nations Clinical, Research</author><author>Education, Alliance</author></authors></contributors><auth-address>Department of Surgery, University of Washington School of Medicine, Seattle, WA, USA.</auth-address><titles><title>Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation</title><secondary-title>Ann Surg</secondary-title></titles><periodical><full-title>Ann Surg</full-title></periodical><pages>875-80</pages><volume>256</volume><number>6</number><edition>2012/06/28</edition><keywords><keyword>Acute Disease</keyword><keyword>Humans</keyword><keyword>Interdisciplinary Communication</keyword><keyword>International Cooperation</keyword><keyword>Pancreatitis/*classification</keyword><keyword>Referral and Consultation</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1528-1140 (Electronic)&#xD;0003-4932 (Linking)</isbn><accession-num>22735715</accession-num><urls><related-urls><url>;(48). The system was defined through three stages, first a meta-analysis of the literature, second a global web-based survey and finally an international consensus symposium. The system is graded into four categories based on determinants where the main ones are infected pancreas necrosis and organ failure. Another difference is that DBC uses the Sepsis-related Organ Failure Assessment score (SOFA-score) ADDIN EN.CITE <EndNote><Cite><Author>Vincent</Author><Year>1996</Year><RecNum>327</RecNum><DisplayText>(54)</DisplayText><record><rec-number>327</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582662575">327</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vincent, J. L.</author><author>Moreno, R.</author><author>Takala, J.</author><author>Willatts, S.</author><author>De Mendonca, A.</author><author>Bruining, H.</author><author>Reinhart, C. K.</author><author>Suter, P. M.</author><author>Thijs, L. G.</author></authors></contributors><auth-address>Erasme University Hospital, Brussels, Belgium.</auth-address><titles><title>The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine</title><secondary-title>Intensive Care Med</secondary-title></titles><periodical><full-title>Intensive Care Med</full-title></periodical><pages>707-10</pages><volume>22</volume><number>7</number><edition>1996/07/01</edition><keywords><keyword>Humans</keyword><keyword>Multiple Organ Failure/*classification/diagnosis/microbiology/mortality</keyword><keyword>Reproducibility of Results</keyword><keyword>Risk Factors</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Sepsis/*complications</keyword><keyword>*Severity of Illness Index</keyword><keyword>Time Factors</keyword></keywords><dates><year>1996</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0342-4642 (Print)&#xD;0342-4642 (Linking)</isbn><accession-num>8844239</accession-num><urls><related-urls><url>;(54) instead of the Marshall score. 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b3RlPgB=

ADDIN EN.CITE.DATA (55). In both systems the severity grade could be correlated to the outcome and prognosis. Whereas mild pancreatitis is self-limiting and associated with almost no mortality or long-term morbidity, poorer outcomes arises with every degree of severity, so that in sever or critical level the morbidity is almost 100% and the mortality rates significant, between 22-80% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYW5zYWw8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (56, 57). Since both systems is based on signs that takes days to weeks to evolve, they could not be used to identify patients at risk of developing a sever AP at admission, which otherwise would have been very beneficial. Multiple attempts to develop such a method have been made, but none have met the challenge of adequate prognostic precision PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWdvdW5hczwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA (58, 59). Beside CECT there are other methods of imaging that are relevant in the diagnosis of AP. Since gallstones are the predominant cause of AP ADDIN EN.CITE <EndNote><Cite><Author>Weiss</Author><Year>2019</Year><RecNum>19</RecNum><DisplayText>(31)</DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579363504">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weiss, F. U.</author><author>Laemmerhirt, F.</author><author>Lerch, M. M.</author></authors></contributors><auth-address>Department of Medicine A, Greifswald Medical School, Greifswald, Germany.</auth-address><titles><title>Etiology and Risk Factors of Acute and Chronic Pancreatitis</title><secondary-title>Visc Med</secondary-title></titles><periodical><full-title>Visc Med</full-title></periodical><pages>73-81</pages><volume>35</volume><number>2</number><edition>2019/06/14</edition><keywords><keyword>Alcohol abuse</keyword><keyword>Etiologic factors</keyword><keyword>Genetic risk</keyword><keyword>Pancreatitis</keyword></keywords><dates><year>2019</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2297-4725 (Print)&#xD;2297-4725 (Linking)</isbn><accession-num>31192240</accession-num><urls><related-urls><url>;(31), abdominal ultrasound is always indicated in the initial phase. For the same reason Magnetic resonance cholangiopancreatography (MRCP) is often performed as a complementary mapping of the biliary tree ADDIN EN.CITE <EndNote><Cite><Author>Mofidi</Author><Year>2008</Year><RecNum>333</RecNum><DisplayText>(60)</DisplayText><record><rec-number>333</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582668167">333</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mofidi, R.</author><author>Lee, A. C.</author><author>Madhavan, K. K.</author><author>Garden, O. J.</author><author>Parks, R. W.</author></authors></contributors><auth-address>Department of Clinical and Surgical Sciences (Surgery), University of Edinburgh, Edinburgh, UK.</auth-address><titles><title>The selective use of magnetic resonance cholangiopancreatography in the imaging of the axial biliary tree in patients with acute gallstone pancreatitis</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>55-60</pages><volume>8</volume><number>1</number><edition>2008/02/07</edition><keywords><keyword>Acute Disease</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Biliary Tract/*pathology</keyword><keyword>*Cholangiopancreatography, Magnetic Resonance</keyword><keyword>Cholecystectomy</keyword><keyword>Female</keyword><keyword>Gallstones/*complications/diagnosis/surgery</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/*complications/diagnosis</keyword></keywords><dates><year>2008</year></dates><isbn>1424-3911 (Electronic)&#xD;1424-3903 (Linking)</isbn><accession-num>18253063</accession-num><urls><related-urls><url>;(60). Endoscopic ultrasound is superior to MRCP when it comes to diagnose gallstone, with the exception of small ones with a diameter less than 5 mm PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb25kbzwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (61). Since it also has the advantage of both diagnostic and interventional capability at the same time, it is likely that its role in the cause of AP will be more developed and utilized in the future. The sensitivity of Magnetic Resonance Imaging (MRI) is equal to CECT when it comes to diagnosis and severity evaluation in AP, and even a bit superior than CECT when it comes to assessing fluid collections and necrosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JnYW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS

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ZT5=

ADDIN EN.CITE.DATA (62). For practical reasons though CECT are more feasible. Management of the patientThere is no targeted treatment for AP, and there for the care is empirical and unspecific with support of vital functions and prevention of complications as the primary focus. To obtain a stable hemodynamic situation is the initial concern. This is done by rather aggressive volume resuscitation (250-500 ml/h of crystalloids) and monitoring of fluid losses. Infusion of fluids should start already at the emergency department, in that an early fluid resuscitation has been showen to be associated with reduced rates of SIRS, organ failure, MODS and hence lower mortality PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJuZG9yZjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA (63, 64). If the pulse is <120 bpm, the mean arterial blood pressure is >65 mmHg with a urinary output of > 0.5 ml/kg/h, the resuscitation is considered adequate ADDIN EN.CITE <EndNote><Cite><Author>Working Group</Author><Year>2013</Year><RecNum>314</RecNum><DisplayText>(43)</DisplayText><record><rec-number>314</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582473026">314</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Working Group, I. A. P. A. P. A. Acute Pancreatitis Guidelines</author></authors></contributors><auth-address>International Association of Pancreatology, UNSW Clinical School Locked Bag 7103, Liverpool, BC NSW 1871, Australia; American Pancreatic Association, PO Box 14906, Minneapolis, MN 55414, USA.</auth-address><titles><title>IAP/APA evidence-based guidelines for the management of acute pancreatitis</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>e1-15</pages><volume>13</volume><number>4 Suppl 2</number><edition>2013/09/27</edition><keywords><keyword>Acute Disease</keyword><keyword>Cholecystectomy</keyword><keyword>Disease Management</keyword><keyword>Fluid Therapy</keyword><keyword>Humans</keyword><keyword>Pancreas/surgery</keyword><keyword>Pancreatitis/*therapy</keyword><keyword>Pancreatitis, Acute Necrotizing/diagnosis/surgery/*therapy</keyword><keyword>Acute pancreatitis</keyword><keyword>Diagnosis</keyword><keyword>Gastroenterology</keyword><keyword>Guidelines</keyword><keyword>Intervention</keyword><keyword>Nutrition</keyword><keyword>Pancreas</keyword><keyword>Prediction</keyword><keyword>Prevention</keyword><keyword>Radiology</keyword><keyword>Surgery</keyword><keyword>Treatment</keyword></keywords><dates><year>2013</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>1424-3911 (Electronic)&#xD;1424-3903 (Linking)</isbn><accession-num>24054878</accession-num><urls><related-urls><url>;(43). In order to avoid oedema due to over-resuscitation, the need for fluids should be repeatedly evaluated PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZS1NYWRhcmlhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh

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ADDIN EN.CITE.DATA (67), The role of antibiotics in AP is a matter of debate. Systemic antibiotics have not been able to show any benefits in preventing infectious complications in any studies ADDIN EN.CITE <EndNote><Cite><Author>Jiang</Author><Year>2012</Year><RecNum>341</RecNum><DisplayText>(68)</DisplayText><record><rec-number>341</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582754982">341</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jiang, K.</author><author>Huang, W.</author><author>Yang, X. N.</author><author>Xia, Q.</author></authors></contributors><auth-address>Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.</auth-address><titles><title>Present and future of prophylactic antibiotics for severe acute pancreatitis</title><secondary-title>World J Gastroenterol</secondary-title></titles><periodical><full-title>World J Gastroenterol</full-title></periodical><pages>279-84</pages><volume>18</volume><number>3</number><edition>2012/02/02</edition><keywords><keyword>Anti-Bacterial Agents/*therapeutic use</keyword><keyword>*Antibiotic Prophylaxis</keyword><keyword>Forecasting</keyword><keyword>Humans</keyword><keyword>Pancreatitis/*drug therapy/mortality</keyword><keyword>PubMed</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Meta-analysis</keyword><keyword>Mortality</keyword><keyword>Prophylactic antibiotics</keyword><keyword>Severe acute pancreatitis</keyword></keywords><dates><year>2012</year><pub-dates><date>Jan 21</date></pub-dates></dates><isbn>2219-2840 (Electronic)&#xD;1007-9327 (Linking)</isbn><accession-num>22294832</accession-num><urls><related-urls><url>;(68), this is true for all grades of AP. Pain relief is of the out most importance early in the course of the disease and should be given promptly upon admission PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGlnbGlhbm88L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

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ADDIN EN.CITE.DATA (69), however, there is no preferred substance or method of administration defined.Beside treating the patient, diagnostics of the aetiology should be performed, primarily with laboratory test and abdominal ultrasound. Could no reason be found, further examinations with MRCP, CT, EUS and genetical analysis should be done ADDIN EN.CITE <EndNote><Cite><Author>Tenner</Author><Year>2013</Year><RecNum>343</RecNum><DisplayText>(70)</DisplayText><record><rec-number>343</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582755909">343</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tenner, S.</author><author>Baillie, J.</author><author>DeWitt, J.</author><author>Vege, S. S.</author><author>American College of, Gastroenterology</author></authors></contributors><auth-address>State University of New York, Downstate Medical Center, Brooklyn, NY, USA.</auth-address><titles><title>American College of Gastroenterology guideline: management of acute pancreatitis</title><secondary-title>Am J Gastroenterol</secondary-title></titles><periodical><full-title>Am J Gastroenterol</full-title></periodical><pages>1400-15; 1416</pages><volume>108</volume><number>9</number><edition>2013/07/31</edition><keywords><keyword>Acute Disease</keyword><keyword>Cholangiopancreatography, Endoscopic Retrograde</keyword><keyword>Drainage</keyword><keyword>Gastroenterology</keyword><keyword>Humans</keyword><keyword>Pancreas/diagnostic imaging/*surgery</keyword><keyword>Pancreatic Ducts/diagnostic imaging/surgery</keyword><keyword>Pancreatitis/diagnostic imaging/*surgery</keyword><keyword>Prognosis</keyword></keywords><dates><year>2013</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1572-0241 (Electronic)&#xD;0002-9270 (Linking)</isbn><accession-num>23896955</accession-num><urls><related-urls><url>;(70). When the aetiology is established, the causative factor should be eliminated, in order to prevent recurrence, for instance at the presence of gall stones, a cholecystectomy at the same admission as the AP reduces the risk of gall stone-related complications with 72% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kYSBDb3N0YTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

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ADDIN EN.CITE.DATA (71). ERCP should be performed only if there are signs of cholangitis, and there are no clear evidence that ERCP should be done in AP with cholestasis without cholangitis ADDIN EN.CITE <EndNote><Cite><Author>Tse</Author><Year>2012</Year><RecNum>346</RecNum><DisplayText>(72)</DisplayText><record><rec-number>346</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582757360">346</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tse, F.</author><author>Yuan, Y.</author></authors></contributors><auth-address>Department of Medicine, Division of Gastroenterology, McMaster University, Hamilton, Canada. tsef@mcmaster.ca.</auth-address><titles><title>Early routine endoscopic retrograde cholangiopancreatography strategy versus early conservative management strategy in acute gallstone pancreatitis</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD009779</pages><number>5</number><edition>2012/05/18</edition><keywords><keyword>Acute Disease</keyword><keyword>Cholangiopancreatography, Endoscopic Retrograde/adverse</keyword><keyword>effects/*methods/mortality</keyword><keyword>Cholestasis/complications</keyword><keyword>Gallstones/*complications</keyword><keyword>Humans</keyword><keyword>Pancreatitis/mortality/*therapy</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2012</year><pub-dates><date>May 16</date></pub-dates></dates><isbn>1469-493X (Electronic)&#xD;1361-6137 (Linking)</isbn><accession-num>22592743</accession-num><urls><related-urls><url>;(72). However, ERCP is also indicated in patients with biliary pancreatitis that for some reason are consider unsuitable for cholecystectomy.In general, there has been a shift towards a more conservative approach with less surgical interventions during the last twenty years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmVlbWFuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA (74), thus confirming the old maxim: ”surgeon, the pancreas is not your friend”.PathogenesisProteas activation and initial cellular damageEven though several etiological factors are known, and several theoretical mechanisms for explaining the pathophysiological pathways behind AP are described, the precise trail is still yet to be clarified. There are debate and consideration over both the precise initial events and the following subsequent reactions ADDIN EN.CITE <EndNote><Cite><Author>Saluja</Author><Year>2019</Year><RecNum>37</RecNum><DisplayText>(75)</DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579449721">37</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saluja, A.</author><author>Dudeja, V.</author><author>Dawra, R.</author><author>Sah, R. P.</author></authors></contributors><auth-address>University of Miami, Miami, Florida.&#xD;Minnesota Gastroenterology, Minneapolis, Minnesota.</auth-address><titles><title>Early Intra-Acinar Events in Pathogenesis of Pancreatitis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>1979-1993</pages><volume>156</volume><number>7</number><edition>2019/02/19</edition><keywords><keyword>Acinar Cells/*enzymology/pathology</keyword><keyword>Animals</keyword><keyword>Cell Death</keyword><keyword>Enzyme Activation</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Inflammation Mediators/metabolism</keyword><keyword>Mutation</keyword><keyword>Pancreas, Exocrine/*enzymology/pathology</keyword><keyword>Pancreatitis/*enzymology/genetics/pathology</keyword><keyword>Phenotype</keyword><keyword>Signal Transduction</keyword><keyword>Trypsin/genetics/*metabolism</keyword><keyword>Trypsinogen/genetics/*metabolism</keyword><keyword>*Acute Pancreatitis</keyword><keyword>*Cathepsin B</keyword><keyword>*Chronic Pancreatitis</keyword><keyword>*Trypsin</keyword></keywords><dates><year>2019</year><pub-dates><date>May</date></pub-dates></dates><isbn>1528-0012 (Electronic)&#xD;0016-5085 (Linking)</isbn><accession-num>30776339</accession-num><urls><related-urls><url>;(75). However, over a century ago, Hans Chiari (1851-1916) proposed premature proteas activation and following autodigestion as a central happening in the early development of AP ADDIN EN.CITE <EndNote><Cite><Author>Chiari</Author><Year>1896</Year><RecNum>38</RecNum><DisplayText>(76)</DisplayText><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579451515">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiari, H.</author></authors></contributors><titles><title>Uber die Selbstverdaung des menshlichen Pankreas</title><secondary-title>Z Heilik</secondary-title></titles><periodical><full-title>Z Heilik</full-title></periodical><pages>69-96</pages><volume>17</volume><dates><year>1896</year><pub-dates><date>1896</date></pub-dates></dates><urls><related-urls><url>;(76). This is still generally recognized to be correct and has been verified repeatedly in experimental models over the years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2ZiYXVlcjwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+

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ADDIN EN.CITE.DATA (77-79). Among the proteases, trypsin is considered to be the primary suspect since, it is the most abundant, very potent and has the ability of activating the other proteases as well as trypsinogen, and hence itself. Indeed, premature activation of trypsinogen into trypsin is generally accepted as the key step in the early development of the disease ADDIN EN.CITE <EndNote><Cite><Author>Regner</Author><Year>2008</Year><RecNum>42</RecNum><DisplayText>(80)</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579511400">42</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Regner, S.</author><author>Manjer, J.</author><author>Appelros, S.</author><author>Hjalmarsson, C.</author><author>Sadic, J.</author><author>Borgstrom, A.</author></authors></contributors><auth-address>Department of Surgery, Malmo University Hospital, Lund University, Lund, Sweden. sara.regner@med.lu.se</auth-address><titles><title>Protease activation, pancreatic leakage, and inflammation in acute pancreatitis: differences between mild and severe cases and changes over the first three days</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>600-7</pages><volume>8</volume><number>6</number><edition>2008/10/14</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Amylases/blood</keyword><keyword>C-Reactive Protein/metabolism</keyword><keyword>Carboxypeptidase B/blood</keyword><keyword>Chemokine CCL2/blood/urine</keyword><keyword>Enzyme Activation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Inflammation</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/*classification/*enzymology/physiopathology</keyword><keyword>Peptide Hydrolases/*blood</keyword><keyword>Trypsin/blood</keyword><keyword>Trypsinogen/blood</keyword></keywords><dates><year>2008</year></dates><isbn>1424-3911 (Electronic)&#xD;1424-3903 (Linking)</isbn><accession-num>18849642</accession-num><urls><related-urls><url>;(80). The untimely activation of trypsinogen could theoretically occur; inside the acinar cells, interstitially or intraductal. Intracellular activation has been intensely studied, and verified in several studies over the years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib2ZiYXVlcjwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+

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ADDIN EN.CITE.DATA (77, 81). The predominantly explanatory model behind is the “co-localization theory” which states that during stress, the zymogen granules for some reason confluence with the lysosomes of the cells ADDIN EN.CITE <EndNote><Cite><Author>Steer</Author><Year>1987</Year><RecNum>404</RecNum><DisplayText>(82)</DisplayText><record><rec-number>404</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583166943">404</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Steer, M. L.</author><author>Meldolesi, J.</author></authors></contributors><titles><title>The cell biology of experimental pancreatitis</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>144-50</pages><volume>316</volume><number>3</number><edition>1987/01/15</edition><keywords><keyword>Animals</keyword><keyword>Ceruletide</keyword><keyword>Choline Deficiency/complications</keyword><keyword>Diet</keyword><keyword>Disease Models, Animal</keyword><keyword>Humans</keyword><keyword>Pancreas/metabolism</keyword><keyword>Pancreatitis/etiology/*metabolism</keyword></keywords><dates><year>1987</year><pub-dates><date>Jan 15</date></pub-dates></dates><isbn>0028-4793 (Print)&#xD;0028-4793 (Linking)</isbn><accession-num>3540666</accession-num><urls><related-urls><url>;(82), forming an intracellular vacuole ADDIN EN.CITE <EndNote><Cite><Author>Kolodecik</Author><Year>2009</Year><RecNum>407</RecNum><DisplayText>(83)</DisplayText><record><rec-number>407</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583170423">407</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kolodecik, T.</author><author>Gorelick, F.</author><author>Thrower, E.</author></authors></contributors><auth-address>Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven CT 06520.</auth-address><titles><title>Genetic and Pharmacologic Manipulation of Vacuolar Atpase; Effects on Zymogen Activation in Pancreatic Acini</title><secondary-title>Open Access Anim Physiol</secondary-title></titles><periodical><full-title>Open Access Anim Physiol</full-title></periodical><pages>1-11</pages><volume>2009</volume><number>1</number><edition>2009/11/19</edition><dates><year>2009</year><pub-dates><date>Nov 19</date></pub-dates></dates><isbn>1179-2779 (Print)</isbn><accession-num>21572923</accession-num><urls><related-urls><url>;(83). This is a hallmark for acinar cell damage and could be caused by some factor blocking the apical exocytosis ADDIN EN.CITE <EndNote><Cite><Author>Sherwood</Author><Year>2007</Year><RecNum>408</RecNum><DisplayText>(84)</DisplayText><record><rec-number>408</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583170679">408</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sherwood, M. W.</author><author>Prior, I. A.</author><author>Voronina, S. G.</author><author>Barrow, S. L.</author><author>Woodsmith, J. D.</author><author>Gerasimenko, O. V.</author><author>Petersen, O. H.</author><author>Tepikin, A. V.</author></authors></contributors><auth-address>Physiological Laboratory, University of Liverpool, Crown Street, Liverpool L69 3BX, UK.</auth-address><titles><title>Activation of trypsinogen in large endocytic vacuoles of pancreatic acinar cells</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci U S A</full-title></periodical><pages>5674-9</pages><volume>104</volume><number>13</number><edition>2007/03/17</edition><keywords><keyword>Animals</keyword><keyword>Calcium/metabolism</keyword><keyword>Cells, Cultured</keyword><keyword>Dextrans/chemistry</keyword><keyword>*Endocytosis</keyword><keyword>Enzyme Activation</keyword><keyword>Fluorescent Dyes/pharmacology</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Mice</keyword><keyword>Pancreas/*cytology</keyword><keyword>Pancreatitis/metabolism</keyword><keyword>Protein Transport</keyword><keyword>Trypsin/chemistry</keyword><keyword>Trypsinogen/*metabolism</keyword><keyword>Vacuoles/metabolism</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar 27</date></pub-dates></dates><isbn>0027-8424 (Print)&#xD;0027-8424 (Linking)</isbn><accession-num>17363470</accession-num><urls><related-urls><url>;(84). These lysosomes contain hydrolases, where the most abundant, Cathepsin B have the ability to activate trypsinogen into trypsin ADDIN EN.CITE <EndNote><Cite><Author>Steer</Author><Year>1996</Year><RecNum>44</RecNum><DisplayText>(85)</DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579515910">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Steer, M. L.</author><author>Saluja, A. K.</author></authors></contributors><titles><title>Lysosomal enzymes and pancreatitis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>965-7</pages><volume>110</volume><number>3</number><edition>1996/03/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Lysosomes/*enzymology</keyword><keyword>Pancreas/*enzymology</keyword><keyword>Pancreatitis/*enzymology</keyword><keyword>Rats</keyword></keywords><dates><year>1996</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>8608914</accession-num><urls><related-urls><url>;(85). However, it has been observed that digestive enzymes and lysosome hydrolases colocalize in the same cellular compartment in healthy humans as well, indicating that other factors and conditions might affect whether vacuolization and premature intracellular activation of trypsinogen occurs ADDIN EN.CITE <EndNote><Cite><Author>Halangk</Author><Year>2005</Year><RecNum>45</RecNum><DisplayText>(86)</DisplayText><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579516592">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Halangk, W.</author><author>Lerch, M. M.</author></authors></contributors><auth-address>Division of Experimental Surgery, Department of Surgery, Otto-von-Guericke-Universitat, Magdeburg, Leipziger Strasse, 44 D-39120 Magdeburg, Germany. walter.halangk@medizin.uni-magdeburg.de</auth-address><titles><title>Early events in acute pancreatitis</title><secondary-title>Clin Lab Med</secondary-title></titles><periodical><full-title>Clin Lab Med</full-title></periodical><pages>1-15</pages><volume>25</volume><number>1</number><edition>2005/03/08</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Calcium Signaling/physiology</keyword><keyword>Cathepsin B/*metabolism</keyword><keyword>Humans</keyword><keyword>Pancreas, Exocrine/*enzymology</keyword><keyword>Pancreatitis/*metabolism/*physiopathology</keyword><keyword>Trypsin/*metabolism</keyword></keywords><dates><year>2005</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0272-2712 (Print)&#xD;0272-2712 (Linking)</isbn><accession-num>15749229</accession-num><urls><related-urls><url>;(86). 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ADDIN EN.CITE.DATA (88). Under physiological conditions the Ca2+ concentration of the acinar cells are higher in the endoplasmatic reticulum (ER) and the extracellular space than intracellularly, 100?M compared to 100nM ADDIN EN.CITE <EndNote><Cite><Author>Petersen</Author><Year>1998</Year><RecNum>47</RecNum><DisplayText>(89)</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579687278">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petersen, O. H.</author><author>Gerasimenko, O. V.</author><author>Gerasimenko, J. V.</author><author>Mogami, H.</author><author>Tepikin, A. V.</author></authors></contributors><auth-address>MRC Secretory Control Research Group, Physiological Laboratory, University of Liverpool, UK.</auth-address><titles><title>The calcium store in the nuclear envelope</title><secondary-title>Cell Calcium</secondary-title></titles><periodical><full-title>Cell Calcium</full-title></periodical><pages>87-90</pages><volume>23</volume><number>2-3</number><edition>1998/05/28</edition><keywords><keyword>Animals</keyword><keyword>Biological Transport</keyword><keyword>Calcium/*metabolism</keyword><keyword>Calcium Channels/metabolism</keyword><keyword>Calcium-Transporting ATPases/metabolism</keyword><keyword>Endoplasmic Reticulum/*metabolism</keyword><keyword>Nuclear Envelope/*metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb-Mar</date></pub-dates></dates><isbn>0143-4160 (Print)&#xD;0143-4160 (Linking)</isbn><accession-num>9601603</accession-num><urls><related-urls><url>(98)90106-3</electronic-resource-num></record></Cite></EndNote>(89). If the inositol 1,4,5-triphoste receptor (IP3R) is activated a rapid elevation of Ca2+ levels occurs in the apical end of the intracellular space ADDIN EN.CITE <EndNote><Cite><Author>Streb</Author><Year>1984</Year><RecNum>49</RecNum><DisplayText>(90)</DisplayText><record><rec-number>49</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579688373">49</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Streb, H.</author><author>Bayerdorffer, E.</author><author>Haase, W.</author><author>Irvine, R. F.</author><author>Schulz, I.</author></authors></contributors><titles><title>Effect of inositol-1,4,5-trisphosphate on isolated subcellular fractions of rat pancreas</title><secondary-title>J Membr Biol</secondary-title></titles><periodical><full-title>J Membr Biol</full-title></periodical><pages>241-53</pages><volume>81</volume><number>3</number><edition>1984/01/01</edition><keywords><keyword>Animals</keyword><keyword>Calcium/metabolism</keyword><keyword>Cell Fractionation</keyword><keyword>Cell Membrane/metabolism/ultrastructure</keyword><keyword>Cell Membrane Permeability</keyword><keyword>Inositol 1,4,5-Trisphosphate</keyword><keyword>Inositol Phosphates/*pharmacology</keyword><keyword>Kinetics</keyword><keyword>Male</keyword><keyword>Microscopy, Electron</keyword><keyword>Pancreas/cytology/drug effects/*metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Inbred Strains</keyword><keyword>Receptors, Muscarinic/drug effects</keyword><keyword>Subcellular Fractions/metabolism/ultrastructure</keyword><keyword>Sugar Phosphates/*pharmacology</keyword></keywords><dates><year>1984</year></dates><isbn>0022-2631 (Print)&#xD;0022-2631 (Linking)</isbn><accession-num>6334162</accession-num><urls><related-urls><url>;(90) which will lead to a release of the zymogen granules through exocytosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRlcnNlbjwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

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ADDIN EN.CITE.DATA (92, 93). Since a high intracellular Ca2+- concentration is toxic to most cells and will, depending on the degree of calcium load, induce apoptosis or necrosis ADDIN EN.CITE <EndNote><Cite><Author>Giorgi</Author><Year>2008</Year><RecNum>54</RecNum><DisplayText>(94)</DisplayText><record><rec-number>54</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579690423">54</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Giorgi, C.</author><author>Romagnoli, A.</author><author>Pinton, P.</author><author>Rizzuto, R.</author></authors></contributors><auth-address>Department of Experimental and Diagnostic Medicine, Section of General Pathology, Via Borsari 46, 44100 Ferrara, Italy.</auth-address><titles><title>Ca2+ signaling, mitochondria and cell death</title><secondary-title>Curr Mol Med</secondary-title></titles><periodical><full-title>Curr Mol Med</full-title></periodical><pages>119-30</pages><volume>8</volume><number>2</number><edition>2008/03/14</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Autophagy</keyword><keyword>*Calcium Signaling</keyword><keyword>*Cell Death</keyword><keyword>Humans</keyword><keyword>Mitochondria/*metabolism</keyword><keyword>Models, Biological</keyword><keyword>Necrosis/metabolism</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2008</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1566-5240 (Print)&#xD;1566-5240 (Linking)</isbn><accession-num>18336292</accession-num><urls><related-urls><url>;(94), it is important that Ca2+ quickly returns to normal, which it normally does when stimulation ends, there are also several mechanisms for ensuring that Ca2+-levels are adequate. A maintained elevated level of intracellular Ca2+ has been described as a possible pathophysiological explanation, driving inhibition of defence mechanisms and activation of intracellular trypsinogen PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (95-98). It has been showed that bile acids are capable of inducing high intracellular Ca2 +-peaks and prolonged elevated intracellular Ca2+-levels. This is done both by inhibiting Ca2+utake to the ER, and by potentiate the release of Ca2+ from the ER by opening two Ca2+-channels of the ER, via IP3R and ryadine receptor (RyR), and in this way enhancing further influx of Ca2+PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HZXJhc2ltZW5rbzwvQXV0aG9yPjxZZWFyPjIwMDY8L1ll

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ADDIN EN.CITE.DATA (101, 102). There is no evidence that AP is generated through intraductal activation of trypsinogen into trypsin ADDIN EN.CITE <EndNote><Cite><Author>Fernandez-del Castillo</Author><Year>1994</Year><RecNum>65</RecNum><DisplayText>(103)</DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579703205">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fernandez-del Castillo, C.</author><author>Schmidt, J.</author><author>Warshaw, A. L.</author><author>Rattner, D. W.</author></authors></contributors><auth-address>Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston 02114.</auth-address><titles><title>Interstitial protease activation is the central event in progression to necrotizing pancreatitis</title><secondary-title>Surgery</secondary-title></titles><periodical><full-title>Surgery</full-title></periodical><pages>497-504</pages><volume>116</volume><number>3</number><edition>1994/09/01</edition><keywords><keyword>Animals</keyword><keyword>Ceruletide</keyword><keyword>Edema/*etiology/metabolism/pathology</keyword><keyword>Enteropeptidase/physiology</keyword><keyword>Enzyme Activation</keyword><keyword>Male</keyword><keyword>Necrosis</keyword><keyword>Oligopeptides/blood/urine</keyword><keyword>Pancreatitis/*etiology/metabolism/pathology</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Trypsinogen/*metabolism</keyword></keywords><dates><year>1994</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0039-6060 (Print)&#xD;0039-6060 (Linking)</isbn><accession-num>8079180</accession-num><urls><related-urls><url>;(103).Since trypsin itself shares the ability to activate trypsinogen with Cathepsin B and enterokinase, there are systems for regulating this autoactivation mainly consisting of the already mentioned protease inhibitors. One major such inhibitor is Serine Protease Inhibitor Kazal type 1 (SPINK1) also called Pancreatic Secretory trypsin inhibitor (PSTI), present in the acinar cells ADDIN EN.CITE <EndNote><Cite><Author>Hirota</Author><Year>2006</Year><RecNum>68</RecNum><DisplayText>(104)</DisplayText><record><rec-number>68</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579710779">68</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hirota, M.</author><author>Ohmuraya, M.</author><author>Baba, H.</author></authors></contributors><auth-address>Department of Gastroenterological Surgery, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-0811, Japan.</auth-address><titles><title>The role of trypsin, trypsin inhibitor, and trypsin receptor in the onset and aggravation of pancreatitis</title><secondary-title>J Gastroenterol</secondary-title></titles><periodical><full-title>J Gastroenterol</full-title></periodical><pages>832-6</pages><volume>41</volume><number>9</number><edition>2006/10/19</edition><keywords><keyword>Animals</keyword><keyword>Carrier Proteins/genetics/metabolism</keyword><keyword>DNA/genetics</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Pancreatitis/genetics/*metabolism</keyword><keyword>Receptor, PAR-2/*metabolism</keyword><keyword>Trypsin/*metabolism</keyword><keyword>Trypsin Inhibitor, Kazal Pancreatic</keyword><keyword>Trypsin Inhibitors/*metabolism</keyword><keyword>Trypsinogen/genetics/metabolism</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0944-1174 (Print)&#xD;0944-1174 (Linking)</isbn><accession-num>17048046</accession-num><urls><related-urls><url>;(104). Under normal conditions it deactivates the small amount of trypsinogen that becomes converted into active trypsin and thereby preventing autodigestion and upholding the integrity of the acinar cells. If for some reason the amount of activated trypsin exceeds the capacity of PSTI a subsequent cascade of events leading to activation of more trypsinogen and other protease precursors. This is a process were calcium once again matters, since the inhibitory process is decelerated in presence of increased intracellular calcium levels allowing trypsin activation to persist longer PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TemlsYWd5aTwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+

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ADDIN EN.CITE.DATA (105). Mutations in the genes responsible for SPINK1 is associated with increases incidence of acute pancreatitis in children ADDIN EN.CITE <EndNote><Cite><Author>Nabi</Author><Year>2020</Year><RecNum>70</RecNum><DisplayText>(106)</DisplayText><record><rec-number>70</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579715303">70</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nabi, Z.</author><author>Talukdar, R.</author><author>Venkata, R.</author><author>Aslam, M.</author><author>Shava, U.</author><author>Reddy, D. N.</author></authors></contributors><auth-address>Asian Institute of Gastroenterology, 6-3-661, Hyderabad, 500082, India. zaheernabi1978@.&#xD;Asian Institute of Gastroenterology, 6-3-661, Hyderabad, 500082, India.</auth-address><titles><title>Genetic Evaluation of Children with Idiopathic Recurrent Acute Pancreatitis</title><secondary-title>Dig Dis Sci</secondary-title></titles><periodical><full-title>Dig Dis Sci</full-title></periodical><edition>2020/01/05</edition><keywords><keyword>Children</keyword><keyword>Genetic mutations</keyword><keyword>Pancreatitis</keyword></keywords><dates><year>2020</year><pub-dates><date>Jan 3</date></pub-dates></dates><isbn>1573-2568 (Electronic)&#xD;0163-2116 (Linking)</isbn><accession-num>31900721</accession-num><urls><related-urls><url>;(106), probably due to diminished trypsin inhibitory effect ADDIN EN.CITE <EndNote><Cite><Author>Whitcomb</Author><Year>1999</Year><RecNum>79</RecNum><DisplayText>(107)</DisplayText><record><rec-number>79</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579768740">79</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Whitcomb, D. C.</author></authors></contributors><auth-address>Division of Gastroenterology and Hepatology, Centre for Genomic Sciences, 571 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA.</auth-address><titles><title>Genes means pancreatitis</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>150-1</pages><volume>44</volume><number>2</number><edition>1999/01/23</edition><keywords><keyword>Acute Disease</keyword><keyword>Chronic Disease</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Pancreatitis/*genetics</keyword><keyword>Trypsinogen/genetics</keyword></keywords><dates><year>1999</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0017-5749 (Print)&#xD;0017-5749 (Linking)</isbn><accession-num>9895368</accession-num><urls><related-urls><url>;(107).Part from Trypsin inhibition, also regulation of pH to some extent acts as a stabilizing factor preventing pre-emptive activation of trypsin ADDIN EN.CITE <EndNote><Cite><Author>Rinderknecht</Author><Year>1988</Year><RecNum>73</RecNum><DisplayText>(108)</DisplayText><record><rec-number>73</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579727590">73</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rinderknecht, H.</author></authors></contributors><auth-address>Research Service, Veterans Administration Medical Center, Sepulveda, CA.</auth-address><titles><title>Fatal pancreatitis, a consequence of excessive leukocyte stimulation?</title><secondary-title>Int J Pancreatol</secondary-title></titles><periodical><full-title>Int J Pancreatol</full-title></periodical><pages>105-12</pages><volume>3</volume><number>2-3</number><edition>1988/03/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Enzyme Precursors/metabolism</keyword><keyword>Humans</keyword><keyword>*Leukocytes/immunology</keyword><keyword>Leukotriene B4/metabolism</keyword><keyword>Pancreas/enzymology</keyword><keyword>Pancreatic Elastase/metabolism</keyword><keyword>Pancreatitis/*etiology/immunology</keyword><keyword>Tumor Necrosis Factor-alpha/metabolism</keyword></keywords><dates><year>1988</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0169-4197 (Print)&#xD;0169-4197 (Linking)</isbn><accession-num>2834471</accession-num><urls><related-urls><url>;(108).Autophagy is a protective mechanism in which the cells breaks down and recycles various cytoplasmic materials from cells that are damaged, malfunctioning or old PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbnRvbnVjY2k8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy

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ADDIN EN.CITE.DATA (109). This is a process that is important to all cells, but specially to the acinar cells since they are very productive. Impaired autophagy of the acinar cells also leads to unstable cells and activation of trypsinogen ADDIN EN.CITE <EndNote><Cite><Author>Lee</Author><Year>2019</Year><RecNum>72</RecNum><DisplayText>(110)</DisplayText><record><rec-number>72</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579727285">72</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lee, P. J.</author><author>Papachristou, G. I.</author></authors></contributors><auth-address>Division of Gastroenterology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.&#xD;Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. papachri@pitt.edu.</auth-address><titles><title>New insights into acute pancreatitis</title><secondary-title>Nat Rev Gastroenterol Hepatol</secondary-title></titles><periodical><full-title>Nat Rev Gastroenterol Hepatol</full-title></periodical><pages>479-496</pages><volume>16</volume><number>8</number><edition>2019/05/30</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Calcium Signaling/physiology</keyword><keyword>Disease Management</keyword><keyword>Disease Models, Animal</keyword><keyword>Endoplasmic Reticulum Stress/physiology</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>Nutritional Support/methods</keyword><keyword>Pancreatitis/*diagnosis/etiology/physiopathology/*therapy</keyword><keyword>Severity of Illness Index</keyword><keyword>Terminology as Topic</keyword><keyword>Trypsinogen/metabolism</keyword></keywords><dates><year>2019</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1759-5053 (Electronic)&#xD;1759-5045 (Linking)</isbn><accession-num>31138897</accession-num><urls><related-urls><url>;(110).Another substance that have proven able of trypsinogen activation is matrix metalloproteinase-9 (MMP-9) ADDIN EN.CITE <EndNote><Cite><Author>Awla</Author><Year>2012</Year><RecNum>109</RecNum><DisplayText>(111)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579883910">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Awla, D.</author><author>Abdulla, A.</author><author>Syk, I.</author><author>Jeppsson, B.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Section for Surgery, Lund University, S-205 02 Malmo, Sweden.</auth-address><titles><title>Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>711-9</pages><volume>91</volume><number>5</number><edition>2011/11/22</edition><keywords><keyword>Acinar Cells/drug effects/*metabolism/*pathology</keyword><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Blotting, Western</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Flow Cytometry</keyword><keyword>Matrix Metalloproteinase 9/*physiology</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>Neutrophils/*enzymology</keyword><keyword>Pancreatitis/drug therapy/*metabolism/*pathology</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Taurocholic Acid/pharmacology</keyword><keyword>Trypsinogen/*metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>May</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>22100390</accession-num><urls><related-urls><url>;(111). This somewhat complicates the picture, since it is a substance released from different cell types including activated neutrophils and thus should come into play downstream of protease activation. However, neutrophils them self has the ability of activating trypsinogen ADDIN EN.CITE <EndNote><Cite><Author>Abdulla</Author><Year>2011</Year><RecNum>84</RecNum><DisplayText>(112)</DisplayText><record><rec-number>84</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579773154">84</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdulla, A.</author><author>Awla, D.</author><author>Thorlacius, H.</author><author>Regner, S.</author></authors></contributors><auth-address>Department of Surgery, Clinical Sciences, Lund University, Malmo, Sweden.</auth-address><titles><title>Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>975-82</pages><volume>90</volume><number>5</number><edition>2011/08/04</edition><keywords><keyword>Acinar Cells/enzymology/pathology</keyword><keyword>Acute Disease</keyword><keyword>Amylases/metabolism</keyword><keyword>Animals</keyword><keyword>Cholagogues and Choleretics/toxicity</keyword><keyword>Enzyme Activation</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Activation</keyword><keyword>*Neutrophils/metabolism/pathology</keyword><keyword>Pancreatitis/chemically induced/*enzymology/immunology/pathology</keyword><keyword>Taurocholic Acid/toxicity</keyword><keyword>Trypsinogen/*metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>21810937</accession-num><urls><related-urls><url>;(112) and infiltration of neutrophils into the pancreas does not seem to be necessary for this to happen ADDIN EN.CITE <EndNote><Cite><Author>Awla</Author><Year>2011</Year><RecNum>111</RecNum><DisplayText>(113)</DisplayText><record><rec-number>111</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579885763">111</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Awla, D.</author><author>Abdulla, A.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Section for Surgery Malmo, Lund University, 205 02 Malmo, Sweden.</auth-address><titles><title>TLR4 but not TLR2 regulates inflammation and tissue damage in acute pancreatitis induced by retrograde infusion of taurocholate</title><secondary-title>Inflamm Res</secondary-title></titles><periodical><full-title>Inflamm Res</full-title></periodical><pages>1093-8</pages><volume>60</volume><number>12</number><edition>2011/08/25</edition><keywords><keyword>Animals</keyword><keyword>Chemokine CXCL2/blood/metabolism</keyword><keyword>Leukocyte Count</keyword><keyword>Lung/enzymology</keyword><keyword>Mice</keyword><keyword>Mice, Inbred BALB C</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>Neutrophil Infiltration</keyword><keyword>Pancreatitis, Acute Necrotizing/chemically</keyword><keyword>induced/immunology/*metabolism/pathology</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Taurocholic Acid/adverse effects</keyword><keyword>Toll-Like Receptor 2/deficiency/metabolism</keyword><keyword>Toll-Like Receptor 4/deficiency/genetics/*metabolism</keyword><keyword>Trypsinogen/metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1420-908X (Electronic)&#xD;1023-3830 (Linking)</isbn><accession-num>21863370</accession-num><urls><related-urls><url>;(113). MMP-9 appears to be an important link in the interrelationship between proteolytic activation and neutrophil extravasation in AP.Except pre-mature activation of trypsinogen another early event of importance in the course of AP is that Nuclear Factor-κB (NF-κB) for some reason becomes activated ADDIN EN.CITE <EndNote><Cite><Author>Raraty</Author><Year>2005</Year><RecNum>91</RecNum><DisplayText>(114)</DisplayText><record><rec-number>91</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579798995">91</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Raraty, M. G.</author><author>Murphy, J. A.</author><author>McLoughlin, E.</author><author>Smith, D.</author><author>Criddle, D.</author><author>Sutton, R.</author></authors></contributors><auth-address>Division of Surgery and Oncology, University of Liverpool, Liverpool L69 3BX, UK. mraraty@liverpool.ac.uk</auth-address><titles><title>Mechanisms of acinar cell injury in acute pancreatitis</title><secondary-title>Scand J Surg</secondary-title></titles><periodical><full-title>Scand J Surg</full-title></periodical><pages>89-96</pages><volume>94</volume><number>2</number><edition>2005/08/23</edition><keywords><keyword>Acute Disease</keyword><keyword>Apoptosis</keyword><keyword>Calcium/metabolism</keyword><keyword>Cholecystokinin/physiology</keyword><keyword>Cytosol/chemistry</keyword><keyword>Humans</keyword><keyword>Necrosis</keyword><keyword>Neutrophil Infiltration</keyword><keyword>Pancreas/*cytology/enzymology</keyword><keyword>Pancreatitis/*pathology/*physiopathology</keyword><keyword>Phosphatidylinositol 3-Kinases/physiology</keyword></keywords><dates><year>2005</year></dates><isbn>1457-4969 (Print)&#xD;1457-4969 (Linking)</isbn><accession-num>16111088</accession-num><urls><related-urls><url>;(114). 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ADDIN EN.CITE.DATA (116), but also generation of reactive oxygen species (ROS) is responsible for initiating an intra acinar NF-κB cascade ADDIN EN.CITE <EndNote><Cite><Author>Sah</Author><Year>2013</Year><RecNum>77</RecNum><DisplayText>(117)</DisplayText><record><rec-number>77</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579733208">77</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sah, R. P.</author><author>Dawra, R. K.</author><author>Saluja, A. K.</author></authors></contributors><auth-address>Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.</auth-address><titles><title>New insights into the pathogenesis of pancreatitis</title><secondary-title>Curr Opin Gastroenterol</secondary-title></titles><periodical><full-title>Curr Opin Gastroenterol</full-title></periodical><pages>523-30</pages><volume>29</volume><number>5</number><edition>2013/07/31</edition><keywords><keyword>Acute Disease</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>NF-kappa B/metabolism</keyword><keyword>Pancreatitis/*etiology/genetics/metabolism</keyword><keyword>Pancreatitis, Chronic/etiology/genetics/metabolism</keyword><keyword>Signal Transduction/physiology</keyword><keyword>Systemic Inflammatory Response Syndrome/etiology/physiopathology</keyword><keyword>Trypsin/physiology</keyword><keyword>Trypsinogen/metabolism</keyword></keywords><dates><year>2013</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1531-7056 (Electronic)&#xD;0267-1379 (Linking)</isbn><accession-num>23892538</accession-num><urls><related-urls><url>;(117). Local and systemic inflammationRegardless of the underlying mechanism, premature activation of trypsinogen and/or activation of the NF-κB cascade will initiate a chain reaction of further activation of proteases that will cause damage and eventually death of the acinar cells ADDIN EN.CITE <EndNote><Cite><Author>Gaiser</Author><Year>2011</Year><RecNum>80</RecNum><DisplayText>(118)</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579769165">80</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gaiser, S.</author><author>Daniluk, J.</author><author>Liu, Y.</author><author>Tsou, L.</author><author>Chu, J.</author><author>Lee, W.</author><author>Longnecker, D. S.</author><author>Logsdon, C. D.</author><author>Ji, B.</author></authors></contributors><auth-address>Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.</auth-address><titles><title>Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>1379-88</pages><volume>60</volume><number>10</number><edition>2011/04/08</edition><keywords><keyword>Animals</keyword><keyword>Enzyme Activation/*genetics</keyword><keyword>*Gene Expression Regulation</keyword><keyword>Intracellular Fluid/metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Pancreatitis, Acute Necrotizing/enzymology/*genetics</keyword><keyword>RNA, Messenger/*genetics</keyword><keyword>Reverse Transcriptase Polymerase Chain Reaction</keyword><keyword>Secretory Pathway</keyword><keyword>Trypsinogen/biosynthesis/*genetics</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1468-3288 (Electronic)&#xD;0017-5749 (Linking)</isbn><accession-num>21471572</accession-num><urls><related-urls><url>;(118). This injury constitutes the initial phase in the development of AP and will set off a sequence of events leading to an inflammatory response syndrome which constitutes the second phase of AP ADDIN EN.CITE <EndNote><Cite><Author>Saluja</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(119)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579771514">81</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saluja, A. K.</author><author>Lerch, M. M.</author><author>Phillips, P. A.</author><author>Dudeja, V.</author></authors></contributors><auth-address>Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA. asaluja@umn.edu</auth-address><titles><title>Why does pancreatic overstimulation cause pancreatitis?</title><secondary-title>Annu Rev Physiol</secondary-title></titles><periodical><full-title>Annu Rev Physiol</full-title></periodical><pages>249-69</pages><volume>69</volume><edition>2006/10/25</edition><keywords><keyword>Animals</keyword><keyword>Cholecystokinin/physiology</keyword><keyword>Ethanol/pharmacology</keyword><keyword>Extracellular Space/physiology</keyword><keyword>Humans</keyword><keyword>Pancreas/*physiopathology</keyword><keyword>Pancreatitis/*physiopathology</keyword><keyword>Solvents/pharmacology</keyword></keywords><dates><year>2007</year></dates><isbn>0066-4278 (Print)&#xD;0066-4278 (Linking)</isbn><accession-num>17059357</accession-num><urls><related-urls><url>;(119). The inflammation is not an immediate happening but develops somewhat gradually after the protease activation. There is a significant overlap of these two phases but for the understanding of the pathophysiology of AP it is a useful division. The inflammatory reaction includes enhanced vasodilation, increased permeability of the vessels and infiltration of leukocytes, primarily neutrophils and monocytes, into the pancreatic tissue ADDIN EN.CITE <EndNote><Cite><Author>Bhatia</Author><Year>2009</Year><RecNum>82</RecNum><DisplayText>(120)</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579772217">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhatia, M.</author></authors></contributors><auth-address>Department of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Centre for life Sciences, 28 Medical Drive, Singapore 117456. mbhatia@nus.edu.sg</auth-address><titles><title>Acute pancreatitis as a model of SIRS</title><secondary-title>Front Biosci (Landmark Ed)</secondary-title></titles><periodical><full-title>Front Biosci (Landmark Ed)</full-title></periodical><pages>2042-50</pages><volume>14</volume><edition>2009/03/11</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Disease Models, Animal</keyword><keyword>Pancreatitis/*physiopathology</keyword><keyword>Systemic Inflammatory Response Syndrome/*physiopathology</keyword></keywords><dates><year>2009</year><pub-dates><date>Jan 1</date></pub-dates></dates><isbn>1093-4715 (Electronic)&#xD;1093-4715 (Linking)</isbn><accession-num>19273184</accession-num><urls><related-urls><url>;(120). 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ADDIN EN.CITE.DATA (121) and it has been demonstrated that it constitutes a rate limiting step in the development of the disease ADDIN EN.CITE <EndNote><Cite><Author>Abdulla</Author><Year>2011</Year><RecNum>84</RecNum><DisplayText>(112)</DisplayText><record><rec-number>84</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579773154">84</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdulla, A.</author><author>Awla, D.</author><author>Thorlacius, H.</author><author>Regner, S.</author></authors></contributors><auth-address>Department of Surgery, Clinical Sciences, Lund University, Malmo, Sweden.</auth-address><titles><title>Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>975-82</pages><volume>90</volume><number>5</number><edition>2011/08/04</edition><keywords><keyword>Acinar Cells/enzymology/pathology</keyword><keyword>Acute Disease</keyword><keyword>Amylases/metabolism</keyword><keyword>Animals</keyword><keyword>Cholagogues and Choleretics/toxicity</keyword><keyword>Enzyme Activation</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Activation</keyword><keyword>*Neutrophils/metabolism/pathology</keyword><keyword>Pancreatitis/chemically induced/*enzymology/immunology/pathology</keyword><keyword>Taurocholic Acid/toxicity</keyword><keyword>Trypsinogen/*metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>21810937</accession-num><urls><related-urls><url>;(112). The inflammatory response is mediated by the immune system, which is composed of two parts, the adaptive, and the innate immune system, each holding different roles, challenges and mechanisms. The adaptive immune system is mainly made up by B and T lymphocytes that powerfully responds with a highly tailored precision towards specific recognized antigens. Their ability to identify different antigens are due to the fact that, part from elimination, the adaptive immune system holds the task of developing an immunological memory ADDIN EN.CITE <EndNote><Cite><Author>Bonilla</Author><Year>2010</Year><RecNum>85</RecNum><DisplayText>(122)</DisplayText><record><rec-number>85</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579780702">85</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bonilla, F. A.</author><author>Oettgen, H. C.</author></authors></contributors><auth-address>Division of Immunology, Children&apos;s Hospital Boston, Boston, MA 02115, USA. Francisco.bonilla@childrens.harvard.edu</auth-address><titles><title>Adaptive immunity</title><secondary-title>J Allergy Clin Immunol</secondary-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>S33-40</pages><volume>125</volume><number>2 Suppl 2</number><edition>2010/01/12</edition><keywords><keyword>*Adaptive Immunity</keyword><keyword>Animals</keyword><keyword>Antigen Presentation</keyword><keyword>B-Lymphocytes/*immunology</keyword><keyword>Cell Communication</keyword><keyword>Epitopes/immunology</keyword><keyword>Humans</keyword><keyword>Immunogenetic Phenomena</keyword><keyword>Lymphocyte Activation</keyword><keyword>Lymphocyte Subsets/*immunology</keyword><keyword>Lymphopoiesis/genetics</keyword><keyword>T-Lymphocytes/*immunology</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1097-6825 (Electronic)&#xD;0091-6749 (Linking)</isbn><accession-num>20061006</accession-num><urls><related-urls><url>;(122).The innate immune system which constitutes the first line of defence, using several different ways of action, does not possess a long-lasting immunological memory but instead uses molecules that are broadly shared by pathogens, but distinguished from hosts endogenous molecules, as its starting signal ADDIN EN.CITE <EndNote><Cite><Author>Riera Romo</Author><Year>2016</Year><RecNum>86</RecNum><DisplayText>(123)</DisplayText><record><rec-number>86</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579782255">86</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Riera Romo, M.</author><author>Perez-Martinez, D.</author><author>Castillo Ferrer, C.</author></authors></contributors><auth-address>Pharmacology Department, Centre of Marine Bioproducts, Havana, Cuba.&#xD;Tumour Immunology Direction, Centre of Molecular Immunology, Havana, Cuba.&#xD;Biochemistry Department, Faculty of Biology, University of Havana, Havana, Cuba.</auth-address><titles><title>Innate immunity in vertebrates: an overview</title><secondary-title>Immunology</secondary-title></titles><periodical><full-title>Immunology</full-title></periodical><pages>125-39</pages><volume>148</volume><number>2</number><edition>2016/02/16</edition><keywords><keyword>Adaptive Immunity</keyword><keyword>Animals</keyword><keyword>*Biological Evolution</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>*Immunity, Innate</keyword><keyword>*Immunotherapy</keyword><keyword>Vertebrates/*immunology</keyword><keyword>*defence mechanisms</keyword><keyword>*evolutionary history</keyword><keyword>*infection</keyword><keyword>*innate immunity</keyword><keyword>*vertebrates</keyword></keywords><dates><year>2016</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1365-2567 (Electronic)&#xD;0019-2805 (Linking)</isbn><accession-num>26878338</accession-num><urls><related-urls><url>;(123). These recognition molecules are called Pathogen-Associated Molecular Patterns (PAMPS) and they will trigger Pattern Recognition Receptors (PRRs) that are present on the inflammatory cells that are already present, scattered around in the different tissues of the body ADDIN EN.CITE <EndNote><Cite><Author>Janeway</Author><Year>1989</Year><RecNum>87</RecNum><DisplayText>(124)</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579783793">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Janeway, C. A., Jr.</author></authors></contributors><auth-address>Section of Immunology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510.</auth-address><titles><title>Approaching the asymptote? Evolution and revolution in immunology</title><secondary-title>Cold Spring Harb Symp Quant Biol</secondary-title></titles><periodical><full-title>Cold Spring Harb Symp Quant Biol</full-title></periodical><pages>1-13</pages><volume>54 Pt 1</volume><edition>1989/01/01</edition><keywords><keyword>Allergy and Immunology/*trends</keyword><keyword>Animals</keyword><keyword>Biological Evolution</keyword><keyword>Histocompatibility Antigens</keyword><keyword>Humans</keyword><keyword>Lymphocytes/immunology</keyword><keyword>Receptors, Immunologic</keyword><keyword>Signal Transduction/immunology</keyword></keywords><dates><year>1989</year></dates><isbn>0091-7451 (Print)&#xD;0091-7451 (Linking)</isbn><accession-num>2700931</accession-num><urls><related-urls><url>;(124). 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ADDIN EN.CITE.DATA (125, 126). Upon recognition of PAMPS or DAMPS, PRRs activate signaling pathways in the immunological cells controling the expression of immune response genes ADDIN EN.CITE <EndNote><Cite><Author>Janeway</Author><Year>1992</Year><RecNum>89</RecNum><DisplayText>(127)</DisplayText><record><rec-number>89</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579784704">89</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Janeway, C. A., Jr.</author></authors></contributors><auth-address>Section of Immunobiology, Yale University, New Haven, CT.</auth-address><titles><title>The immune system evolved to discriminate infectious nonself from noninfectious self</title><secondary-title>Immunol Today</secondary-title></titles><periodical><full-title>Immunol Today</full-title></periodical><pages>11-6</pages><volume>13</volume><number>1</number><edition>1992/01/11</edition><keywords><keyword>Animals</keyword><keyword>Biological Evolution</keyword><keyword>Humans</keyword><keyword>Immune System/*physiology</keyword><keyword>Infections/*immunology</keyword><keyword>Receptors, Immunologic/genetics</keyword></keywords><dates><year>1992</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0167-5699 (Print)&#xD;0167-5699 (Linking)</isbn><accession-num>1739426</accession-num><urls><related-urls><url>(92)90198-G</electronic-resource-num></record></Cite></EndNote>(127). The PRRs are singel-pass membrane-spanning receptors recognizing lipopolysaccarides, endotoxins or other PAMPS and DAMPS, and transmitting the signal from the extracellular milieu to the nuclues of the cell. The first PRRs to be discovered were the Toll Like Rceeptors (TLRs) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZW1haXRyZTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+

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ADDIN EN.CITE.DATA (128, 129), of which today 10 are identified in humans, and three more are known in mice ADDIN EN.CITE <EndNote><Cite><Author>Mahla</Author><Year>2013</Year><RecNum>95</RecNum><DisplayText>(130)</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579801287">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mahla, R. S.</author><author>Reddy, M. C.</author><author>Prasad, D. V.</author><author>Kumar, H.</author></authors></contributors><auth-address>Laboratory of Immunology, Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) , Bhopal , India.</auth-address><titles><title>Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>248</pages><volume>4</volume><edition>2013/09/14</edition><keywords><keyword>disease pathogenesis</keyword><keyword>innate immunity</keyword><keyword>innate sensors</keyword><keyword>sugar associated PAMPs</keyword><keyword>vaccinology</keyword></keywords><dates><year>2013</year><pub-dates><date>Sep 2</date></pub-dates></dates><isbn>1664-3224 (Print)&#xD;1664-3224 (Linking)</isbn><accession-num>24032031</accession-num><urls><related-urls><url>;(130). Especially TLR-4 has been showen to be of importance in the development of AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YaXBpbmc8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (113, 131). The intracellular signaling pathways initiated by TLRs are complex and go either over the fast MyD88 signalingway activating NF-κB, or the more delayed pathway that uses MAP-kinase and TIR-domain-containing adapter-inducing interferon-β (TIRF) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWtlZGE8L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (134-136). The Cyclooxygenases are enzymes that are important mediators of inflammation, in that they converts the fatty acid arachidonic acid into prostanoids, which is a subgroup of the signal substances eicosanoids and includes prostaglandins, prostacyclins and trombaxanes ADDIN EN.CITE <EndNote><Cite><Author>Needleman</Author><Year>1986</Year><RecNum>101</RecNum><DisplayText>(137)</DisplayText><record><rec-number>101</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579816695">101</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Needleman, P.</author><author>Turk, J.</author><author>Jakschik, B. A.</author><author>Morrison, A. R.</author><author>Lefkowith, J. B.</author></authors></contributors><titles><title>Arachidonic acid metabolism</title><secondary-title>Annu Rev Biochem</secondary-title></titles><periodical><full-title>Annu Rev Biochem</full-title></periodical><pages>69-102</pages><volume>55</volume><edition>1986/01/01</edition><keywords><keyword>Animals</keyword><keyword>Arachidonate Lipoxygenases</keyword><keyword>Arachidonic Acid</keyword><keyword>Arachidonic Acids/*metabolism</keyword><keyword>Binding Sites</keyword><keyword>Cytochrome P-450 Enzyme System/metabolism</keyword><keyword>Fatty Acids, Essential/deficiency</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Leukotriene B4/metabolism</keyword><keyword>Lipoxygenase/metabolism</keyword><keyword>Prostaglandin-Endoperoxide Synthases/metabolism</keyword><keyword>SRS-A/metabolism</keyword><keyword>Wounds and Injuries/metabolism</keyword></keywords><dates><year>1986</year></dates><isbn>0066-4154 (Print)&#xD;0066-4154 (Linking)</isbn><accession-num>3017195</accession-num><urls><related-urls><url>;(137). There are two types of COX in humans COX-1 and COX-2 and especially cytokine induced formation of COX-2 is associated with AP and the systemic complications that could arise PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb25nPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (138). The chemokines secreted will create a chemotactical gradient that will attract neutrophils to leave the circulation and migrate into the pancreatic tissue. Here they will exert their tasks using proteolytic enzymes, free radicals such as ROS and other defence mechanisms, and while doing so further promoting the development of inflammation ADDIN EN.CITE <EndNote><Cite><Author>Weiss</Author><Year>1989</Year><RecNum>112</RecNum><DisplayText>(139)</DisplayText><record><rec-number>112</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579896294">112</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weiss, S. J.</author></authors></contributors><auth-address>Simpson Memorial Research Institute, Department of Medicine, University of Michigan Medical Center, Ann Arbor 48109.</auth-address><titles><title>Tissue destruction by neutrophils</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>365-76</pages><volume>320</volume><number>6</number><edition>1989/02/09</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Hypochlorous Acid/metabolism</keyword><keyword>Inflammation/*metabolism</keyword><keyword>NADH, NADPH Oxidoreductases/metabolism</keyword><keyword>NADPH Oxidases</keyword><keyword>Neutrophils/enzymology/*physiology</keyword><keyword>Oxygen/metabolism</keyword></keywords><dates><year>1989</year><pub-dates><date>Feb 9</date></pub-dates></dates><isbn>0028-4793 (Print)&#xD;0028-4793 (Linking)</isbn><accession-num>2536474</accession-num><urls><related-urls><url>;(139).After extravasation the invading neutrophils are further stimulated and activated either by cytokines, PAMPS, DAMPS or many other inflammatory substances and a degranulation within the cell occurs. This will lead to cytoplasmic proteins such as Myeloperoxidase (MPO), matrix metalloproteinases (MMPs) or nuclear contents (for example Neutrophil Extracellular Traps (NETs)) being released from the neutrophils. From the surface of activated neutrophils microparticles (MPs) will be shed off PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3JyZWdhYXJkPC9BdXRob3I+PFllYXI+MTk5NzwvWWVh

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ADDIN EN.CITE.DATA (140-143). These substances will further boost the signalling pathway and recruit more neutrophils.Beside neutrophils and platelets which are the main sources of the signal substances in AP, the acinar cells them self are able to produce cytokines such as Macrophage inflammatory protein-2 (MIP-2), Interleukine-8 (IL-8), Tumor Necrotic Factor α (TNFα), keratocyte cytokine and Monocyte chemotactic protein-1 (MCP-1)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmFkeTwvQXV0aG9yPjxZZWFyPjE5OTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (144-147). Furthermore, other cell types, such as ductal cells or tissue resident macrophages are also believed to have the ability of synthetizing and secreting cytokines ADDIN EN.CITE <EndNote><Cite><Author>Vonlaufen</Author><Year>2007</Year><RecNum>118</RecNum><DisplayText>(148)</DisplayText><record><rec-number>118</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579962763">118</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vonlaufen, A.</author><author>Apte, M. V.</author><author>Imhof, B. A.</author><author>Frossard, J. L.</author></authors></contributors><auth-address>Pancreatic Research Group, South Western Sydney Clinical School, University of New South Wales, Sydney, Australia. alain.vonlaufen@unsw.edu.au</auth-address><titles><title>The role of inflammatory and parenchymal cells in acute pancreatitis</title><secondary-title>J Pathol</secondary-title></titles><periodical><full-title>J Pathol</full-title></periodical><pages>239-48</pages><volume>213</volume><number>3</number><edition>2007/09/26</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Cell Adhesion/physiology</keyword><keyword>Cell Adhesion Molecules/immunology</keyword><keyword>Cell Movement/physiology</keyword><keyword>Chemokines/immunology</keyword><keyword>Chemotaxis, Leukocyte</keyword><keyword>Extracellular Matrix/physiology</keyword><keyword>Humans</keyword><keyword>Leukocytes/immunology</keyword><keyword>Pancreas, Exocrine/immunology/pathology/*physiology</keyword><keyword>Pancreatitis/*immunology/pathology</keyword></keywords><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0022-3417 (Print)&#xD;0022-3417 (Linking)</isbn><accession-num>17893879</accession-num><urls><related-urls><url>;(148).The subsequent inflammation will impair the microcirculation, with hypoxia and cellular damage as the result. Eventually, this will result in necrosis of pancreatic tissue PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaG91PC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (149). This will yield additional burst of inflammatory substances, such as activated complement component 3 (C3), TNFα, nitric oxide, ROS, interleukins and platelet activating factor ADDIN EN.CITE <EndNote><Cite><Author>Bhatia</Author><Year>2005</Year><RecNum>409</RecNum><DisplayText>(150)</DisplayText><record><rec-number>409</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583185208">409</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhatia, M.</author></authors></contributors><auth-address>Department of Pharmacology, National University of Singapore, Faculty of Medicine, Singapore. mbhatia@nus.edu.sg</auth-address><titles><title>Inflammatory response on the pancreatic acinar cell injury</title><secondary-title>Scand J Surg</secondary-title></titles><periodical><full-title>Scand J Surg</full-title></periodical><pages>97-102</pages><volume>94</volume><number>2</number><edition>2005/08/23</edition><keywords><keyword>Acute Disease</keyword><keyword>CD40 Antigens/analysis</keyword><keyword>Humans</keyword><keyword>Inflammation Mediators/*physiology</keyword><keyword>Intercellular Adhesion Molecule-1/physiology</keyword><keyword>Interleukin-1/analysis</keyword><keyword>Interleukin-10/analysis</keyword><keyword>Multiple Organ Failure/*physiopathology</keyword><keyword>Neprilysin/physiology</keyword><keyword>Pancreas/*cytology</keyword><keyword>Pancreatitis/*pathology</keyword><keyword>Severe Acute Respiratory Syndrome/*physiopathology</keyword><keyword>Substance P/physiology</keyword><keyword>Tumor Necrosis Factor-alpha/analysis</keyword></keywords><dates><year>2005</year></dates><isbn>1457-4969 (Print)&#xD;1457-4969 (Linking)</isbn><accession-num>16111089</accession-num><urls><related-urls><url>;(150), that will result in capillary leakage, and due to the related and neighbouring conditions and location, damage to the bowel mucosa and ensuing permeability and impaired barrier function of the intestine. This could then lead to a translocation of bacteria into the necrotic pancreatic tissue, and this is considered to be the capital factor for infected necrosis ADDIN EN.CITE <EndNote><Cite><Author>Wu</Author><Year>2014</Year><RecNum>395</RecNum><DisplayText>(151)</DisplayText><record><rec-number>395</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583097648">395</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wu, L. M.</author><author>Sankaran, S. J.</author><author>Plank, L. D.</author><author>Windsor, J. A.</author><author>Petrov, M. S.</author></authors></contributors><auth-address>Department of Surgery, University of Auckland, Auckland, New Zealand.</auth-address><titles><title>Meta-analysis of gut barrier dysfunction in patients with acute pancreatitis</title><secondary-title>Br J Surg</secondary-title></titles><periodical><full-title>Br J Surg</full-title></periodical><pages>1644-56</pages><volume>101</volume><number>13</number><edition>2014/10/22</edition><keywords><keyword>Acute Disease</keyword><keyword>Epidemiologic Methods</keyword><keyword>Gastrointestinal Diseases/*physiopathology</keyword><keyword>Gastrointestinal Tract/*physiopathology</keyword><keyword>Humans</keyword><keyword>Pancreatitis/*physiopathology</keyword></keywords><dates><year>2014</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1365-2168 (Electronic)&#xD;0007-1323 (Linking)</isbn><accession-num>25334028</accession-num><urls><related-urls><url>;(151). These infectious complications emerge not immediately but around a week after onset. When they arise they will further boost release of cytokines and chemokines, leading to clinical deterioration of the patient, and a subsequent elevation of the risk for organ failure and death ADDIN EN.CITE <EndNote><Cite><Author>Petrov</Author><Year>2010</Year><RecNum>396</RecNum><DisplayText>(152)</DisplayText><record><rec-number>396</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583098005">396</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petrov, M. S.</author><author>Shanbhag, S.</author><author>Chakraborty, M.</author><author>Phillips, A. R.</author><author>Windsor, J. A.</author></authors></contributors><auth-address>Department of Surgery, The University of Auckland, Auckland, New Zealand. max.petrov@</auth-address><titles><title>Organ failure and infection of pancreatic necrosis as determinants of mortality in patients with acute pancreatitis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>813-20</pages><volume>139</volume><number>3</number><edition>2010/06/15</edition><keywords><keyword>Bacterial Infections/etiology/*mortality</keyword><keyword>Critical Illness</keyword><keyword>Humans</keyword><keyword>Multiple Organ Failure/etiology/*mortality</keyword><keyword>Pancreatitis, Acute Necrotizing/complications/*mortality</keyword><keyword>Prognosis</keyword><keyword>Risk Assessment</keyword><keyword>Risk Factors</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1528-0012 (Electronic)&#xD;0016-5085 (Linking)</isbn><accession-num>20540942</accession-num><urls><related-urls><url>;(152)The expelled signal substances will, if the inflammation aggravates, leave the pancreas through the vena porta and enter the circulation. This will lead to distant cells being activated, initiating a chain reaction that will subsequently, if continued, lead to a systemic inflammatory response syndrome (SIRS), which is a condition were the normal physiology of the immune system are derailed. The systemic outflow of cytokines and chemokines will promote increased capillary permeability and leakage, and subsequent migration of leukocytes into all kinds of tissue. As a consequence, released proteases and ROS yield further tissue damage and deterioration of microcirculation that will further promote tissue damage ADDIN EN.CITE <EndNote><Cite><Author>Osman</Author><Year>1999</Year><RecNum>397</RecNum><DisplayText>(153)</DisplayText><record><rec-number>397</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583098737">397</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Osman, M. O.</author><author>Jensen, S. L.</author></authors></contributors><auth-address>Department of Surgery, Aarhus University Hospital, Aarhus, Denmark.</auth-address><titles><title>Acute pancreatitis: the pathophysiological role of cytokines and integrins. New trends for treatment?</title><secondary-title>Dig Surg</secondary-title></titles><periodical><full-title>Dig Surg</full-title></periodical><pages>347-62</pages><volume>16</volume><number>5</number><edition>1999/11/24</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Cytokines/*physiology</keyword><keyword>Humans</keyword><keyword>Integrins/*physiology</keyword><keyword>Pancreatitis/*physiopathology/*therapy</keyword></keywords><dates><year>1999</year></dates><isbn>0253-4886 (Print)&#xD;0253-4886 (Linking)</isbn><accession-num>10567792</accession-num><urls><related-urls><url>;(153). Eventually this will lead to organ degradation and failure. 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ADDIN EN.CITE.DATA (154). Repeated cytokine burst will result in multiple organ dysfunction syndrome (MODS) if they continue ADDIN EN.CITE <EndNote><Cite><Author>Halonen</Author><Year>2002</Year><RecNum>399</RecNum><DisplayText>(155)</DisplayText><record><rec-number>399</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583100024">399</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Halonen, K. I.</author><author>Pettila, V.</author><author>Leppaniemi, A. K.</author><author>Kemppainen, E. A.</author><author>Puolakkainen, P. A.</author><author>Haapiainen, R. K.</author></authors></contributors><auth-address>Department of Gastroenterological and General Surgery, Meilahti Hospital, Helsinki University Central Hospital, Finland.</auth-address><titles><title>Multiple organ dysfunction associated with severe acute pancreatitis</title><secondary-title>Crit Care Med</secondary-title></titles><periodical><full-title>Crit Care Med</full-title></periodical><pages>1274-9</pages><volume>30</volume><number>6</number><edition>2002/06/20</edition><keywords><keyword>Apache</keyword><keyword>Acute Disease</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Female</keyword><keyword>*Hospital Mortality</keyword><keyword>Humans</keyword><keyword>Intensive Care Units</keyword><keyword>Length of Stay</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Multiple Organ Failure/classification/*complications</keyword><keyword>Pancreatitis/classification/*complications</keyword><keyword>Predictive Value of Tests</keyword><keyword>ROC Curve</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0090-3493 (Print)&#xD;0090-3493 (Linking)</isbn><accession-num>12072681</accession-num><urls><related-urls><url>;(155). Organ failure is something that occurs earliest 24 hours into the course of the disease, but could evolve any time during the following days. If the onset is early, i.e. in the first week after onset, it is generally considered to be due to sterile inflammation, whether later onset is thought to be caused by septic complication, most often infected pancreatic necrosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2ZpZGk8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (154). The severity and hence mortality are lower if the organ failure develops early, i.e. less than 48 hours after onset, compared to later ADDIN EN.CITE <EndNote><Cite><Author>Blum</Author><Year>2001</Year><RecNum>401</RecNum><DisplayText>(156)</DisplayText><record><rec-number>401</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583100844">401</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Blum, T.</author><author>Maisonneuve, P.</author><author>Lowenfels, A. B.</author><author>Lankisch, P. G.</author></authors></contributors><auth-address>Department of Internal Medicine, Municipal Clinic of Luneburg, Germany.</auth-address><titles><title>Fatal outcome in acute pancreatitis: its occurrence and early prediction</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>237-41</pages><volume>1</volume><number>3</number><edition>2002/07/18</edition><keywords><keyword>Apache</keyword><keyword>Acute Disease</keyword><keyword>Electrolytes/blood</keyword><keyword>Enzymes/blood</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Hematocrit</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/diagnosis/*epidemiology/mortality</keyword><keyword>Predictive Value of Tests</keyword><keyword>Survival Rate</keyword><keyword>Time Factors</keyword></keywords><dates><year>2001</year></dates><isbn>1424-3903 (Print)&#xD;1424-3903 (Linking)</isbn><accession-num>12120201</accession-num><urls><related-urls><url>;(156). Quite naturally there is a significant increase in mortality, from 10% to 35-50%, between single organ failure and MODS due to AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZW5uZXI8L0F1dGhvcj48WWVhcj4xOTg1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (157, 158). LeukocytesLeukocytes are the cells of the immune system and encompass different types of cells, including Granulocytes, B-lymphocytes, T-lymphocytes and monocytes. Of these the granulocytes are the most predominant, making up 50-70% of the total circulating population ADDIN EN.CITE <EndNote><Cite><Author>Mestas</Author><Year>2004</Year><RecNum>113</RecNum><DisplayText>(159)</DisplayText><record><rec-number>113</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579905826">113</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mestas, J.</author><author>Hughes, C. C.</author></authors></contributors><auth-address>Center for Immunology and Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697.</auth-address><titles><title>Of mice and not men: differences between mouse and human immunology</title><secondary-title>J Immunol</secondary-title></titles><periodical><full-title>J Immunol</full-title></periodical><pages>2731-8</pages><volume>172</volume><number>5</number><edition>2004/02/24</edition><keywords><keyword>Animals</keyword><keyword>*Disease Models, Animal</keyword><keyword>Humans</keyword><keyword>Immune System/*anatomy &amp; histology/cytology/*immunology/metabolism</keyword><keyword>Immune System Diseases/genetics/immunology/metabolism/therapy</keyword><keyword>Mice</keyword><keyword>*Models, Animal</keyword><keyword>Species Specificity</keyword></keywords><dates><year>2004</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>0022-1767 (Print)&#xD;0022-1767 (Linking)</isbn><accession-num>14978070</accession-num><urls><related-urls><url>;(159). They are produced in the bone marrow and mature through several steps namely myeloblast, promyelocyte, myelocyte, metamyelocyte, band cell and finally polymorphonuclear leukocytes (PMNLs) ADDIN EN.CITE <EndNote><Cite><Author>Borregaard</Author><Year>2010</Year><RecNum>119</RecNum><DisplayText>(160)</DisplayText><record><rec-number>119</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580114070">119</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Borregaard, N.</author></authors></contributors><auth-address>The Granulocyte Research Laboratory, Department of Hematology, National University Hospital (Rigshospitalet), University of Copenhagen, DK-2100 Copenhagen, Denmark. borregaard@rh.dk</auth-address><titles><title>Neutrophils, from marrow to microbes</title><secondary-title>Immunity</secondary-title></titles><periodical><full-title>Immunity</full-title></periodical><pages>657-70</pages><volume>33</volume><number>5</number><edition>2010/11/26</edition><keywords><keyword>Animals</keyword><keyword>Anti-Infective Agents/*immunology</keyword><keyword>Bone Marrow/*immunology</keyword><keyword>Cell Adhesion/immunology</keyword><keyword>Cell Adhesion Molecules/immunology</keyword><keyword>Exocytosis/immunology</keyword><keyword>Hematopoiesis/immunology</keyword><keyword>Hematopoietic Stem Cells/immunology</keyword><keyword>Humans</keyword><keyword>Infections/*immunology/*microbiology</keyword><keyword>Mice</keyword><keyword>Neutrophils/*immunology/*microbiology</keyword><keyword>Phagocytosis/immunology</keyword><keyword>Secretory Vesicles/*immunology</keyword><keyword>Transendothelial and Transepithelial Migration/immunology</keyword></keywords><dates><year>2010</year><pub-dates><date>Nov 24</date></pub-dates></dates><isbn>1097-4180 (Electronic)&#xD;1074-7613 (Linking)</isbn><accession-num>21094463</accession-num><urls><related-urls><url>;(160). Each day around 2x1011 PMNL are released from the bone marrow. They constitute a group of different types of cells, namely granulocyte neutrophils, eosinophil, basophils and mast cell PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmVlZHZlbGQ8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

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ADDIN EN.CITE.DATA (161), which all have different functions. For clarity, only the term neutrophils (meaning) granulocyte neutrophils will be used in the future in this thesis. Neutrophils will circulate the body, and upon signal from chemoattractants, such as cytokines and chemokines, they will invade the affected tissue, and there fulfilling their immunological task. This recruitment of neutrophils is a central process in all kinds of inflammation and has in numerous studies been shown to be of extreme importance in the development and course of AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmR1bGxhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

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ADDIN EN.CITE.DATA (18, 112, 162, 163), where it constitutes the most rate-limiting step ADDIN EN.CITE <EndNote><Cite><Author>Sandoval</Author><Year>1996</Year><RecNum>122</RecNum><DisplayText>(164)</DisplayText><record><rec-number>122</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580120070">122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sandoval, D.</author><author>Gukovskaya, A.</author><author>Reavey, P.</author><author>Gukovsky, S.</author><author>Sisk, A.</author><author>Braquet, P.</author><author>Pandol, S. J.</author><author>Poucell-Hatton, S.</author></authors></contributors><auth-address>Department of Medicine, Veterans Affairs Medical Center, University of California San Diego, La Jolla, USA.</auth-address><titles><title>The role of neutrophils and platelet-activating factor in mediating experimental pancreatitis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>1081-91</pages><volume>111</volume><number>4</number><edition>1996/10/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Amylases/metabolism</keyword><keyword>Animals</keyword><keyword>Ceruletide</keyword><keyword>*Diterpenes</keyword><keyword>Ginkgolides</keyword><keyword>Lactones/pharmacology</keyword><keyword>Lipase/metabolism</keyword><keyword>Male</keyword><keyword>Neutrophils/*physiology</keyword><keyword>Pancreatitis/*etiology/metabolism/pathology</keyword><keyword>Platelet Activating Factor/*physiology</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1996</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>8831604</accession-num><urls><related-urls><url>(96)70077-x</electronic-resource-num></record></Cite></EndNote>(164). Consequently, it has been demonstrated that depletion of neutrophils will ameliorate the course of AP giving rise to a more modest disease, both concerning local and systemic inflammatory response ADDIN EN.CITE <EndNote><Cite><Author>Abdulla</Author><Year>2011</Year><RecNum>84</RecNum><DisplayText>(112)</DisplayText><record><rec-number>84</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579773154">84</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdulla, A.</author><author>Awla, D.</author><author>Thorlacius, H.</author><author>Regner, S.</author></authors></contributors><auth-address>Department of Surgery, Clinical Sciences, Lund University, Malmo, Sweden.</auth-address><titles><title>Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>975-82</pages><volume>90</volume><number>5</number><edition>2011/08/04</edition><keywords><keyword>Acinar Cells/enzymology/pathology</keyword><keyword>Acute Disease</keyword><keyword>Amylases/metabolism</keyword><keyword>Animals</keyword><keyword>Cholagogues and Choleretics/toxicity</keyword><keyword>Enzyme Activation</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Activation</keyword><keyword>*Neutrophils/metabolism/pathology</keyword><keyword>Pancreatitis/chemically induced/*enzymology/immunology/pathology</keyword><keyword>Taurocholic Acid/toxicity</keyword><keyword>Trypsinogen/*metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>21810937</accession-num><urls><related-urls><url>;(112). In the host defence system, the neutrophils act as one of the first responders and holds the functions of defeating invading microorganisms and to clear necrotic debris PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaXRrby1TYXJzYXQ8L0F1dGhvcj48WWVhcj4yMDAwPC9Z

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ADDIN EN.CITE.DATA (141, 166, 167). The process in which the activated neutrophils releases the antimicrobial substances they hold in their intracellular granules is called degranulation ADDIN EN.CITE <EndNote><Cite><Author>Soehnlein</Author><Year>2009</Year><RecNum>130</RecNum><DisplayText>(168)</DisplayText><record><rec-number>130</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580131924">130</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Soehnlein, O.</author></authors></contributors><auth-address>Institute of Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen University, Aachen, Germany. osoehnlein@ukaachen.de</auth-address><titles><title>Direct and alternative antimicrobial mechanisms of neutrophil-derived granule proteins</title><secondary-title>J Mol Med (Berl)</secondary-title></titles><periodical><full-title>J Mol Med (Berl)</full-title></periodical><pages>1157-64</pages><volume>87</volume><number>12</number><edition>2009/07/31</edition><keywords><keyword>Animals</keyword><keyword>Anti-Infective Agents/metabolism/pharmacology</keyword><keyword>*Antimicrobial Cationic Peptides/metabolism/pharmacology</keyword><keyword>Bacteria/*drug effects</keyword><keyword>Bacterial Infections/immunology</keyword><keyword>*Blood Proteins/metabolism/pharmacology</keyword><keyword>*Cell Degranulation</keyword><keyword>Humans</keyword><keyword>Macrophages/immunology</keyword><keyword>*Neutrophils/immunology/physiology</keyword><keyword>Phagocytosis</keyword></keywords><dates><year>2009</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1432-1440 (Electronic)&#xD;0946-2716 (Linking)</isbn><accession-num>19641860</accession-num><urls><related-urls><url>;(168). There are four types of granules in the cytoplasm of neutrophils namely; the azurophilic or primary granules, the specific or secondary granules, the tertiary or gelatinase granules and secretory vesicles, which all contains different enzymes and peptides. The primary granules contain and release; myeloperoxidase (MPO), different elastases, heparin-binding proteins and Cathepsin G. The secondary granules release; ATPase, lysozyme, NADPH oxidase, histaminase among others and tertiary granules contain substances such as; Cathepsin, collagenase and gelatinase (MMP-9 is a gelatinase also known as Gelatinase B) ADDIN EN.CITE <EndNote><Cite><Author>Lominadze</Author><Year>2005</Year><RecNum>129</RecNum><DisplayText>(169)</DisplayText><record><rec-number>129</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580131650">129</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lominadze, G.</author><author>Powell, D. W.</author><author>Luerman, G. C.</author><author>Link, A. J.</author><author>Ward, R. A.</author><author>McLeish, K. R.</author></authors></contributors><auth-address>Department of Medicine, University of Louisville and the Veterans Affairs Medical Center, Louisville, Kentucky 40202, USA.</auth-address><titles><title>Proteomic analysis of human neutrophil granules</title><secondary-title>Mol Cell Proteomics</secondary-title></titles><periodical><full-title>Mol Cell Proteomics</full-title></periodical><pages>1503-21</pages><volume>4</volume><number>10</number><edition>2005/06/30</edition><keywords><keyword>Actins/metabolism</keyword><keyword>Ammonium Sulfate</keyword><keyword>Cytoplasmic Granules/*metabolism</keyword><keyword>Electrophoresis, Gel, Two-Dimensional</keyword><keyword>Gelatinases/analysis</keyword><keyword>Humans</keyword><keyword>Neutrophils/*metabolism</keyword><keyword>Proteome/*analysis</keyword><keyword>*Proteomics</keyword><keyword>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</keyword></keywords><dates><year>2005</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1535-9476 (Print)&#xD;1535-9476 (Linking)</isbn><accession-num>15985654</accession-num><urls><related-urls><url>;(169). The content of the secretory vesicles and tertiary granules are mostly involved in the process of adhesion and extravasation whereas the primary and secondary granules holds most of the direct microbial killing tasks ADDIN EN.CITE <EndNote><Cite><Author>Borregaard</Author><Year>2007</Year><RecNum>131</RecNum><DisplayText>(170)</DisplayText><record><rec-number>131</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580136435">131</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Borregaard, N.</author><author>Sorensen, O. E.</author><author>Theilgaard-Monch, K.</author></authors></contributors><auth-address>The Granulocyte Research Laboratory, Department of Hematology, University of Copenhagen, Rigshospitalet, DK-2100, Denmark. borregaard@rh.dk</auth-address><titles><title>Neutrophil granules: a library of innate immunity proteins</title><secondary-title>Trends Immunol</secondary-title></titles><periodical><full-title>Trends Immunol</full-title></periodical><pages>340-5</pages><volume>28</volume><number>8</number><edition>2007/07/14</edition><keywords><keyword>Acute-Phase Proteins/*physiology</keyword><keyword>Antimicrobial Cationic Peptides/*physiology</keyword><keyword>Cytoplasmic Granules/*metabolism</keyword><keyword>Gene Expression Profiling</keyword><keyword>Humans</keyword><keyword>*Immunity, Innate</keyword><keyword>Lipocalin-2</keyword><keyword>Lipocalins</keyword><keyword>Neutrophils/*immunology/metabolism/ultrastructure</keyword><keyword>Proto-Oncogene Proteins/*physiology</keyword><keyword>Vesicle-Associated Membrane Protein 2/physiology</keyword></keywords><dates><year>2007</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1471-4906 (Print)&#xD;1471-4906 (Linking)</isbn><accession-num>17627888</accession-num><urls><related-urls><url>;(170). Around 5% of the total protein content of neutrophils are made up by the enzyme Myeloperoxidase (MPO), which upon activation functions as a producer of hypochlorous acid and several microbicidal reactive oxidants ADDIN EN.CITE <EndNote><Cite><Author>Hampton</Author><Year>1998</Year><RecNum>132</RecNum><DisplayText>(171)</DisplayText><record><rec-number>132</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580138618">132</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hampton, M. B.</author><author>Kettle, A. J.</author><author>Winterbourn, C. C.</author></authors></contributors><auth-address>Department of Pathology, Christchurch School of Medicine, Christchurch, New Zealand.</auth-address><titles><title>Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>3007-17</pages><volume>92</volume><number>9</number><edition>1998/10/27</edition><keywords><keyword>Bacteria</keyword><keyword>Cytoplasmic Granules/enzymology</keyword><keyword>Granulomatous Disease, Chronic/enzymology</keyword><keyword>Humans</keyword><keyword>Hydrogen Peroxide/metabolism</keyword><keyword>Hydroxyl Radical</keyword><keyword>Hypochlorous Acid/metabolism</keyword><keyword>NADPH Oxidases/deficiency/physiology</keyword><keyword>Neutrophils/enzymology/*physiology/ultrastructure</keyword><keyword>Oxidants/*physiology</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxidative Stress</keyword><keyword>Oxygen/physiology</keyword><keyword>Peroxidase/deficiency/*physiology</keyword><keyword>Phagocytosis</keyword><keyword>Phagosomes/enzymology/*physiology</keyword><keyword>*Respiratory Burst</keyword><keyword>Singlet Oxygen</keyword><keyword>Superoxides/metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Nov 1</date></pub-dates></dates><isbn>0006-4971 (Print)&#xD;0006-4971 (Linking)</isbn><accession-num>9787133</accession-num><urls><related-urls><url>;(171). 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ADDIN EN.CITE.DATA (172, 173).Neutrophils share the ability of phagocytosis with several other cell types of the immune system. After extravasation, the neutrophils follow a strict trail of chemoattractants until they reach the invading pathogen which they then capsulate into a phagosome. The neutrophil then kills the invading microorganism by releasing its granular content into the Phagosome ADDIN EN.CITE <EndNote><Cite><Author>Hager</Author><Year>2010</Year><RecNum>136</RecNum><DisplayText>(174)</DisplayText><record><rec-number>136</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580157267">136</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hager, M.</author><author>Cowland, J. B.</author><author>Borregaard, N.</author></authors></contributors><auth-address>Granulocyte Research Laboratory, Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.</auth-address><titles><title>Neutrophil granules in health and disease</title><secondary-title>J Intern Med</secondary-title></titles><periodical><full-title>J Intern Med</full-title></periodical><pages>25-34</pages><volume>268</volume><number>1</number><edition>2010/05/26</edition><keywords><keyword>Animals</keyword><keyword>Cell Differentiation/genetics</keyword><keyword>Cytoplasmic Granules/metabolism</keyword><keyword>Gene Expression Regulation</keyword><keyword>Granulomatous Disease, Chronic/metabolism/pathology</keyword><keyword>Humans</keyword><keyword>Leukocyte Disorders/metabolism/*pathology</keyword><keyword>Leukocyte-Adhesion Deficiency Syndrome/metabolism/pathology</keyword><keyword>Mice</keyword><keyword>Neutropenia/metabolism/pathology</keyword><keyword>Neutrophils/pathology/*physiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1365-2796 (Electronic)&#xD;0954-6820 (Linking)</isbn><accession-num>20497300</accession-num><urls><related-urls><url>;(174). Since the granule proteins could be secreted both into the phagosome or into the extracellular milieu, they could act both intracellular and extracellular PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2xhY3prb3dza2E8L0F1dGhvcj48WWVhcj4yMDEzPC9Z

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ADDIN EN.CITE.DATA (176). The enzyme responsible for this is NADPH-oxidase that acts by producing the superoxide anion which will start a chain reaction were it spontaneously reacts with other molecules yielding different free radicals ADDIN EN.CITE <EndNote><Cite><Author>Inoguchi</Author><Year>2003</Year><RecNum>138</RecNum><DisplayText>(177)</DisplayText><record><rec-number>138</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580162258">138</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Inoguchi, T.</author><author>Sonta, T.</author><author>Tsubouchi, H.</author><author>Etoh, T.</author><author>Kakimoto, M.</author><author>Sonoda, N.</author><author>Sato, N.</author><author>Sekiguchi, N.</author><author>Kobayashi, K.</author><author>Sumimoto, H.</author><author>Utsumi, H.</author><author>Nawata, H.</author></authors></contributors><auth-address>Departments of Medicine and Bioregulatory Science and Molecular and Structure Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. toyoshi@intmed3.med.jyushu-u.ac.jp</auth-address><titles><title>Protein kinase C-dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD(P)H oxidase</title><secondary-title>J Am Soc Nephrol</secondary-title></titles><periodical><full-title>J Am Soc Nephrol</full-title></periodical><pages>S227-32</pages><volume>14</volume><number>8 Suppl 3</number><edition>2003/07/23</edition><keywords><keyword>Animals</keyword><keyword>Blood Vessels/*metabolism</keyword><keyword>Diabetes Mellitus/*metabolism</keyword><keyword>Humans</keyword><keyword>NADPH Oxidases/*metabolism</keyword><keyword>Protein Kinase C/metabolism</keyword><keyword>Reactive Oxygen Species/*metabolism</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1046-6673 (Print)&#xD;1046-6673 (Linking)</isbn><accession-num>12874436</accession-num><urls><related-urls><url>;(177). These radicals, which are of the outmost importance for the function of the neutrophils, also has the disadvantage of being harmful to the host as well. Already before the invasion of neutrophils there are some oxidative stress in the pancreas due to the hypoxia yielded by the local inflammation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYXJzaGF3PC9BdXRob3I+PFllYXI+MTk3ODwvWWVhcj48

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ADDIN EN.CITE.DATA (178, 179), this initial oxidative stress will be further much exacerbated by the ROS expelled by the recruited, activated neutrophils. In the pathogenesis of AP, and especially severe AP, this oxidative burst and high concentration of free radicals is believed to play a crucial role ADDIN EN.CITE <EndNote><Cite><Author>Tsai</Author><Year>1998</Year><RecNum>141</RecNum><DisplayText>(180)</DisplayText><record><rec-number>141</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580202205">141</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tsai, K.</author><author>Wang, S. S.</author><author>Chen, T. S.</author><author>Kong, C. W.</author><author>Chang, F. Y.</author><author>Lee, S. D.</author><author>Lu, F. J.</author></authors></contributors><auth-address>Department of Medicine, Veterans General Hospital, Taipei, Taiwan, Republic of China.</auth-address><titles><title>Oxidative stress: an important phenomenon with pathogenetic significance in the progression of acute pancreatitis</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>850-5</pages><volume>42</volume><number>6</number><edition>1998/08/06</edition><keywords><keyword>Acute Disease</keyword><keyword>Antioxidants/*analysis</keyword><keyword>Ascorbic Acid/blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Lipid Peroxidation</keyword><keyword>Luminescent Measurements</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>*Oxidative Stress</keyword><keyword>Pancreatitis/*blood</keyword><keyword>Statistics, Nonparametric</keyword><keyword>Superoxides/*blood</keyword><keyword>Thiobarbituric Acid Reactive Substances/analysis</keyword><keyword>Vitamin E/blood</keyword></keywords><dates><year>1998</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0017-5749 (Print)&#xD;0017-5749 (Linking)</isbn><accession-num>9691925</accession-num><urls><related-urls><url>;(180), so ROS must be considered a double-edge sword.The third way in which neutrophils exert its duties in the host-defence system is by creating NETs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbm48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE.DATA (141) in a process called NETosis. Here activated neutrophils expel nuclear content in the form of web like structures. These NETs will act in several ways to disarm an intruding pathogen ADDIN EN.CITE <EndNote><Cite><Author>Brinkmann</Author><Year>2012</Year><RecNum>142</RecNum><DisplayText>(181)</DisplayText><record><rec-number>142</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580203963">142</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brinkmann, V.</author><author>Zychlinsky, A.</author></authors></contributors><auth-address>Microscopy Core Facility, Max Planck Institute for Infection Biology, 10117 Berlin, Germany. brinkmann@mpiib-berlin.mpg.de</auth-address><titles><title>Neutrophil extracellular traps: is immunity the second function of chromatin?</title><secondary-title>J Cell Biol</secondary-title></titles><periodical><full-title>J Cell Biol</full-title></periodical><pages>773-83</pages><volume>198</volume><number>5</number><edition>2012/09/05</edition><keywords><keyword>Animals</keyword><keyword>Autoimmunity/immunology</keyword><keyword>Cell Death/immunology</keyword><keyword>Chromatin/*immunology</keyword><keyword>Humans</keyword><keyword>Infections/immunology</keyword><keyword>Neutrophil Activation/*immunology</keyword><keyword>Neutrophils/*immunology</keyword></keywords><dates><year>2012</year><pub-dates><date>Sep 3</date></pub-dates></dates><isbn>1540-8140 (Electronic)&#xD;0021-9525 (Linking)</isbn><accession-num>22945932</accession-num><urls><related-urls><url>;(181), but the precise matters in which this is done is still not totally understood. Even though NETosis is of great importance for the protection of the organism by killing invaders and limiting dissemination of pathogens, it is also involved in the pathogenesis and pathophysiology of several conditions ADDIN EN.CITE <EndNote><Cite><Author>Brinkmann</Author><Year>2018</Year><RecNum>143</RecNum><DisplayText>(182)</DisplayText><record><rec-number>143</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580205331">143</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brinkmann, V.</author></authors></contributors><titles><title>Neutrophil Extracellular Traps in the Second Decade</title><secondary-title>J Innate Immun</secondary-title></titles><periodical><full-title>J Innate Immun</full-title></periodical><pages>414-421</pages><volume>10</volume><number>5-6</number><edition>2018/06/18</edition><keywords><keyword>Animals</keyword><keyword>Autoimmunity</keyword><keyword>Bacterial Infections/*immunology</keyword><keyword>Blood Coagulation</keyword><keyword>Extracellular Traps/*immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Inflammation/*immunology</keyword><keyword>Neutrophils/*immunology</keyword><keyword>Thrombosis/*immunology</keyword><keyword>*Autoimmunity</keyword><keyword>*Bacterial infection</keyword><keyword>*Cancer</keyword><keyword>*Coagulation</keyword><keyword>*Extracellular traps</keyword><keyword>*Inflammation</keyword></keywords><dates><year>2018</year></dates><isbn>1662-8128 (Electronic)&#xD;1662-811X (Linking)</isbn><accession-num>29909412</accession-num><urls><related-urls><url>;(182). This is also true in AP, were NETs are involved in both trypsinogen activation, neutrophil recruitment and hence tissue damage PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJ6YTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (183). More about the role of NETs will be dealt with later in this thesis.Neutrophil recruitment and extravasationBefore the neutrophils can perform their tasks, they must leave the circulation and enter the extravascular space. This is a key happening in the development of inflammation in general and specifically in AP where it constitutes a rate limiting step in the tissue damage that is associated with the disease PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmR1bGxhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

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ADDIN EN.CITE.DATA (112, 164, 184). The process of neutrophil recruitment and extravasation is characterized by a close interaction between neutrophils and the endothelial cells in the vessel walls of the microcirculation. It is divided into several steps, in which epithelial surface receptors of the integrin and selectin families are activated to form adhesive interactions with ligands on circulating cells ADDIN EN.CITE <EndNote><Cite><Author>Ley</Author><Year>2007</Year><RecNum>146</RecNum><DisplayText>(185)</DisplayText><record><rec-number>146</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580213650">146</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ley, K.</author><author>Laudanna, C.</author><author>Cybulsky, M. I.</author><author>Nourshargh, S.</author></authors></contributors><auth-address>Robert M. Berne Cardiovascular Research Center and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA. klaus@</auth-address><titles><title>Getting to the site of inflammation: the leukocyte adhesion cascade updated</title><secondary-title>Nat Rev Immunol</secondary-title></titles><periodical><full-title>Nat Rev Immunol</full-title></periodical><pages>678-89</pages><volume>7</volume><number>9</number><edition>2007/08/25</edition><keywords><keyword>Animals</keyword><keyword>Cell Adhesion/*immunology</keyword><keyword>Cell Movement</keyword><keyword>Endothelial Cells/immunology</keyword><keyword>Humans</keyword><keyword>Inflammation/*immunology</keyword><keyword>Integrins/metabolism</keyword><keyword>Leukocyte Rolling</keyword><keyword>Leukocytes/*immunology</keyword><keyword>Mice</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1474-1741 (Electronic)&#xD;1474-1733 (Linking)</isbn><accession-num>17717539</accession-num><urls><related-urls><url>;(185). This is done as a direct answer to the specific stimuli exerted by chemokines, cytokines and other inflammatory mediators PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWNvbjwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (186, 187). Essential for the neutrophil recruitment to occur is that the surfaces receptors and adhesion molecules are upregulated, which is performed either by the just previously mentioned mediators or directly by PRR-mediated detection ADDIN EN.CITE <EndNote><Cite><Author>Sadik</Author><Year>2011</Year><RecNum>148</RecNum><DisplayText>(187)</DisplayText><record><rec-number>148</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580217686">148</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sadik, C. D.</author><author>Kim, N. D.</author><author>Luster, A. D.</author></authors></contributors><auth-address>Division of Rheumatology, Allergy, and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.</auth-address><titles><title>Neutrophils cascading their way to inflammation</title><secondary-title>Trends Immunol</secondary-title></titles><periodical><full-title>Trends Immunol</full-title></periodical><pages>452-60</pages><volume>32</volume><number>10</number><edition>2011/08/16</edition><keywords><keyword>Animals</keyword><keyword>Bone Marrow/immunology</keyword><keyword>Cell Movement</keyword><keyword>Chemokines/*immunology/metabolism</keyword><keyword>Humans</keyword><keyword>*Immunity, Innate</keyword><keyword>Inflammation/*immunology/metabolism/pathology</keyword><keyword>Leukocyte Count</keyword><keyword>Mice</keyword><keyword>Neutrophil Infiltration/*immunology</keyword><keyword>*Neutrophils/immunology/metabolism</keyword><keyword>Receptors, Chemokine/*immunology/metabolism</keyword><keyword>Signal Transduction/*immunology</keyword></keywords><dates><year>2011</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1471-4981 (Electronic)&#xD;1471-4906 (Linking)</isbn><accession-num>21839682</accession-num><urls><related-urls><url>;(187). When there is an increased expression of surface molecules on the cellular surface, the fine-tuned process of neutrophil adhesion and transmigration will occur, this is done in four clearly defined steps namely; 1: rolling, when the neutrophils are tethered and the velocity of the circulation cells are reduced. 2: Adhesion, when the neutrophils come to a full arrest, and a week adhesive interaction between endothelial cells and neutrophils is formed. 3: Crawling, when a firm adhesion is established and the neutrophils crawl the endothelium following a chemokine gradient towards the site of transmigration. 4: Transmigration, when the neutrophils leave the vessels either paracellular (between endothelial cells) or transcellular (through epithelial cells) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXRjaGVyPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48

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ADDIN EN.CITE.DATA (188-190). During these different step selectins are mostly responsible for rolling, whereas integrins play their part in the phase of adhesion, crawling and transmission.Selectins are glycoproteins that belong to the family of cell adhesion molecules or CAMs. There are three known types of selections namely P-selectin, E-selectin and L-selectin, where the different letters refer to the cell type in which they were originally found (namely P for platelets, E for endothelium and L for leukocytes) ADDIN EN.CITE <EndNote><Cite><Author>Kansas</Author><Year>1996</Year><RecNum>152</RecNum><DisplayText>(191)</DisplayText><record><rec-number>152</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580247771">152</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kansas, G. S.</author></authors></contributors><auth-address>Department of Microbiology-Immunology, Northwestern Medical School, Chicago, IL 60611, USA.</auth-address><titles><title>Selectins and their ligands: current concepts and controversies</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>3259-87</pages><volume>88</volume><number>9</number><edition>1996/11/01</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Ligands</keyword><keyword>*Selectins/chemistry/genetics/metabolism</keyword></keywords><dates><year>1996</year><pub-dates><date>Nov 1</date></pub-dates></dates><isbn>0006-4971 (Print)&#xD;0006-4971 (Linking)</isbn><accession-num>8896391</accession-num><urls><related-urls><url>;(191). P-selectin is continuously produced and stored in secretary granules of the endothelial cells or platelets. These granules are called Wiebel -Palade bodies in the endothelium and α-granules in platelets. Upon stimulation from inflammatory mediators such as ROS, thrombin, cysteinyl leukotrienes, histamine, MCP-1 or MIP-2 the granules rapidly fuse with the cellular membrane and within minutes P-selectin is expressed on the cellular surface ADDIN EN.CITE <EndNote><Cite><Author>Petri</Author><Year>2008</Year><RecNum>153</RecNum><DisplayText>(192)</DisplayText><record><rec-number>153</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580248504">153</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petri, B.</author><author>Phillipson, M.</author><author>Kubes, P.</author></authors></contributors><auth-address>Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary, AB, Canada.</auth-address><titles><title>The physiology of leukocyte recruitment: an in vivo perspective</title><secondary-title>J Immunol</secondary-title></titles><periodical><full-title>J Immunol</full-title></periodical><pages>6439-46</pages><volume>180</volume><number>10</number><edition>2008/05/06</edition><keywords><keyword>Animals</keyword><keyword>Chemotaxis, Leukocyte/*physiology</keyword><keyword>Humans</keyword><keyword>Inflammation/*immunology</keyword></keywords><dates><year>2008</year><pub-dates><date>May 15</date></pub-dates></dates><isbn>0022-1767 (Print)&#xD;0022-1767 (Linking)</isbn><accession-num>18453558</accession-num><urls><related-urls><url>;(192). Transcription of P-selectin can also be induced by some cytokines PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW88L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (194). E-selectin associates with several ligands including PSGL-1, membrane activated complex (Mac)-1, CD44 and murine E-selectin ligand -1 ADDIN EN.CITE <EndNote><Cite><Author>Chase</Author><Year>2012</Year><RecNum>156</RecNum><DisplayText>(195)</DisplayText><record><rec-number>156</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580250483">156</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chase, S. D.</author><author>Magnani, J. L.</author><author>Simon, S. I.</author></authors></contributors><auth-address>University of California Davis, Davis, CA, USA.</auth-address><titles><title>E-selectin ligands as mechanosensitive receptors on neutrophils in health and disease</title><secondary-title>Ann Biomed Eng</secondary-title></titles><periodical><full-title>Ann Biomed Eng</full-title></periodical><pages>849-59</pages><volume>40</volume><number>4</number><edition>2012/01/25</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>CD18 Antigens/metabolism</keyword><keyword>Calcium/metabolism</keyword><keyword>E-Selectin/*metabolism</keyword><keyword>Humans</keyword><keyword>Hyaluronan Receptors/metabolism</keyword><keyword>Inflammation/*metabolism/pathology</keyword><keyword>Ligands</keyword><keyword>*MAP Kinase Signaling System</keyword><keyword>Membrane Glycoproteins/metabolism</keyword><keyword>Mice</keyword><keyword>*Neutrophil Activation</keyword><keyword>Neutrophils/*metabolism/pathology</keyword><keyword>Phosphorylation</keyword><keyword>*Transendothelial and Transepithelial Migration</keyword><keyword>p38 Mitogen-Activated Protein Kinases/metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1573-9686 (Electronic)&#xD;0090-6964 (Linking)</isbn><accession-num>22271244</accession-num><urls><related-urls><url>;(195). L selectin protrudes from the cell body of the leukocytes and has a role in optimizing the interactions between leukocytes and endothelial cells ADDIN EN.CITE <EndNote><Cite><Author>Ivetic</Author><Year>2018</Year><RecNum>157</RecNum><DisplayText>(196)</DisplayText><record><rec-number>157</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580251084">157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ivetic, A.</author></authors></contributors><auth-address>BHF Centre for Research Excellence, School of Cardiovascular Medicine &amp; Sciences, Faculty of Life Sciences &amp; Medicine, King&apos;s College London, James Black Centre 125, Coldharbour Lane, London, SE5 9NU, UK. aleksandar.ivetic@kcl.ac.uk.</auth-address><titles><title>A head-to-tail view of L-selectin and its impact on neutrophil behaviour</title><secondary-title>Cell Tissue Res</secondary-title></titles><periodical><full-title>Cell Tissue Res</full-title></periodical><pages>437-453</pages><volume>371</volume><number>3</number><edition>2018/01/22</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Cell Polarity</keyword><keyword>Humans</keyword><keyword>L-Selectin/chemistry/*metabolism</keyword><keyword>Neutrophils/*cytology/metabolism</keyword><keyword>Protein Domains</keyword><keyword>Signal Transduction</keyword><keyword>*Ectodomain shedding</keyword><keyword>*L-selectin</keyword><keyword>*Leukocyte trafficking</keyword><keyword>*Neutrophil</keyword><keyword>*Signalling</keyword></keywords><dates><year>2018</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1432-0878 (Electronic)&#xD;0302-766X (Linking)</isbn><accession-num>29353325</accession-num><urls><related-urls><url>;(196).When the selectins and their preferred ligands interact and bind to each other the velocity of the circulating leukocytes is reduced , the cells are tethered and leukocytes are considered to be rolling when the speed is down approximately 50 times compared to normal ADDIN EN.CITE <EndNote><Cite><Author>Tedder</Author><Year>1995</Year><RecNum>158</RecNum><DisplayText>(197)</DisplayText><record><rec-number>158</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580251898">158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tedder, T. F.</author><author>Steeber, D. A.</author><author>Chen, A.</author><author>Engel, P.</author></authors></contributors><auth-address>Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.</auth-address><titles><title>The selectins: vascular adhesion molecules</title><secondary-title>FASEB J</secondary-title></titles><periodical><full-title>FASEB J</full-title></periodical><pages>866-73</pages><volume>9</volume><number>10</number><edition>1995/07/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Adhesion</keyword><keyword>Cell Adhesion Molecules/chemistry/*physiology</keyword><keyword>Cell Movement</keyword><keyword>E-Selectin</keyword><keyword>Endothelium, Vascular/physiology</keyword><keyword>Humans</keyword><keyword>Inflammation/drug therapy</keyword><keyword>L-Selectin</keyword><keyword>Leukocytes/physiology</keyword><keyword>Mice</keyword><keyword>P-Selectin</keyword><keyword>Platelet Membrane Glycoproteins/chemistry/*physiology</keyword></keywords><dates><year>1995</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0892-6638 (Print)&#xD;0892-6638 (Linking)</isbn><accession-num>7542213</accession-num><urls><related-urls><url>;(197). 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ADDIN EN.CITE.DATA (198). There are however differences between man and mice also in the aspect of selectins, and there are data implying that P-selectin is most important for neutrophil rolling among mice, whereas E-selectin holds that function in humans ADDIN EN.CITE <EndNote><Cite><Author>Yao</Author><Year>1999</Year><RecNum>160</RecNum><DisplayText>(199)</DisplayText><record><rec-number>160</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580252566">160</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yao, L.</author><author>Setiadi, H.</author><author>Xia, L.</author><author>Laszik, Z.</author><author>Taylor, F. B.</author><author>McEver, R. P.</author></authors></contributors><auth-address>W.K. Warren Medical Research Institute, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73104, USA.</auth-address><titles><title>Divergent inducible expression of P-selectin and E-selectin in mice and primates</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>3820-8</pages><volume>94</volume><number>11</number><edition>1999/11/26</edition><keywords><keyword>Animals</keyword><keyword>E-Selectin/biosynthesis/*genetics</keyword><keyword>Gene Expression Regulation/*drug effects</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Oncostatin M</keyword><keyword>P-Selectin/biosynthesis/*genetics</keyword><keyword>Peptides/*pharmacology</keyword><keyword>Primates</keyword><keyword>RNA, Messenger/biosynthesis/genetics</keyword><keyword>Species Specificity</keyword><keyword>Tumor Necrosis Factor-alpha/*pharmacology</keyword></keywords><dates><year>1999</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>0006-4971 (Print)&#xD;0006-4971 (Linking)</isbn><accession-num>10572097</accession-num><urls><related-urls><url>;(199).When p-selectin has slowed down the neutrophils the next step in the recruitment process is adhesion, when the cells will come to a complete halt, and start to firmly attach to the activated endothelium. Here the integrins come into play. Integrins are heterodimeric proteins made up by an α-unit and a β-unit expressed on the surface of leukocytes upon stimulation by chemokines. There are 18 α subunits and 8 β subunits in mammal, and for a long time it was thought that only β2 integrins were expressed on leukocytes. Even though it is now demonstrated that both β1 and β3 are displayed as well, β2 integrins is still considered the capital leukocyte integrins, and the best known β2 integrins are; Lymphocyte function antigen (LFA)-1 and Macrophage-1 antigen (Mac)-1. Another name for Mac-1 is complement receptor 3, and it is only expressed on myeloid cell, whereas LFA-1 is found on both lymphocytes and other leukocytes ADDIN EN.CITE <EndNote><Cite><Author>Kelly</Author><Year>2007</Year><RecNum>161</RecNum><DisplayText>(200)</DisplayText><record><rec-number>161</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580463685">161</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kelly, M.</author><author>Hwang, J. M.</author><author>Kubes, P.</author></authors></contributors><auth-address>Department of Pathology, Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Alberta, Canada.</auth-address><titles><title>Modulating leukocyte recruitment in inflammation</title><secondary-title>J Allergy Clin Immunol</secondary-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>3-10</pages><volume>120</volume><number>1</number><edition>2007/06/15</edition><keywords><keyword>Animals</keyword><keyword>Asthma/immunology</keyword><keyword>Cell Adhesion</keyword><keyword>*Chemotaxis, Leukocyte</keyword><keyword>Humans</keyword><keyword>Hypersensitivity/immunology</keyword><keyword>Inflammation/*immunology</keyword><keyword>Leukocyte Rolling</keyword><keyword>Leukocytes/*immunology</keyword></keywords><dates><year>2007</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0091-6749 (Print)&#xD;0091-6749 (Linking)</isbn><accession-num>17559914</accession-num><urls><related-urls><url>;(200). The ligands of LFA-1, which mac-1 also binds to, is the transmembrane glycoprotein ICAMs (abbreviation of Intra cellular adhesion molecule) that belongs to the immunoglobulin superfamily ADDIN EN.CITE <EndNote><Cite><Author>Smith</Author><Year>2008</Year><RecNum>165</RecNum><DisplayText>(201)</DisplayText><record><rec-number>165</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580465908">165</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, C. W.</author></authors></contributors><auth-address>Department of Pediatrics, Baylor College of Medicine, Children&apos;s Nutrition Research Center, 1100 Bates, Rm 6014, Houston, TX 77030, USA. wsmith@bcm.tmc.edu</auth-address><titles><title>3. Adhesion molecules and receptors</title><secondary-title>J Allergy Clin Immunol</secondary-title></titles><periodical><full-title>J Allergy Clin Immunol</full-title></periodical><pages>S375-9; quiz S414</pages><volume>121</volume><number>2 Suppl</number><edition>2008/02/05</edition><keywords><keyword>Animals</keyword><keyword>Blood Platelets/physiology</keyword><keyword>Cell Adhesion/physiology</keyword><keyword>Cell Adhesion Molecules/deficiency/*metabolism/physiology</keyword><keyword>Cell Movement/physiology</keyword><keyword>Endothelium</keyword><keyword>Humans</keyword><keyword>Immunoglobulins/physiology</keyword><keyword>Integrins/physiology</keyword><keyword>Junctional Adhesion Molecules</keyword><keyword>Leukocyte Rolling/physiology</keyword><keyword>Leukocytes/physiology</keyword><keyword>Receptors, Cell Surface/*metabolism</keyword><keyword>Selectins/physiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1097-6825 (Electronic)&#xD;0091-6749 (Linking)</isbn><accession-num>18241685</accession-num><urls><related-urls><url>;(201). There are several known ICAMs but the cardinal one is ICAM-1 .They are expressed on the surface of endothelial cells, and the expression is up-regulated by proinflammatory cytokines ADDIN EN.CITE <EndNote><Cite><Author>Kim</Author><Year>2008</Year><RecNum>162</RecNum><DisplayText>(202)</DisplayText><record><rec-number>162</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580463832">162</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim, H.</author><author>Hwang, J. S.</author><author>Woo, C. H.</author><author>Kim, E. Y.</author><author>Kim, T. H.</author><author>Cho, K. J.</author><author>Kim, J. H.</author><author>Seo, J. M.</author><author>Lee, S. S.</author></authors></contributors><auth-address>School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.</auth-address><titles><title>TNF-alpha-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells</title><secondary-title>Exp Mol Med</secondary-title></titles><periodical><full-title>Exp Mol Med</full-title></periodical><pages>167-75</pages><volume>40</volume><number>2</number><edition>2008/05/01</edition><keywords><keyword>Cell Line</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Epithelial Cells/metabolism</keyword><keyword>Humans</keyword><keyword>Intercellular Adhesion Molecule-1/*physiology</keyword><keyword>Microscopy, Confocal</keyword><keyword>Trachea/cytology/*metabolism</keyword><keyword>Tumor Necrosis Factor-alpha/*physiology</keyword><keyword>Up-Regulation/*physiology</keyword><keyword>rac GTP-Binding Proteins/*metabolism</keyword></keywords><dates><year>2008</year><pub-dates><date>Apr 30</date></pub-dates></dates><isbn>1226-3613 (Print)&#xD;1226-3613 (Linking)</isbn><accession-num>18446055</accession-num><urls><related-urls><url>;(202) but also by trypsin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJ0d2lnPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48

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ADDIN EN.CITE.DATA (204). The crawling is a process were the interaction of mac-1 and ICAM seems to be holding extra importance ADDIN EN.CITE <EndNote><Cite><Author>Phillipson</Author><Year>2006</Year><RecNum>167</RecNum><DisplayText>(205)</DisplayText><record><rec-number>167</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580469595">167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Phillipson, M.</author><author>Heit, B.</author><author>Colarusso, P.</author><author>Liu, L.</author><author>Ballantyne, C. M.</author><author>Kubes, P.</author></authors></contributors><auth-address>Immunology Research Group, Department of Physiology and Biophysics, University of Calgary, Calgary T2N 4N1, Alberta, Canada.</auth-address><titles><title>Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade</title><secondary-title>J Exp Med</secondary-title></titles><periodical><full-title>J Exp Med</full-title></periodical><pages>2569-75</pages><volume>203</volume><number>12</number><edition>2006/11/23</edition><keywords><keyword>Animals</keyword><keyword>Cell Adhesion/genetics/immunology</keyword><keyword>Cell Movement/genetics/*immunology</keyword><keyword>Inflammation/genetics/immunology/pathology</keyword><keyword>Leukocyte Rolling/genetics/*immunology</keyword><keyword>Lymphocyte Function-Associated Antigen-1/genetics/physiology</keyword><keyword>Macrophage-1 Antigen/genetics/physiology</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>Neutrophils/*immunology/pathology</keyword><keyword>Venules/immunology/pathology</keyword></keywords><dates><year>2006</year><pub-dates><date>Nov 27</date></pub-dates></dates><isbn>0022-1007 (Print)&#xD;0022-1007 (Linking)</isbn><accession-num>17116736</accession-num><urls><related-urls><url>;(205). Even though neutrophils not necessarily have to pass the vessel wall paracellular, 70 % of them do, and an inhibited crawling results in fewer extravascular neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Phillipson</Author><Year>2008</Year><RecNum>170</RecNum><DisplayText>(206)</DisplayText><record><rec-number>170</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580471798">170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Phillipson, M.</author><author>Kaur, J.</author><author>Colarusso, P.</author><author>Ballantyne, C. M.</author><author>Kubes, P.</author></authors></contributors><auth-address>Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.</auth-address><titles><title>Endothelial domes encapsulate adherent neutrophils and minimize increases in vascular permeability in paracellular and transcellular emigration</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e1649</pages><volume>3</volume><number>2</number><edition>2008/02/26</edition><keywords><keyword>Animals</keyword><keyword>*Capillary Permeability</keyword><keyword>Endothelium, Vascular/*physiology/ultrastructure</keyword><keyword>*Leukocyte Rolling</keyword><keyword>Macrophage-1 Antigen</keyword><keyword>Mice</keyword><keyword>Neutrophils/*physiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Feb 20</date></pub-dates></dates><isbn>1932-6203 (Electronic)&#xD;1932-6203 (Linking)</isbn><accession-num>18297135</accession-num><urls><related-urls><url>;(206). Transmigration is the final step in the recruitment of neutrophils that will then follow the chemotactic gradient towards the sources of the inflammation. Transmigration is defined as the neutrophils crossing the endothelium, base membrane and pericytes, and it constitutes a critical step in both the innate immune response as in the neutrophil derived tissue injury PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (207). It is also the step of the process where the knowledge is most limited. What is known however is that transmigration consists of a complex multistep cascade involving several adhesive molecules including; platelet/endothelial cell adhesion molecule (PECAM)-1, junction adhesion molecules (JAMs), endothelia cell-selective adhesion molecule (ESAM) and vascular endothelial cadherin ADDIN EN.CITE <EndNote><Cite><Author>Petri</Author><Year>2006</Year><RecNum>172</RecNum><DisplayText>(208)</DisplayText><record><rec-number>172</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580474573">172</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petri, B.</author><author>Bixel, M. G.</author></authors></contributors><auth-address>Max-Planck-Institute of Molecular Biomedicine, Munster, Germany.</auth-address><titles><title>Molecular events during leukocyte diapedesis</title><secondary-title>FEBS J</secondary-title></titles><periodical><full-title>FEBS J</full-title></periodical><pages>4399-407</pages><volume>273</volume><number>19</number><edition>2006/09/13</edition><keywords><keyword>12E7 Antigen</keyword><keyword>Animals</keyword><keyword>Antigens, CD/physiology</keyword><keyword>Capillary Permeability</keyword><keyword>Cell Adhesion Molecules/physiology</keyword><keyword>Cell Movement/*physiology</keyword><keyword>Endothelial Cells/*physiology</keyword><keyword>Humans</keyword><keyword>Immunoglobulins/physiology</keyword><keyword>Leukocytes/*physiology</keyword><keyword>Platelet Endothelial Cell Adhesion Molecule-1/physiology</keyword><keyword>Receptors, Cell Surface</keyword><keyword>Vascular Cell Adhesion Molecule-1/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1742-464X (Print)&#xD;1742-464X (Linking)</isbn><accession-num>16965541</accession-num><urls><related-urls><url>;(208). There are also mechanisms at play where the leukocytes change their shape by rearrangement of their cytoskeleton, and also changes in the extracellular matrix are involved in the process of transmigration PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (209, 210). This is also a course in which MMPs like MMP-9 from activated neutrophils are supposed to play a role ADDIN EN.CITE <EndNote><Cite><Author>Stamenkovic</Author><Year>2003</Year><RecNum>175</RecNum><DisplayText>(211)</DisplayText><record><rec-number>175</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580477676">175</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stamenkovic, I.</author></authors></contributors><auth-address>Experimental Pathology Division, Institut Universitaire de Pathologie, Universite de Lausanne, 25 Rue du Bagnon, CH-1011 Lausanne, Switzerland.</auth-address><titles><title>Extracellular matrix remodelling: the role of matrix metalloproteinases</title><secondary-title>J Pathol</secondary-title></titles><periodical><full-title>J Pathol</full-title></periodical><pages>448-64</pages><volume>200</volume><number>4</number><edition>2003/07/08</edition><keywords><keyword>Bone Development/physiology</keyword><keyword>Cadherins/metabolism</keyword><keyword>Cytokines/metabolism</keyword><keyword>Enzyme Activation</keyword><keyword>Enzyme Inhibitors/therapeutic use</keyword><keyword>Extracellular Matrix/*enzymology/*pathology</keyword><keyword>Growth Substances/metabolism</keyword><keyword>Humans</keyword><keyword>Matrix Metalloproteinase Inhibitors</keyword><keyword>Matrix Metalloproteinases/*physiology</keyword><keyword>Neoplasm Invasiveness</keyword><keyword>Neoplasm Metastasis</keyword><keyword>Neoplasms/drug therapy/*enzymology</keyword><keyword>Wound Healing/physiology</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0022-3417 (Print)&#xD;0022-3417 (Linking)</isbn><accession-num>12845612</accession-num><urls><related-urls><url>;(211).Even though the function of selectins and integrins somewhat overlap, they all have unique properties and play an important role in neutrophil extravasation and hence in inflammation, not least in AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJ0bWFuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA (198). Neutrophil extracellular traps (NETs)As mentioned earlier the formation of NETs is the third strategy that neutrophils use to combat pathogens beside degranulation and phagocytosis. NETs are, like the name implies net-like structures composed of condensed chromatin (DNA and histones), both nuclear and mitochondrial, that is scattered with cytosolic and granule proteins PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbm48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbm48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ZE5vdGU+

ADDIN EN.CITE.DATA (141). NETs have been shown to neutralize; bacteria PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbm48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbm48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy

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ADDIN EN.CITE.DATA (212), fungi ADDIN EN.CITE <EndNote><Cite><Author>Urban</Author><Year>2006</Year><RecNum>177</RecNum><DisplayText>(213)</DisplayText><record><rec-number>177</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580512372">177</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Urban, C. F.</author><author>Reichard, U.</author><author>Brinkmann, V.</author><author>Zychlinsky, A.</author></authors></contributors><auth-address>Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Schumannstrasse 21/22, 10117 Berlin, Germany. curban@mpiib-berlin.mpg.de</auth-address><titles><title>Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms</title><secondary-title>Cell Microbiol</secondary-title></titles><periodical><full-title>Cell Microbiol</full-title></periodical><pages>668-76</pages><volume>8</volume><number>4</number><edition>2006/03/22</edition><keywords><keyword>Candida albicans/*physiology</keyword><keyword>Histones/physiology</keyword><keyword>Humans</keyword><keyword>Hyphae/*physiology</keyword><keyword>In Vitro Techniques</keyword><keyword>Microbial Viability</keyword><keyword>Neutrophil Activation</keyword><keyword>Neutrophils/*immunology</keyword><keyword>*Phagocytosis</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1462-5814 (Print)&#xD;1462-5814 (Linking)</isbn><accession-num>16548892</accession-num><urls><related-urls><url>;(213) and parasites ADDIN EN.CITE <EndNote><Cite><Author>Abi Abdallah</Author><Year>2012</Year><RecNum>178</RecNum><DisplayText>(214)</DisplayText><record><rec-number>178</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580512482">178</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abi Abdallah, D. S.</author><author>Lin, C.</author><author>Ball, C. J.</author><author>King, M. R.</author><author>Duhamel, G. E.</author><author>Denkers, E. Y.</author></authors></contributors><auth-address>Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA.</auth-address><titles><title>Toxoplasma gondii triggers release of human and mouse neutrophil extracellular traps</title><secondary-title>Infect Immun</secondary-title></titles><periodical><full-title>Infect Immun</full-title></periodical><pages>768-77</pages><volume>80</volume><number>2</number><edition>2011/11/23</edition><keywords><keyword>Animals</keyword><keyword>Cell Line</keyword><keyword>Extracellular Signal-Regulated MAP Kinases/*metabolism</keyword><keyword>Extracellular Space/*immunology</keyword><keyword>Female</keyword><keyword>Gene Expression Regulation/immunology</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Activation</keyword><keyword>Neutrophils/*metabolism/*parasitology</keyword><keyword>Toll-Like Receptors/genetics/metabolism</keyword><keyword>Toxoplasma/*physiology</keyword><keyword>Toxoplasmosis, Animal/*immunology</keyword></keywords><dates><year>2012</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1098-5522 (Electronic)&#xD;0019-9567 (Linking)</isbn><accession-num>22104111</accession-num><urls><related-urls><url>;(214), and it is also believed that NETs has the ability to impede further spreading of both bacterial and fungal infections PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWxrZXI8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (215, 216), and hence play a vital role in the innate immune system, The knowledge of the precise mechanisms behind this is still very limited ADDIN EN.CITE <EndNote><Cite><Author>Papayannopoulos</Author><Year>2018</Year><RecNum>188</RecNum><DisplayText>(217)</DisplayText><record><rec-number>188</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580814568">188</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Papayannopoulos, V.</author></authors></contributors><auth-address>The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.</auth-address><titles><title>Neutrophil extracellular traps in immunity and disease</title><secondary-title>Nat Rev Immunol</secondary-title></titles><periodical><full-title>Nat Rev Immunol</full-title></periodical><pages>134-147</pages><volume>18</volume><number>2</number><edition>2017/10/11</edition><keywords><keyword>Animals</keyword><keyword>Autoimmune Diseases/immunology</keyword><keyword>Chromatin Assembly and Disassembly/immunology</keyword><keyword>Extracellular Traps/*immunology/metabolism</keyword><keyword>Host Microbial Interactions/immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Infections/immunology</keyword><keyword>Inflammation/immunology</keyword><keyword>Models, Immunological</keyword><keyword>Neoplasms/immunology</keyword><keyword>Neutrophils/*immunology/metabolism</keyword><keyword>Reactive Oxygen Species/metabolism</keyword><keyword>Signal Transduction/immunology</keyword><keyword>Thrombosis/immunology</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1474-1741 (Electronic)&#xD;1474-1733 (Linking)</isbn><accession-num>28990587</accession-num><urls><related-urls><url>;(217). However, since it holds great power it can also be harmful under certain conditions, and indeed uncontrolled or inadequate NET production is supposed to play a part in the pathogenesis of many diseases such as thrombosis ADDIN EN.CITE <EndNote><Cite><Author>Fuchs</Author><Year>2010</Year><RecNum>204</RecNum><DisplayText>(218)</DisplayText><record><rec-number>204</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580849688">204</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fuchs, T. A.</author><author>Brill, A.</author><author>Duerschmied, D.</author><author>Schatzberg, D.</author><author>Monestier, M.</author><author>Myers, D. D., Jr.</author><author>Wrobleski, S. K.</author><author>Wakefield, T. W.</author><author>Hartwig, J. H.</author><author>Wagner, D. D.</author></authors></contributors><auth-address>Immune Disease Institute, Boston, MA 02115, USA.</auth-address><titles><title>Extracellular DNA traps promote thrombosis</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci U S A</full-title></periodical><pages>15880-5</pages><volume>107</volume><number>36</number><edition>2010/08/28</edition><keywords><keyword>Animals</keyword><keyword>DNA/*isolation &amp; purification</keyword><keyword>Humans</keyword><keyword>Thrombosis/*etiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep 7</date></pub-dates></dates><isbn>1091-6490 (Electronic)&#xD;0027-8424 (Linking)</isbn><accession-num>20798043</accession-num><urls><related-urls><url>;(218), autoimmune diseases such as rheumatoid arteritis and Systemic Lupus Erythematosus (SLE) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXJjaWEtUm9tbzwvQXV0aG9yPjxZZWFyPjIwMTE8L1ll

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ADDIN EN.CITE.DATA (221) and cancer ADDIN EN.CITE <EndNote><Cite><Author>Papayannopoulos</Author><Year>2018</Year><RecNum>188</RecNum><DisplayText>(217)</DisplayText><record><rec-number>188</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580814568">188</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Papayannopoulos, V.</author></authors></contributors><auth-address>The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.</auth-address><titles><title>Neutrophil extracellular traps in immunity and disease</title><secondary-title>Nat Rev Immunol</secondary-title></titles><periodical><full-title>Nat Rev Immunol</full-title></periodical><pages>134-147</pages><volume>18</volume><number>2</number><edition>2017/10/11</edition><keywords><keyword>Animals</keyword><keyword>Autoimmune Diseases/immunology</keyword><keyword>Chromatin Assembly and Disassembly/immunology</keyword><keyword>Extracellular Traps/*immunology/metabolism</keyword><keyword>Host Microbial Interactions/immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Infections/immunology</keyword><keyword>Inflammation/immunology</keyword><keyword>Models, Immunological</keyword><keyword>Neoplasms/immunology</keyword><keyword>Neutrophils/*immunology/metabolism</keyword><keyword>Reactive Oxygen Species/metabolism</keyword><keyword>Signal Transduction/immunology</keyword><keyword>Thrombosis/immunology</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1474-1741 (Electronic)&#xD;1474-1733 (Linking)</isbn><accession-num>28990587</accession-num><urls><related-urls><url>;(217), but also in acute pancreatitis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJ6YTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (222). It was found that PMNLs that was exposed to the plant-derived terpene ester; phorbol 12-myristate 13-acetate (PMA) decondensed its chromatin, after which the cell membrane ruptured and the nuclear content was expelled ADDIN EN.CITE <EndNote><Cite><Author>Tsan</Author><Year>1980</Year><RecNum>181</RecNum><DisplayText>(223)</DisplayText><record><rec-number>181</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580557310">181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tsan, M. F.</author></authors></contributors><titles><title>Phorbol myristate acetate induced neutrophil autotoxicity</title><secondary-title>J Cell Physiol</secondary-title></titles><periodical><full-title>J Cell Physiol</full-title></periodical><pages>327-34</pages><volume>105</volume><number>2</number><edition>1980/11/01</edition><keywords><keyword>Cell Aggregation</keyword><keyword>Cell Line</keyword><keyword>Cell Survival/drug effects</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hydrogen Peroxide/metabolism/pharmacology</keyword><keyword>Multiple Myeloma</keyword><keyword>Neutrophils/*physiology</keyword><keyword>Ovarian Neoplasms</keyword><keyword>Oxygen/metabolism</keyword><keyword>Phorbols/*pharmacology</keyword><keyword>Tetradecanoylphorbol Acetate/*pharmacology</keyword></keywords><dates><year>1980</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0021-9541 (Print)&#xD;0021-9541 (Linking)</isbn><accession-num>7193215</accession-num><urls><related-urls><url>;(223). PMA activates protein kinase C (PKC) that triggers the production of ROS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWNoczwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (141). Now many more proteins such as calprotectin, cathelicidins, defensins and actin have been found on NETs ADDIN EN.CITE <EndNote><Cite><Author>Urban</Author><Year>2006</Year><RecNum>177</RecNum><DisplayText>(213)</DisplayText><record><rec-number>177</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580512372">177</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Urban, C. F.</author><author>Reichard, U.</author><author>Brinkmann, V.</author><author>Zychlinsky, A.</author></authors></contributors><auth-address>Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Schumannstrasse 21/22, 10117 Berlin, Germany. curban@mpiib-berlin.mpg.de</auth-address><titles><title>Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms</title><secondary-title>Cell Microbiol</secondary-title></titles><periodical><full-title>Cell Microbiol</full-title></periodical><pages>668-76</pages><volume>8</volume><number>4</number><edition>2006/03/22</edition><keywords><keyword>Candida albicans/*physiology</keyword><keyword>Histones/physiology</keyword><keyword>Humans</keyword><keyword>Hyphae/*physiology</keyword><keyword>In Vitro Techniques</keyword><keyword>Microbial Viability</keyword><keyword>Neutrophil Activation</keyword><keyword>Neutrophils/*immunology</keyword><keyword>*Phagocytosis</keyword></keywords><dates><year>2006</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1462-5814 (Print)&#xD;1462-5814 (Linking)</isbn><accession-num>16548892</accession-num><urls><related-urls><url>;(213). Before the discovery of NETs it had been observed that the levels cell free DNA (cfDNA) was elevated in various diseases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (224-226), including AP and to such extent that it had been suggested as an early prognostic marker ADDIN EN.CITE <EndNote><Cite><Author>Gornik</Author><Year>2011</Year><RecNum>186</RecNum><DisplayText>(227)</DisplayText><record><rec-number>186</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580679772">186</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gornik, O.</author><author>Gornik, I.</author><author>Wagner, J.</author><author>Radic, D.</author><author>Lauc, G.</author></authors></contributors><titles><title>Evaluation of cell-free DNA in plasma and serum as early predictors of severity in acute pancreatitis</title><secondary-title>Pancreas</secondary-title></titles><periodical><full-title>Pancreas</full-title></periodical><pages>787-8</pages><volume>40</volume><number>5</number><edition>2011/06/16</edition><keywords><keyword>Adult</keyword><keyword>Biomarkers/blood</keyword><keyword>DNA/*blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Pancreatitis/*blood/diagnosis</keyword><keyword>Plasma/chemistry</keyword><keyword>Predictive Value of Tests</keyword><keyword>Serum/chemistry</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1536-4828 (Electronic)&#xD;0885-3177 (Linking)</isbn><accession-num>21673541</accession-num><urls><related-urls><url>;(227). As mentioned NETosis was found to be a cell death mechanism that also had bactericidal effect and that ROS played an important role. It was later found that NETs could also be generated in a fashion that did not end up with the downfall of the neutrophil, but in which a vital anucleate phagocytic cytoplast persisted after NETs had been secreted. This was a process that were named non-lytic NETosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZaXBwPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (229). The mechanisms behind NETosis are complex and still remains elusive, however some basic pathways have been identified as critical in the process, and it seems that ROS play a key role in the cascade that eventually forms NETs. The main route here is that the membrane-associated protein complex NADPH (nicotinamide adenine dinucleotide phosphatase)-oxidase generates ROS that will trigger MPO which will stimulate and translocate the enzyme neutrophil elastase (NE) from the azurophilic granules where it is stored to the cellular nucleus ADDIN EN.CITE <EndNote><Cite><Author>Papayannopoulos</Author><Year>2010</Year><RecNum>192</RecNum><DisplayText>(230)</DisplayText><record><rec-number>192</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580826309">192</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Papayannopoulos, V.</author><author>Metzler, K. D.</author><author>Hakkim, A.</author><author>Zychlinsky, A.</author></authors></contributors><auth-address>Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.</auth-address><titles><title>Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps</title><secondary-title>J Cell Biol</secondary-title></titles><periodical><full-title>J Cell Biol</full-title></periodical><pages>677-91</pages><volume>191</volume><number>3</number><edition>2010/10/27</edition><keywords><keyword>Animals</keyword><keyword>Disease Models, Animal</keyword><keyword>Extracellular Space/*metabolism</keyword><keyword>Humans</keyword><keyword>Klebsiella Infections/immunology/microbiology</keyword><keyword>Klebsiella pneumoniae</keyword><keyword>Leukocyte Elastase/deficiency/*metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Neutrophils/*cytology/*enzymology/immunology</keyword><keyword>Peroxidase/*metabolism</keyword><keyword>Reference Values</keyword></keywords><dates><year>2010</year><pub-dates><date>Nov 1</date></pub-dates></dates><isbn>1540-8140 (Electronic)&#xD;0021-9525 (Linking)</isbn><accession-num>20974816</accession-num><urls><related-urls><url>;(230). Well in the nucleus NE will perform its proteolytical action on the histones, hence disrupting the chromatin structures in ways that to a large extent are unknown. It has been shown that if NADPH-oxidase is inhibited NETs formation in vitro is reduced PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWNoczwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (222). The importance of NADPH oxidase in the process is further strengthened by the fact that patients with the genetic condition Chronic Granulomatosis Disease (CGD) in which there is a defective function of NADPH-oxidase, lacks the ability to form NETs ADDIN EN.CITE <EndNote><Cite><Author>Bianchi</Author><Year>2009</Year><RecNum>190</RecNum><DisplayText>(231)</DisplayText><record><rec-number>190</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580823183">190</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bianchi, M.</author><author>Hakkim, A.</author><author>Brinkmann, V.</author><author>Siler, U.</author><author>Seger, R. A.</author><author>Zychlinsky, A.</author><author>Reichenbach, J.</author></authors></contributors><auth-address>Division of Immunology/Haematology/BMT, University Children&apos;s Hospital Zurich, Zurich, Switzerland.</auth-address><titles><title>Restoration of NET formation by gene therapy in CGD controls aspergillosis</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>2619-22</pages><volume>114</volume><number>13</number><edition>2009/06/23</edition><keywords><keyword>Antifungal Agents/metabolism</keyword><keyword>Aspergillosis/etiology/genetics/metabolism/*prevention &amp; control</keyword><keyword>Aspergillus nidulans</keyword><keyword>Chemotaxis, Leukocyte/*genetics/immunology</keyword><keyword>Child</keyword><keyword>*Genetic Therapy/methods</keyword><keyword>Granulomatous Disease, Chronic/complications/genetics/immunology/*therapy</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Neutrophils/metabolism/*physiology</keyword></keywords><dates><year>2009</year><pub-dates><date>Sep 24</date></pub-dates></dates><isbn>1528-0020 (Electronic)&#xD;0006-4971 (Linking)</isbn><accession-num>19541821</accession-num><urls><related-urls><url>;(231). Furthermore, inhibition of the signalling pathway Raf-MEK-ERK that is upstream of NADPH oxidase, also obstruct the formation of NETs ADDIN EN.CITE <EndNote><Cite><Author>Hakkim</Author><Year>2011</Year><RecNum>191</RecNum><DisplayText>(232)</DisplayText><record><rec-number>191</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580825572">191</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hakkim, A.</author><author>Fuchs, T. A.</author><author>Martinez, N. E.</author><author>Hess, S.</author><author>Prinz, H.</author><author>Zychlinsky, A.</author><author>Waldmann, H.</author></authors></contributors><auth-address>Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin.</auth-address><titles><title>Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation</title><secondary-title>Nat Chem Biol</secondary-title></titles><periodical><full-title>Nat Chem Biol</full-title></periodical><pages>75-7</pages><volume>7</volume><number>2</number><edition>2010/12/21</edition><keywords><keyword>Extracellular Signal-Regulated MAP Kinases/*metabolism</keyword><keyword>Humans</keyword><keyword>MAP Kinase Kinase Kinases/*metabolism</keyword><keyword>Neutrophils/*metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1552-4469 (Electronic)&#xD;1552-4450 (Linking)</isbn><accession-num>21170021</accession-num><urls><related-urls><url>;(232). Even though, the role of NADPH oxidase and ROS seams to central in NETosis, there are other stimuli, such as nicotine, ionomycin and immune complexes that induces NETs independent of NADPH oxidase, and instead are relying on ROS generated by mitochondria PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3VkYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (229, 235), indicating that there are other pathways of NETs-formation, that might generate a somewhat different kind of NETs. For the nuclear decondensation to occur another modification is implicated namely, citrullination (i.e. conversion of the amino acid arginine into the non-ribosomal encoded amino acid citrulline) of the chromatin ADDIN EN.CITE <EndNote><Cite><Author>Rohrbach</Author><Year>2012</Year><RecNum>195</RecNum><DisplayText>(236)</DisplayText><record><rec-number>195</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580832255">195</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rohrbach, A. S.</author><author>Slade, D. J.</author><author>Thompson, P. R.</author><author>Mowen, K. A.</author></authors></contributors><auth-address>Department of Chemical Physiology, The Scripps Research Institute La Jolla, CA, USA.</auth-address><titles><title>Activation of PAD4 in NET formation</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>360</pages><volume>3</volume><edition>2012/12/25</edition><keywords><keyword>Net</keyword><keyword>Pad4</keyword><keyword>citrullination</keyword><keyword>deimination</keyword><keyword>neutrophil</keyword></keywords><dates><year>2012</year></dates><isbn>1664-3224 (Electronic)&#xD;1664-3224 (Linking)</isbn><accession-num>23264775</accession-num><urls><related-urls><url>;(236). This is a process that is driven by the enzyme protein-arginine deiminase type 4 (PAD-4), that has been shown to promote the formation of NETs, and consequently, inhibition of PAD-4 reduces NETosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (238, 239). The happenings upstream of NADPH -oxidase, what actually starts off the whole process are mainly unknown. Autophagy could also somehow play a role in NET formation, exactly how is benighted, but increased ROS promotes autophagy ADDIN EN.CITE <EndNote><Cite><Author>Filomeni</Author><Year>2015</Year><RecNum>205</RecNum><DisplayText>(240)</DisplayText><record><rec-number>205</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581331446">205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Filomeni, G.</author><author>De Zio, D.</author><author>Cecconi, F.</author></authors></contributors><auth-address>1] Cell Stress and Survival Unit, Danish Cancer Society Research Center, Copenhagen, Denmark [2] IRCCS Fondazione Santa Lucia and Department of Biology, University of Rome &apos;Tor Vergata&apos;, Rome, Italy.</auth-address><titles><title>Oxidative stress and autophagy: the clash between damage and metabolic needs</title><secondary-title>Cell Death Differ</secondary-title></titles><periodical><full-title>Cell Death Differ</full-title></periodical><pages>377-88</pages><volume>22</volume><number>3</number><edition>2014/09/27</edition><keywords><keyword>Animals</keyword><keyword>Autophagy/*physiology</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Oxidative Stress/*physiology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2015</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1476-5403 (Electronic)&#xD;1350-9047 (Linking)</isbn><accession-num>25257172</accession-num><urls><related-urls><url>;(240), which will further increase the amount of ROS, thus sustaining the oxidative burst PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0dGFjaGFyeWE8L0F1dGhvcj48WWVhcj4yMDE1PC9Z

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ADDIN EN.CITE.DATA (241). Also, inhibition of the protein-kinase; mammalian target of Rapamycin (mTOR), which is a regulator and promotor of autophagy lead to decreased levels of NETs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0ludHVyZmY8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NY0ludHVyZmY8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

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ADDIN EN.CITE.DATA (242).Platelets are somehow also involved in NETosis. This will be further outlined in the Platelets chapter.Another issue concerning NETs is control and degradation of the NETs itself. Impaired degradation for any reason is thought to play a role in several pathological conditions including thrombosis and several autoimmune diseases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GdWNoczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (218, 243). If this play any role in the pathogenesis of AP is still unknown and hence beyond the scope of this thesis.Even though there are grooving evidence that NETs are involved in AP the exact role it plays in the development of the disease is still enigmatic.MicroparticlesMicroparticles (MPs) are small fragments or vesicles measuring between 0.1-1?m in diameter that are released from the cell membranes ADDIN EN.CITE <EndNote><Cite><Author>Gyorgy</Author><Year>2011</Year><RecNum>209</RecNum><DisplayText>(244)</DisplayText><record><rec-number>209</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581337669">209</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gyorgy, B.</author><author>Szabo, T. G.</author><author>Pasztoi, M.</author><author>Pal, Z.</author><author>Misjak, P.</author><author>Aradi, B.</author><author>Laszlo, V.</author><author>Pallinger, E.</author><author>Pap, E.</author><author>Kittel, A.</author><author>Nagy, G.</author><author>Falus, A.</author><author>Buzas, E. I.</author></authors></contributors><auth-address>Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Nagyvarad ter, Hungary.</auth-address><titles><title>Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles</title><secondary-title>Cell Mol Life Sci</secondary-title></titles><periodical><full-title>Cell Mol Life Sci</full-title></periodical><pages>2667-88</pages><volume>68</volume><number>16</number><edition>2011/05/12</edition><keywords><keyword>Autoimmune Diseases/diagnosis/metabolism</keyword><keyword>Biomarkers/metabolism</keyword><keyword>Cell-Derived Microparticles/chemistry/metabolism/*physiology</keyword><keyword>Exosomes/chemistry/metabolism/*physiology</keyword><keyword>Humans</keyword><keyword>Neoplasms/diagnosis/metabolism</keyword><keyword>Particle Size</keyword><keyword>Proteome/metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1420-9071 (Electronic)&#xD;1420-682X (Linking)</isbn><accession-num>21560073</accession-num><urls><related-urls><url>;(244). They are shed off from the surface of almost every cell type during either apoptosis or activation. They are most extensively studied in platelets where they were initially observed (190) and here they are known to act as a pro-coagulant ADDIN EN.CITE <EndNote><Cite><Author>O&apos;Brien</Author><Year>1955</Year><RecNum>210</RecNum><DisplayText>(245)</DisplayText><record><rec-number>210</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581340071">210</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>O&apos;Brien, J. R.</author></authors></contributors><titles><title>The platelet-like activity of serum</title><secondary-title>Br J Haematol</secondary-title></titles><periodical><full-title>Br J Haematol</full-title></periodical><pages>223-8</pages><volume>1</volume><number>2</number><edition>1955/04/01</edition><keywords><keyword>*Blood Platelets</keyword><keyword>Humans</keyword><keyword>*Serum</keyword><keyword>*blood serum</keyword></keywords><dates><year>1955</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0007-1048 (Print)&#xD;0007-1048 (Linking)</isbn><accession-num>13240010</accession-num><urls><related-urls><url>;(245), however, MPs derived from activated neutrophils and activated endothelial cells are gaining more and more interest. Microparticles are found in the circulation, in different concentrations, in both healthy and sick persons. Under normal conditions they are release at a rather slow speed, upholding a modest steady state ADDIN EN.CITE <EndNote><Cite><Author>Cocucci</Author><Year>2009</Year><RecNum>220</RecNum><DisplayText>(246)</DisplayText><record><rec-number>220</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581367967">220</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cocucci, E.</author><author>Racchetti, G.</author><author>Meldolesi, J.</author></authors></contributors><auth-address>Center of Excellence in Cell Development, Vita-Salute San Raffaele University, via Olgettina 58, 20132 Milan, Italy.</auth-address><titles><title>Shedding microvesicles: artefacts no more</title><secondary-title>Trends Cell Biol</secondary-title></titles><periodical><full-title>Trends Cell Biol</full-title></periodical><pages>43-51</pages><volume>19</volume><number>2</number><edition>2009/01/16</edition><keywords><keyword>Animals</keyword><keyword>*Artifacts</keyword><keyword>Cell Membrane/*physiology</keyword><keyword>Exocytosis/*physiology</keyword><keyword>Exosomes/*physiology</keyword><keyword>Humans</keyword><keyword>Inflammation Mediators/physiology</keyword><keyword>Neoplastic Processes</keyword><keyword>Protein Transport/physiology</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1879-3088 (Electronic)&#xD;0962-8924 (Linking)</isbn><accession-num>19144520</accession-num><urls><related-urls><url>;(246), but the amount increases in patients with diseases such as cancer and sepsis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWV1d2xhbmQ8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy

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ADDIN EN.CITE.DATA (247, 248).When microparticles are formed, an outward blebbing of the plasma membrane and a proteolytic cleavage of the cytoskeleton occur, leading to the release of a vesicular MPs ADDIN EN.CITE <EndNote><Cite><Author>Geddings</Author><Year>2014</Year><RecNum>215</RecNum><DisplayText>(249)</DisplayText><record><rec-number>215</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581341754">215</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Geddings, J. E.</author><author>Mackman, N.</author></authors></contributors><auth-address>Nigel Mackman, PhD, Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA, Tel.: +1 919 843 3961, Fax: +1 919 966 7639, E-mail: nmackman@med.unc.edu.</auth-address><titles><title>New players in haemostasis and thrombosis</title><secondary-title>Thromb Haemost</secondary-title></titles><periodical><full-title>Thromb Haemost</full-title></periodical><pages>570-4</pages><volume>111</volume><number>4</number><edition>2014/02/28</edition><keywords><keyword>Animals</keyword><keyword>Anticoagulants/therapeutic use</keyword><keyword>Apoptosis</keyword><keyword>Blood Coagulation</keyword><keyword>Cell-Derived Microparticles/*metabolism</keyword><keyword>Drug Discovery</keyword><keyword>Factor XII/metabolism</keyword><keyword>Hemostasis/physiology</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Models, Animal</keyword><keyword>Neutrophils/*physiology</keyword><keyword>Thromboplastin/metabolism</keyword><keyword>Thrombosis/*blood/drug therapy</keyword><keyword>Coagulation factors</keyword><keyword>arterial thrombosis</keyword><keyword>deep-vein thrombosis</keyword><keyword>microparticles</keyword><keyword>thrombosis</keyword></keywords><dates><year>2014</year><pub-dates><date>Apr 1</date></pub-dates></dates><isbn>2567-689X (Electronic)&#xD;0340-6245 (Linking)</isbn><accession-num>24573314</accession-num><urls><related-urls><url>;(249). The mechanisms behind shedding of MPs are still unknown, but it has been shown to be a fast process, within minutes after activation ADDIN EN.CITE <EndNote><Cite><Author>MacKenzie</Author><Year>2001</Year><RecNum>216</RecNum><DisplayText>(250)</DisplayText><record><rec-number>216</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581342102">216</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>MacKenzie, A.</author><author>Wilson, H. L.</author><author>Kiss-Toth, E.</author><author>Dower, S. K.</author><author>North, R. A.</author><author>Surprenant, A.</author></authors></contributors><auth-address>Institute of Molecular Physiology, University of Sheffield, Sheffield S10 2TN, United Kingdom.</auth-address><titles><title>Rapid secretion of interleukin-1beta by microvesicle shedding</title><secondary-title>Immunity</secondary-title></titles><periodical><full-title>Immunity</full-title></periodical><pages>825-35</pages><volume>15</volume><number>5</number><edition>2001/12/01</edition><keywords><keyword>Cell Line</keyword><keyword>Humans</keyword><keyword>Interleukin-1/*immunology/*metabolism</keyword><keyword>Microscopy, Electron, Scanning</keyword><keyword>Monocytes/*immunology/ultrastructure</keyword><keyword>Secretory Vesicles/immunology/ultrastructure</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1074-7613 (Print)&#xD;1074-7613 (Linking)</isbn><accession-num>11728343</accession-num><urls><related-urls><url>(01)00229-1</electronic-resource-num></record></Cite></EndNote>(250), and is characterized by a rapid increases in intracellular Ca2+ ADDIN EN.CITE <EndNote><Cite><Author>Wiedmer</Author><Year>1991</Year><RecNum>217</RecNum><DisplayText>(251)</DisplayText><record><rec-number>217</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581342403">217</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wiedmer, T.</author><author>Sims, P. J.</author></authors></contributors><auth-address>Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City 73104.</auth-address><titles><title>Participation of protein kinases in complement C5b-9-induced shedding of platelet plasma membrane vesicles</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>2880-6</pages><volume>78</volume><number>11</number><edition>1991/12/01</edition><keywords><keyword>Blood Platelets/*physiology/ultrastructure</keyword><keyword>Calcium/physiology</keyword><keyword>Calmodulin/physiology</keyword><keyword>Cell Membrane/physiology</keyword><keyword>Complement Membrane Attack Complex/*pharmacology</keyword><keyword>Cyclic AMP/pharmacology</keyword><keyword>Humans</keyword><keyword>In Vitro Techniques</keyword><keyword>Myosin-Light-Chain Kinase/physiology</keyword><keyword>Phosphorylation</keyword><keyword>Protein Kinases/*physiology</keyword><keyword>Sphingosine/pharmacology</keyword><keyword>Vanadates/pharmacology</keyword></keywords><dates><year>1991</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>0006-4971 (Print)&#xD;0006-4971 (Linking)</isbn><accession-num>1659468</accession-num><urls><related-urls><url>;(251). 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ADDIN EN.CITE.DATA (252). This might be the reason why they are shed off in the first place, but much of their role still remains elusive. In the physiological state there is an asymmetry between the outer an the inner cell membrane with the lipids phosphatidylcholine (PC) and HYPERLINK "" \o "Learn more about Sphingomyelin from ScienceDirect's AI-generated Topic Pages" sphingomyelin (SM) on the external membrane layer, and HYPERLINK "" \o "Learn more about Phosphatidylserine from ScienceDirect's AI-generated Topic Pages" phosphatidylserine (PS) and HYPERLINK "" \o "Learn more about Phosphatidylethanolamine from ScienceDirect's AI-generated Topic Pages" phosphatidyl-ethanolamine (PE) on the inner side of the cell membrane. When MPs are shed off, there is a loss of membrane asymmetry and PS is translocate to the outer membrane on the MPs ADDIN EN.CITE <EndNote><Cite><Author>Piccin</Author><Year>2007</Year><RecNum>221</RecNum><DisplayText>(253)</DisplayText><record><rec-number>221</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581370411">221</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Piccin, A.</author><author>Murphy, W. G.</author><author>Smith, O. P.</author></authors></contributors><auth-address>Irish Blood Transfusion Service, James&apos;s Street, Dublin 8, Ireland. andrea.piccin@ibts.ie</auth-address><titles><title>Circulating microparticles: pathophysiology and clinical implications</title><secondary-title>Blood Rev</secondary-title></titles><periodical><full-title>Blood Rev</full-title></periodical><pages>157-71</pages><volume>21</volume><number>3</number><edition>2006/11/23</edition><keywords><keyword>Blood Cells/*pathology</keyword><keyword>Blood Platelets/pathology</keyword><keyword>Cardiovascular Diseases/blood</keyword><keyword>Cell Membrane/pathology</keyword><keyword>Endothelium, Vascular/*pathology</keyword><keyword>Humans</keyword><keyword>Monocytes/pathology</keyword><keyword>Particle Size</keyword></keywords><dates><year>2007</year><pub-dates><date>May</date></pub-dates></dates><isbn>0268-960X (Print)&#xD;0268-960X (Linking)</isbn><accession-num>17118501</accession-num><urls><related-urls><url>;(253). The translocated PS is negatively charged and is therefore able to attract procoagulant factors ADDIN EN.CITE <EndNote><Cite><Author>Zwaal</Author><Year>1977</Year><RecNum>222</RecNum><DisplayText>(254)</DisplayText><record><rec-number>222</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581370842">222</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zwaal, R. F.</author><author>Comfurius, P.</author><author>van Deenen, L. L.</author></authors></contributors><titles><title>Membrane asymmetry and blood coagulation</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>358-60</pages><volume>268</volume><number>5618</number><edition>1977/07/28</edition><keywords><keyword>*Blood Coagulation</keyword><keyword>Blood Platelets/ultrastructure</keyword><keyword>Cell Membrane/physiology/ultrastructure</keyword><keyword>Erythrocyte Membrane/*physiology/ultrastructure</keyword><keyword>Erythrocytes/*physiology</keyword><keyword>Humans</keyword><keyword>Membrane Lipids/*blood</keyword><keyword>Phospholipids/*blood</keyword></keywords><dates><year>1977</year><pub-dates><date>Jul 28</date></pub-dates></dates><isbn>0028-0836 (Print)&#xD;0028-0836 (Linking)</isbn><accession-num>887167</accession-num><urls><related-urls><url>;(254). The PS on the MPs surface has also been showen to interact with histones ADDIN EN.CITE <EndNote><Cite><Author>Das</Author><Year>2011</Year><RecNum>223</RecNum><DisplayText>(255)</DisplayText><record><rec-number>223</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581371357">223</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Das, R.</author><author>Plow, E. F.</author></authors></contributors><auth-address>Department of Molecular Cardiology, Cleveland Clinic, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland, OH 44195, USA.</auth-address><titles><title>Phosphatidylserine as an anchor for plasminogen and its plasminogen receptor, histone H2B, to the macrophage surface</title><secondary-title>J Thromb Haemost</secondary-title></titles><periodical><full-title>J Thromb Haemost</full-title></periodical><pages>339-49</pages><volume>9</volume><number>2</number><edition>2010/11/03</edition><keywords><keyword>Blotting, Western</keyword><keyword>Flow Cytometry</keyword><keyword>Histones/*metabolism</keyword><keyword>Humans</keyword><keyword>Macrophages/*metabolism</keyword><keyword>Phosphatidylserines/*metabolism</keyword><keyword>Plasminogen/*metabolism</keyword><keyword>Protein Binding</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1538-7836 (Electronic)&#xD;1538-7836 (Linking)</isbn><accession-num>21040449</accession-num><urls><related-urls><url>;(255) which constitutes the major protein in NETs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5VcmJhbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (257). However, the role of MPs in AP is still yet unknown.PlateletsEven though platelets are best known for their tasks in clot formation and haemostasis, they also play a major role in the inflammatory response ADDIN EN.CITE <EndNote><Cite><Author>Ghoshal</Author><Year>2014</Year><RecNum>353</RecNum><DisplayText>(258)</DisplayText><record><rec-number>353</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582807388">353</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ghoshal, K.</author><author>Bhattacharyya, M.</author></authors></contributors><auth-address>Department of Biochemistry, University of Calcutta, 35 Ballygunge Circular Road, Kolkata 700019, India.</auth-address><titles><title>Overview of platelet physiology: its hemostatic and nonhemostatic role in disease pathogenesis</title><secondary-title>ScientificWorldJournal</secondary-title></titles><periodical><full-title>ScientificWorldJournal</full-title></periodical><pages>781857</pages><volume>2014</volume><edition>2014/04/15</edition><keywords><keyword>Blood Platelets/*metabolism/*physiology</keyword><keyword>Hemostatics</keyword><keyword>Humans</keyword><keyword>Platelet Activation/physiology</keyword><keyword>Platelet Aggregation/physiology</keyword><keyword>Receptors, Purinergic P2Y12/metabolism</keyword></keywords><dates><year>2014</year></dates><isbn>1537-744X (Electronic)&#xD;1537-744X (Linking)</isbn><accession-num>24729754</accession-num><urls><related-urls><url>;(258).Platelets or thrombocytes are unnucleated cells of irregular size measuring around 2-3?m in diameter. They are the second most plentiful blood cell after erythrocytes. The platelets are produced in the bone marrow as small fragments of megakaryocytes that are release in an endomitotic process rather than by straight forward cellular duplication ADDIN EN.CITE <EndNote><Cite><Author>George</Author><Year>2000</Year><RecNum>208</RecNum><DisplayText>(259)</DisplayText><record><rec-number>208</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581333756">208</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>George, J. N.</author></authors></contributors><auth-address>Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA. Jim-George@OUHSC.edu</auth-address><titles><title>Platelets</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1531-9</pages><volume>355</volume><number>9214</number><edition>2000/05/09</edition><keywords><keyword>Blood Platelet Disorders/drug therapy/*physiopathology</keyword><keyword>Blood Platelets/*physiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Platelet Glycoprotein GPIb-IX Complex/physiology</keyword><keyword>*Platelet Membrane Glycoproteins</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications, Hematologic/physiopathology</keyword><keyword>Receptors, Cell Surface/*physiology</keyword><keyword>Thrombopoietin/*physiology</keyword></keywords><dates><year>2000</year><pub-dates><date>Apr 29</date></pub-dates></dates><isbn>0140-6736 (Print)&#xD;0140-6736 (Linking)</isbn><accession-num>10801186</accession-num><urls><related-urls><url>(00)02175-9</electronic-resource-num></record></Cite></EndNote>(259). Even though platelets are not eukaryotic they share many features with such cells in that they have mitochondria, actin and myosin filaments and a residual of endoplasmic reticulum. Instead of a nucleus, they contain prepacked proteins and various RNA residues from its original mother cell. Beside this their cytoplasm also contain three distinct types of granules, namely: α-granules, δ-granules (also called dense-granules) and lysosomes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JyZWxsPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA (260, 261). These three types of granules have different tasks and store different substances; α-granules store cytokines, chemokines (CXCL4 being one of the most plentiful), MMP-9 and different factors including P-selectin, factor V and VIII and von Willebrand factor. The δ-granules contain small molecules like polyphosphates, ADP, serotonin, histamine and calcium, necessary for the platelets task of haemostasis. Finally, the lysosomes contain different enzymes able to cleave glycoproteins, glycolipids and glycosaminoglycans PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaWZlcnJpPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48

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ADDIN EN.CITE.DATA (260, 262).Under physiological conditions the platelets circulate around the body along the vessel wall without any interaction ADDIN EN.CITE <EndNote><Cite><Author>Aarts</Author><Year>1984</Year><RecNum>354</RecNum><DisplayText>(263)</DisplayText><record><rec-number>354</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582808251">354</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aarts, P. A.</author><author>Heethaar, R. M.</author><author>Sixma, J. J.</author></authors></contributors><titles><title>Red blood cell deformability influences platelets--vessel wall interaction in flowing blood</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>1228-33</pages><volume>64</volume><number>6</number><edition>1984/12/01</edition><keywords><keyword>Blood Platelets/*physiology</keyword><keyword>Blood Vessels/*physiology</keyword><keyword>Blood Viscosity</keyword><keyword>Chlorpromazine/pharmacology</keyword><keyword>Diamide/pharmacology</keyword><keyword>*Erythrocyte Deformability/drug effects</keyword><keyword>Erythrocyte Indices</keyword><keyword>Hematocrit</keyword><keyword>Humans</keyword><keyword>Isoxsuprine/pharmacology</keyword></keywords><dates><year>1984</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0006-4971 (Print)&#xD;0006-4971 (Linking)</isbn><accession-num>6498337</accession-num><urls><related-urls><url>;(263). However, when there is a damage to the endothelium, the inhibitory functioning production of prostacyclin, nitric oxide and other substances is impaired, and extracellular matrix proteins are exposed into the circulation leading to adherence of the platelets to the vessel wall via different mechanisms ADDIN EN.CITE <EndNote><Cite><Author>Holinstat</Author><Year>2017</Year><RecNum>356</RecNum><DisplayText>(264)</DisplayText><record><rec-number>356</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582811766">356</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Holinstat, M.</author></authors></contributors><auth-address>Department of Pharmacology, University of Michigan, 1150 West Medical Center Drive, 2220D MSRB III, Ann Arbor, MI, 48109-5632, USA. mholinst@umich.edu.&#xD;Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA. mholinst@umich.edu.</auth-address><titles><title>Normal platelet function</title><secondary-title>Cancer Metastasis Rev</secondary-title></titles><periodical><full-title>Cancer Metastasis Rev</full-title></periodical><pages>195-198</pages><volume>36</volume><number>2</number><edition>2017/07/02</edition><keywords><keyword>Animals</keyword><keyword>Blood Platelets/pathology/*physiology</keyword><keyword>Hemostasis/physiology</keyword><keyword>Humans</keyword><keyword>Thrombosis/blood/pathology</keyword><keyword>*Bleeding</keyword><keyword>*Cardiovascular disease</keyword><keyword>*Hemostasis</keyword><keyword>*Immunity</keyword><keyword>*Signal transduction</keyword><keyword>*Thrombosis</keyword></keywords><dates><year>2017</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1573-7233 (Electronic)&#xD;0167-7659 (Linking)</isbn><accession-num>28667366</accession-num><urls><related-urls><url>;(264). This process shares many features with the processes seen in leukocyte adhesion and crawling. The attachment will activate the platelets and also irreversible change the cytoskeleton leading to a morphological metamorphosis in which the platelets change from their normal discoid shape into an activated state with numerous pseudopodia that makes them highly adhesive to other cells and other platelets ADDIN EN.CITE <EndNote><Cite><Author>Vincent</Author><Year>2002</Year><RecNum>357</RecNum><DisplayText>(265)</DisplayText><record><rec-number>357</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582814506">357</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vincent, J. L.</author><author>Yagushi, A.</author><author>Pradier, O.</author></authors></contributors><auth-address>Department of Intensive Care, Erasme University Hospital, Free University of Brussels, Belgium. jlvincen@ulb.ac.be</auth-address><titles><title>Platelet function in sepsis</title><secondary-title>Crit Care Med</secondary-title></titles><periodical><full-title>Crit Care Med</full-title></periodical><pages>S313-7</pages><volume>30</volume><number>5 Suppl</number><edition>2002/05/11</edition><keywords><keyword>Animals</keyword><keyword>Blood Platelets/*physiology</keyword><keyword>Humans</keyword><keyword>Platelet Activation/*physiology</keyword><keyword>Platelet Aggregation/physiology</keyword><keyword>Platelet Glycoprotein GPIIb-IIIa Complex/metabolism/physiology</keyword><keyword>Sepsis/*blood</keyword><keyword>Thrombocytopenia/*blood/physiopathology</keyword></keywords><dates><year>2002</year><pub-dates><date>May</date></pub-dates></dates><isbn>0090-3493 (Print)&#xD;0090-3493 (Linking)</isbn><accession-num>12004253</accession-num><urls><related-urls><url>;(265). The activated platelets will then release the contents of its granules, which will attract more platelets needed for the clot formation ADDIN EN.CITE <EndNote><Cite><Author>Rendu</Author><Year>2001</Year><RecNum>358</RecNum><DisplayText>(266)</DisplayText><record><rec-number>358</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582821136">358</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rendu, F.</author><author>Brohard-Bohn, B.</author></authors></contributors><auth-address>U428 INSERM, Faculte de Pharmacie, 4 Avenue de l&apos;Observatoire, 75006-Paris, France. rendu@pharmacie.univ-paris.fr</auth-address><titles><title>The platelet release reaction: granules&apos; constituents, secretion and functions</title><secondary-title>Platelets</secondary-title></titles><periodical><full-title>Platelets</full-title></periodical><pages>261-73</pages><volume>12</volume><number>5</number><edition>2001/08/07</edition><keywords><keyword>Animals</keyword><keyword>*Blood Platelets/metabolism/physiology/ultrastructure</keyword><keyword>Cytoplasmic Granules/chemistry/classification</keyword><keyword>Humans</keyword><keyword>Intracellular Membranes/metabolism/physiology</keyword><keyword>Transport Vesicles/chemistry/metabolism/*physiology</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0953-7104 (Print)&#xD;0953-7104 (Linking)</isbn><accession-num>11487378</accession-num><urls><related-urls><url>;(266). 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ADDIN EN.CITE.DATA (267). All the details of clot formation, organization and stabilization will not be dealt with here, but this is a highly monitored process including several substances that, if it fails for some reason might lead to thrombosis. However in response to the tissue damage caused by blood-borne pathogens, a coordinated wanted intravascular coagulation could be activated, via a mechanism called immunothrombosis ADDIN EN.CITE <EndNote><Cite><Author>Engelmann</Author><Year>2013</Year><RecNum>359</RecNum><DisplayText>(268)</DisplayText><record><rec-number>359</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582826291">359</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Engelmann, B.</author><author>Massberg, S.</author></authors></contributors><auth-address>Institut fur Laboratoriumsmedizin, Klinikum der Universitat, Ludwig-Maximilians-Universitat, Marchioninistrasse 15, 81377 Munich, Germany. bernd.engelmann@med.uni-muenchen.de</auth-address><titles><title>Thrombosis as an intravascular effector of innate immunity</title><secondary-title>Nat Rev Immunol</secondary-title></titles><periodical><full-title>Nat Rev Immunol</full-title></periodical><pages>34-45</pages><volume>13</volume><number>1</number><edition>2012/12/12</edition><keywords><keyword>Animals</keyword><keyword>Blood Coagulation/immunology</keyword><keyword>Blood Platelets/immunology</keyword><keyword>Hemostasis/immunology</keyword><keyword>Host-Pathogen Interactions/immunology</keyword><keyword>Humans</keyword><keyword>*Immunity, Innate</keyword><keyword>Inflammation/immunology</keyword><keyword>Models, Immunological</keyword><keyword>Thrombosis/*immunology</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1474-1741 (Electronic)&#xD;1474-1733 (Linking)</isbn><accession-num>23222502</accession-num><urls><related-urls><url>;(268). This is a process where the coagulation system seals off infected parts by creating clot barriers, hence preventing dissemination and thus facilitating for the immune system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3VwZW5vdmE8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy

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ADDIN EN.CITE.DATA (270, 271). In this particular context of thrombosis, the NETosis is thought to be triggered by release of von Willebrand factor and P-selectin that will attract and activate the neutrophils PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmlsbDwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (272, 273). Activated platelets have also been showed to activate NETosis via the nuclear protein high-mobility group box 1 (HMBG 1) in interaction with receptor for advanced glycation end products (RAGE) ADDIN EN.CITE <EndNote><Cite><Author>Papayannopoulos</Author><Year>2018</Year><RecNum>188</RecNum><DisplayText>(217)</DisplayText><record><rec-number>188</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580814568">188</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Papayannopoulos, V.</author></authors></contributors><auth-address>The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.</auth-address><titles><title>Neutrophil extracellular traps in immunity and disease</title><secondary-title>Nat Rev Immunol</secondary-title></titles><periodical><full-title>Nat Rev Immunol</full-title></periodical><pages>134-147</pages><volume>18</volume><number>2</number><edition>2017/10/11</edition><keywords><keyword>Animals</keyword><keyword>Autoimmune Diseases/immunology</keyword><keyword>Chromatin Assembly and Disassembly/immunology</keyword><keyword>Extracellular Traps/*immunology/metabolism</keyword><keyword>Host Microbial Interactions/immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate</keyword><keyword>Infections/immunology</keyword><keyword>Inflammation/immunology</keyword><keyword>Models, Immunological</keyword><keyword>Neoplasms/immunology</keyword><keyword>Neutrophils/*immunology/metabolism</keyword><keyword>Reactive Oxygen Species/metabolism</keyword><keyword>Signal Transduction/immunology</keyword><keyword>Thrombosis/immunology</keyword></keywords><dates><year>2018</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1474-1741 (Electronic)&#xD;1474-1733 (Linking)</isbn><accession-num>28990587</accession-num><urls><related-urls><url>;(217).The platelets them self also exert other direct functions in the innate immune system beyond their role in immunothrombosis. On their surface they express TLR2 and TLR4 that, when they bind to bacteria lipopolysaccharide and other PAMPS, activate the platelets which leads to the platelets releasing microbicidal proteins (PMPs), such as thrombocidines and kinocidins from their granules ADDIN EN.CITE <EndNote><Cite><Author>Yeaman</Author><Year>2010</Year><RecNum>373</RecNum><DisplayText>(274)</DisplayText><record><rec-number>373</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582990146">373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yeaman, M. R.</author></authors></contributors><auth-address>Division of Infectious Diseases, St. John&apos;s Cardiovascular Research Center, Harbor-UCLA Medical Center, David Geffen School of Medicine at UCLA, Torrance, CA 90502, USA. MRYeaman@ucla.edu</auth-address><titles><title>Platelets in defense against bacterial pathogens</title><secondary-title>Cell Mol Life Sci</secondary-title></titles><periodical><full-title>Cell Mol Life Sci</full-title></periodical><pages>525-44</pages><volume>67</volume><number>4</number><edition>2009/12/17</edition><keywords><keyword>Animals</keyword><keyword>Bacteria/*immunology/pathogenicity</keyword><keyword>Bacterial Infections/*immunology</keyword><keyword>Blood Platelets/*immunology/microbiology</keyword><keyword>Host-Pathogen Interactions/*immunology</keyword><keyword>Humans</keyword><keyword>Leukocytes/immunology</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1420-9071 (Electronic)&#xD;1420-682X (Linking)</isbn><accession-num>20013024</accession-num><urls><related-urls><url>;(274). The platelets also holds the ability of engulfing invaders much like phagocytes ADDIN EN.CITE <EndNote><Cite><Author>Boukour</Author><Year>2005</Year><RecNum>374</RecNum><DisplayText>(275)</DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582991239">374</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boukour, S.</author><author>Cramer, E. M.</author></authors></contributors><titles><title>Platelet interaction with bacteria</title><secondary-title>Platelets</secondary-title></titles><periodical><full-title>Platelets</full-title></periodical><pages>215-7</pages><volume>16</volume><number>3-4</number><edition>2005/07/14</edition><keywords><keyword>Bacteria/*immunology</keyword><keyword>Blood Platelets/immunology/*microbiology</keyword><keyword>Humans</keyword><keyword>*Immunity, Innate</keyword><keyword>Phagocytosis</keyword></keywords><dates><year>2005</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>0953-7104 (Print)&#xD;0953-7104 (Linking)</isbn><accession-num>16011967</accession-num><urls><related-urls><url>;(275), but since there are no digestive vacuole but other mechanism involved it is not formally phagocytosis but a process termed covercytosis ADDIN EN.CITE <EndNote><Cite><Author>White</Author><Year>2005</Year><RecNum>375</RecNum><DisplayText>(276)</DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582991354">375</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>White, J. G.</author></authors></contributors><auth-address>Department of Pediatrics, University of Minnesota School of Medicine, MMC Box 490, 420 Delaware Street SE, Minneapolis, MN 55455, USA. white003@tc.umn.edu</auth-address><titles><title>Platelets are covercytes, not phagocytes: uptake of bacteria involves channels of the open canalicular system</title><secondary-title>Platelets</secondary-title></titles><periodical><full-title>Platelets</full-title></periodical><pages>121-31</pages><volume>16</volume><number>2</number><edition>2005/04/13</edition><keywords><keyword>Blood Platelets/microbiology/*physiology/ultrastructure</keyword><keyword>Humans</keyword><keyword>Microscopy, Electron, Transmission</keyword><keyword>Phagocytosis/*physiology</keyword><keyword>Vacuoles/microbiology/*physiology/ultrastructure</keyword></keywords><dates><year>2005</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0953-7104 (Print)&#xD;0953-7104 (Linking)</isbn><accession-num>15823869</accession-num><urls><related-urls><url>;(276). Even so the result is similar, with microbes being decomposed by the platelets. The most predominant role of the platelets in this context must however be the feature of neutrophil recruitment and migration. This is performed both through the secretory products released from their granules, but also by direct interactions via ligand binding to receptor, for instance P-selectin/PSGL-1 ADDIN EN.CITE <EndNote><Cite><Author>Zarbock</Author><Year>2007</Year><RecNum>376</RecNum><DisplayText>(277)</DisplayText><record><rec-number>376</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583014913">376</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zarbock, A.</author><author>Polanowska-Grabowska, R. K.</author><author>Ley, K.</author></authors></contributors><auth-address>Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908-1394, USA. az4n@virginia.edu</auth-address><titles><title>Platelet-neutrophil-interactions: linking hemostasis and inflammation</title><secondary-title>Blood Rev</secondary-title></titles><periodical><full-title>Blood Rev</full-title></periodical><pages>99-111</pages><volume>21</volume><number>2</number><edition>2006/09/22</edition><keywords><keyword>Blood Platelets/*physiology</keyword><keyword>Cell Adhesion</keyword><keyword>Cell Adhesion Molecules/metabolism</keyword><keyword>Cell Shape</keyword><keyword>Chemokines/metabolism</keyword><keyword>*Hemostasis</keyword><keyword>Humans</keyword><keyword>Inflammation/*blood/immunology</keyword><keyword>Neutrophils/immunology/*physiology</keyword><keyword>Platelet Activation</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0268-960X (Print)&#xD;0268-960X (Linking)</isbn><accession-num>16987572</accession-num><urls><related-urls><url>;(277). 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ADDIN EN.CITE.DATA (278). This process is dependent of upregulation of p-selectin and PSGL-1 respectively ADDIN EN.CITE <EndNote><Cite><Author>Ait-Oufella</Author><Year>2010</Year><RecNum>378</RecNum><DisplayText>(279)</DisplayText><record><rec-number>378</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583016574">378</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ait-Oufella, H.</author><author>Maury, E.</author><author>Lehoux, S.</author><author>Guidet, B.</author><author>Offenstadt, G.</author></authors></contributors><auth-address>Inserm U970, PAris Research Cardiovascular Center, Paris, France. hafid.aitoufella@sat.aphp.fr</auth-address><titles><title>The endothelium: physiological functions and role in microcirculatory failure during severe sepsis</title><secondary-title>Intensive Care Med</secondary-title></titles><periodical><full-title>Intensive Care Med</full-title></periodical><pages>1286-98</pages><volume>36</volume><number>8</number><edition>2010/05/06</edition><keywords><keyword>Blood Coagulation/immunology</keyword><keyword>Cytokines/metabolism</keyword><keyword>Endothelium/blood supply/immunology/*physiopathology</keyword><keyword>Fibrinolysis/immunology</keyword><keyword>Humans</keyword><keyword>Leukocytes/immunology/metabolism</keyword><keyword>Microcirculation/*immunology/physiology</keyword><keyword>Sepsis/blood/*physiopathology</keyword><keyword>Vasomotor System/immunology</keyword></keywords><dates><year>2010</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1432-1238 (Electronic)&#xD;0342-4642 (Linking)</isbn><accession-num>20443110</accession-num><urls><related-urls><url>;(279). Another important promotor of platelet-neutrophil interaction is the transmembrane protein CD40 ligand (CD40L) which is expressed on platelets after activation. This will increase expression of ICAM-1 on endothelial cells ADDIN EN.CITE <EndNote><Cite><Author>Henn</Author><Year>1998</Year><RecNum>379</RecNum><DisplayText>(280)</DisplayText><record><rec-number>379</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583017392">379</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Henn, V.</author><author>Slupsky, J. R.</author><author>Grafe, M.</author><author>Anagnostopoulos, I.</author><author>Forster, R.</author><author>Muller-Berghaus, G.</author><author>Kroczek, R. A.</author></authors></contributors><auth-address>Molecular Immunology, Robert Koch-Institute, Berlin, Germany.</auth-address><titles><title>CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>591-4</pages><volume>391</volume><number>6667</number><edition>1998/02/19</edition><keywords><keyword>Blood Platelets/*metabolism</keyword><keyword>CD4-Positive T-Lymphocytes/metabolism</keyword><keyword>CD40 Antigens/metabolism</keyword><keyword>CD40 Ligand</keyword><keyword>Cell Adhesion Molecules/metabolism</keyword><keyword>Cells, Cultured</keyword><keyword>Endothelium, Vascular/*pathology</keyword><keyword>Flow Cytometry</keyword><keyword>Humans</keyword><keyword>Inflammation Mediators/*metabolism</keyword><keyword>Membrane Glycoproteins/biosynthesis/*metabolism</keyword><keyword>*Platelet Activation</keyword><keyword>Thrombosis/metabolism/pathology</keyword><keyword>Vasculitis/metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb 5</date></pub-dates></dates><isbn>0028-0836 (Print)&#xD;0028-0836 (Linking)</isbn><accession-num>9468137</accession-num><urls><related-urls><url>;(280), but also of Mac-1 on neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Rahman</Author><Year>2009</Year><RecNum>380</RecNum><DisplayText>(281)</DisplayText><record><rec-number>380</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583017930">380</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rahman, M.</author><author>Zhang, S.</author><author>Chew, M.</author><author>Ersson, A.</author><author>Jeppsson, B.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Departments of Surgery, Malmo University Hospital, Lund University, Malmo S-205 02, Sweden.</auth-address><titles><title>Platelet-derived CD40L (CD154) mediates neutrophil upregulation of Mac-1 and recruitment in septic lung injury</title><secondary-title>Ann Surg</secondary-title></titles><periodical><full-title>Ann Surg</full-title></periodical><pages>783-90</pages><volume>250</volume><number>5</number><edition>2009/10/07</edition><keywords><keyword>Animals</keyword><keyword>Blood Platelets/*metabolism</keyword><keyword>CD40 Ligand/metabolism/*physiology</keyword><keyword>Chemokine CXCL2/pharmacology</keyword><keyword>Lung/immunology/pathology</keyword><keyword>Macrophage-1 Antigen/*metabolism</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Infiltration/*physiology</keyword><keyword>Neutrophils/*metabolism/pathology</keyword><keyword>Pulmonary Edema/etiology/pathology/*physiopathology</keyword><keyword>Sepsis/*complications/immunology</keyword><keyword>*Up-Regulation</keyword></keywords><dates><year>2009</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1528-1140 (Electronic)&#xD;0003-4932 (Linking)</isbn><accession-num>19806052</accession-num><urls><related-urls><url>;(281), which will promote the formation of Platelet-Neutrophil Aggregates (PNA) ADDIN EN.CITE <EndNote><Cite><Author>Pircher</Author><Year>2019</Year><RecNum>381</RecNum><DisplayText>(282)</DisplayText><record><rec-number>381</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583074054">381</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pircher, J.</author><author>Engelmann, B.</author><author>Massberg, S.</author><author>Schulz, C.</author></authors></contributors><auth-address>Medizinische Klinik und Poliklinik I, Klinikum der Universitat Munchen, Ludwig Maximilian University of Munich, Munich, Germany.&#xD;German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.&#xD;Institut fur Laboratoriumsmedizin, Klinikum der Universitat Munchen, Ludwig Maximilian University of Munich, Munich, Germany.</auth-address><titles><title>Platelet-Neutrophil Crosstalk in Atherothrombosis</title><secondary-title>Thromb Haemost</secondary-title></titles><periodical><full-title>Thromb Haemost</full-title></periodical><pages>1274-1282</pages><volume>119</volume><number>8</number><edition>2019/06/30</edition><dates><year>2019</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>2567-689X (Electronic)&#xD;0340-6245 (Linking)</isbn><accession-num>31254975</accession-num><urls><related-urls><url>;(282). Circulating PNA is a well-documented observation in several inflammatory conditions such as; abdominal sepsis ADDIN EN.CITE <EndNote><Cite><Author>Salat</Author><Year>1999</Year><RecNum>382</RecNum><DisplayText>(283)</DisplayText><record><rec-number>382</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583074365">382</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salat, A.</author><author>Bodingbauer, G.</author><author>Boehm, D.</author><author>Murabito, M.</author><author>Tochkow, E.</author><author>Sautner, T.</author><author>Mueller, M. R.</author><author>Fuegger, R.</author></authors></contributors><auth-address>Department of General Surgery, University of Vienna, Austria. andreas.salat@univie.ac.at</auth-address><titles><title>Changes of platelet surface antigens in patients suffering from abdominal septic shock</title><secondary-title>Thromb Res</secondary-title></titles><periodical><full-title>Thromb Res</full-title></periodical><pages>289-94</pages><volume>95</volume><number>6</number><edition>1999/10/20</edition><keywords><keyword>Antigens, CD/blood/immunology</keyword><keyword>Antigens, Human Platelet/*immunology</keyword><keyword>Blood Platelets/*immunology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Shock, Septic/blood/*immunology</keyword><keyword>Thrombocytopenia/immunology</keyword></keywords><dates><year>1999</year><pub-dates><date>Sep 15</date></pub-dates></dates><isbn>0049-3848 (Print)&#xD;0049-3848 (Linking)</isbn><accession-num>10527406</accession-num><urls><related-urls><url>(99)00046-8</electronic-resource-num></record></Cite></EndNote>(283), reperfusion injury ADDIN EN.CITE <EndNote><Cite><Author>Kohler</Author><Year>2011</Year><RecNum>383</RecNum><DisplayText>(284)</DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583074493">383</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kohler, D.</author><author>Birk, P.</author><author>Konig, K.</author><author>Straub, A.</author><author>Eldh, T.</author><author>Morote-Garcia, J. 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ADDIN EN.CITE.DATA (286). Platelets constitute the capital source of polyphosphates (PolyP) in the body. It is stored in the δ-granules of the platelets, and PolyP polymers are secreted upon stimulation in order to potentiate clotting at various points of the coagulation cascade PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdW1ibGU8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (287). Beside this role studies have revealed that PolyP also exerts proinflammatory effects in that it promotes NF-κB signaling, activates the complement system and change the vascular permeability PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (288-290). The precise mechanisms behind synthetization and regulation of PolyP are to a large extent unknown, but the enzyme inositol hexakisphosphate kinase 1 (IP6K1) that is probably only produced in the platelets have been demonstrated crucial in the hemostasis of PolyP, in that mice lacking IP6K1 had reduced levels of PolyP ADDIN EN.CITE <EndNote><Cite><Author>Ghosh</Author><Year>2013</Year><RecNum>369</RecNum><DisplayText>(291)</DisplayText><record><rec-number>369</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582842251">369</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ghosh, S.</author><author>Shukla, D.</author><author>Suman, K.</author><author>Lakshmi, B. J.</author><author>Manorama, R.</author><author>Kumar, S.</author><author>Bhandari, R.</author></authors></contributors><auth-address>Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.</auth-address><titles><title>Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>1478-86</pages><volume>122</volume><number>8</number><edition>2013/06/21</edition><keywords><keyword>Animals</keyword><keyword>Bleeding Time</keyword><keyword>Blood Coagulation</keyword><keyword>Blood Platelets/*metabolism</keyword><keyword>Hemostasis</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>P-Selectin/metabolism</keyword><keyword>Phosphotransferases (Phosphate Group Acceptor)/*physiology</keyword><keyword>Phytic Acid/metabolism</keyword><keyword>Polyphosphates/*metabolism</keyword><keyword>Pulmonary Embolism/metabolism</keyword><keyword>Thrombin/metabolism</keyword><keyword>Thromboembolism/blood</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug 22</date></pub-dates></dates><isbn>1528-0020 (Electronic)&#xD;0006-4971 (Linking)</isbn><accession-num>23782934</accession-num><urls><related-urls><url>;(291). Furthermore, it has been shown that IP6K1 promoted platelet-neutrophil aggregation in a model of endotoxin induced lung inflammation, hence indicating a possible systemic pro-inflammatory role as well PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3U8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (292). As already have been stated the platelets store chemokines in their α-granules. These chemokines are potent attractors and activators of neutrophils and consider to be the main orchestrators of the recruitment ADDIN EN.CITE <EndNote><Cite><Author>Li</Author><Year>2004</Year><RecNum>387</RecNum><DisplayText>(293)</DisplayText><record><rec-number>387</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583075858">387</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Li, X.</author><author>Klintman, D.</author><author>Liu, Q.</author><author>Sato, T.</author><author>Jeppsson, B.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Surgery, Malmo University Hospital, Lund University, Sweden.</auth-address><titles><title>Critical role of CXC chemokines in endotoxemic liver injury in mice</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>443-52</pages><volume>75</volume><number>3</number><edition>2003/12/16</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Chemokine CXCL1</keyword><keyword>Chemokine CXCL2</keyword><keyword>Chemokines</keyword><keyword>Chemokines, CXC/*physiology</keyword><keyword>Cytokines/physiology</keyword><keyword>Endotoxemia/immunology/*pathology</keyword><keyword>Inflammation Mediators</keyword><keyword>Leukocyte Rolling/drug effects/immunology</keyword><keyword>Lipopolysaccharides/pharmacology</keyword><keyword>Liver/blood supply/*pathology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Microcirculation</keyword><keyword>Microscopy, Video</keyword><keyword>Monokines/physiology</keyword><keyword>Reperfusion Injury</keyword></keywords><dates><year>2004</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0741-5400 (Print)&#xD;0741-5400 (Linking)</isbn><accession-num>14673016</accession-num><urls><related-urls><url>;(293). Examples of chemokines that are known to play part in neutrophil migration in inflammatory diseases are CXCL2 (aka. mip-2), CXCL4 (aka. platelet factor-4) and CCL5 (aka. RANTES) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmR1bGxhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

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ADDIN EN.CITE.DATA (294-297). Of these specially CXCL2 have been shown to be of importance in AP, and blocking of its receptor (CXCR2) have been demonstrated to ameliorate AP ADDIN EN.CITE <EndNote><Cite><Author>Bhatia</Author><Year>2007</Year><RecNum>245</RecNum><DisplayText>(298)</DisplayText><record><rec-number>245</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581458587">245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhatia, M.</author><author>Hegde, A.</author></authors></contributors><auth-address>Department of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Bldg MD2, 18 Medical Drive, Singapore 117597, Singapore. mbhatia@nus.edu.sg</auth-address><titles><title>Treatment with antileukinate, a CXCR2 chemokine receptor antagonist, protects mice against acute pancreatitis and associated lung injury</title><secondary-title>Regul Pept</secondary-title></titles><periodical><full-title>Regul Pept</full-title></periodical><pages>40-8</pages><volume>138</volume><number>1</number><edition>2006/10/04</edition><keywords><keyword>Amylases/blood</keyword><keyword>Animals</keyword><keyword>Chemokine CXCL2</keyword><keyword>Chemokines/blood</keyword><keyword>Lung/metabolism/pathology</keyword><keyword>Lung Diseases/*prevention &amp; control</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Oligopeptides/*therapeutic use</keyword><keyword>Pancreas/enzymology/metabolism/pathology</keyword><keyword>Pancreatitis/chemically induced/*prevention &amp; control</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Receptors, Interleukin-8B/*antagonists &amp; inhibitors</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan 10</date></pub-dates></dates><isbn>0167-0115 (Print)&#xD;0167-0115 (Linking)</isbn><accession-num>17014919</accession-num><urls><related-urls><url>;(298), more on the role of chemokines will be outlined in the cytokine, chemokines chapter. The notion that platelets play a key role in AP is further emphasized by the fact that depletion of platelets in mice lead to a reduced numbers of leukocytes in the pancreas and also reduced MPO levels, thus indicating a more moderate course of the disease in a pancreatitis model ADDIN EN.CITE <EndNote><Cite><Author>Abdulla</Author><Year>2011</Year><RecNum>391</RecNum><DisplayText>(294)</DisplayText><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583078179">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdulla, A.</author><author>Awla, D.</author><author>Hartman, H.</author><author>Rahman, M.</author><author>Jeppsson, B.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Section for Surgery, Malmo University Hospital, Lund University, S-205 02 Malmo, Sweden.</auth-address><titles><title>Role of platelets in experimental acute pancreatitis</title><secondary-title>Br J Surg</secondary-title></titles><periodical><full-title>Br J Surg</full-title></periodical><pages>93-103</pages><volume>98</volume><number>1</number><edition>2010/10/01</edition><keywords><keyword>Amylases/blood</keyword><keyword>Animals</keyword><keyword>Antibodies/blood</keyword><keyword>Arginine/adverse effects</keyword><keyword>Blood Platelets/*physiology</keyword><keyword>Ceruletide/adverse effects</keyword><keyword>Chemokine CXCL2/biosynthesis/metabolism</keyword><keyword>Flow Cytometry</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Activation/physiology</keyword><keyword>Pancreatitis/*blood/chemically induced/pathology</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Platelet Aggregation/physiology</keyword><keyword>Platelet Glycoprotein GPIb-IX Complex/immunology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1365-2168 (Electronic)&#xD;0007-1323 (Linking)</isbn><accession-num>20882560</accession-num><urls><related-urls><url>;(294)Complement system The complement system or complement cascade is one of the major pillars of the innate immune system, where it acts as a first line of defense, mediating inflammatory response and linking together different branches of the cellular and humoral immunity. Complements or complement components are small proteins manufactured mostly by hepatocytes, but other cells also produce complements and they are then release into the circulation as inactive precursors. Upon stimulation protease enzymes will cleave the complements and hence activate them. This is true for most of the complement proteins. The complement will after cleavage be formed into one bigger and one smaller fragments where the bigger one is termed b while the smaller is referred to as the a fragment (in complement 2 it is the other way around due to historical reasons ) ADDIN EN.CITE <EndNote><Cite><Author>Walport</Author><Year>2001</Year><RecNum>285</RecNum><DisplayText>(299)</DisplayText><record><rec-number>285</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581683945">285</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Walport, M. J.</author></authors></contributors><auth-address>Division of Medicine, Imperial College of Science, Technology and Medicine, London, United Kingdom. m.walport@ic.ac.uk</auth-address><titles><title>Complement. First of two parts</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>1058-66</pages><volume>344</volume><number>14</number><edition>2001/04/05</edition><keywords><keyword>CD59 Antigens</keyword><keyword>Carrier Proteins</keyword><keyword>Complement Activation</keyword><keyword>Complement C1 Inactivator Proteins/deficiency/metabolism</keyword><keyword>Complement C3 Nephritic Factor/metabolism</keyword><keyword>Complement Factor H/deficiency/metabolism</keyword><keyword>Complement System Proteins/deficiency/immunology/*physiology</keyword><keyword>Hemoglobinuria, Paroxysmal/genetics/immunology</keyword><keyword>Humans</keyword><keyword>Infections/etiology/*immunology</keyword><keyword>Mannose-Binding Lectins</keyword><keyword>Neisseriaceae Infections/immunology</keyword></keywords><dates><year>2001</year><pub-dates><date>Apr 5</date></pub-dates></dates><isbn>0028-4793 (Print)&#xD;0028-4793 (Linking)</isbn><accession-num>11287977</accession-num><urls><related-urls><url>;(299). The complement system has three major tasks in the immunity namely; enable phagocytosis by opsonization (C3b is here the most predominant), promote inflammation by function as an anaphylatoxin attracting macrophages and neutrophils, and finally, membrane attack, performed by a membrane attack complex (MAC), also referred to as the terminal complement complex (sC5b-9), consisting of several different activated complement components that together forms a pore in the cellular membrane of pathogens ADDIN EN.CITE <EndNote><Cite><Author>Dunkelberger</Author><Year>2010</Year><RecNum>286</RecNum><DisplayText>(300)</DisplayText><record><rec-number>286</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581685071">286</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dunkelberger, J. R.</author><author>Song, W. C.</author></authors></contributors><auth-address>Institute for Translational Medicine and Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.</auth-address><titles><title>Complement and its role in innate and adaptive immune responses</title><secondary-title>Cell Res</secondary-title></titles><periodical><full-title>Cell Res</full-title></periodical><pages>34-50</pages><volume>20</volume><number>1</number><edition>2009/12/17</edition><keywords><keyword>Adaptive Immunity/*physiology</keyword><keyword>Animals</keyword><keyword>B-Lymphocytes/immunology</keyword><keyword>Complement System Proteins/*metabolism</keyword><keyword>Host-Pathogen Interactions/*immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Humoral/physiology</keyword><keyword>Immunity, Innate/*physiology</keyword><keyword>Inflammation/*immunology/metabolism/physiopathology</keyword><keyword>Inflammation Mediators/metabolism</keyword><keyword>T-Lymphocytes/immunology</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1748-7838 (Electronic)&#xD;1001-0602 (Linking)</isbn><accession-num>20010915</accession-num><urls><related-urls><url>;(300). Activation of complement components initiate a massive proteolytic cascade, where many activated complements act as proteases them self in a consecutive cleavage process of components. All the details of the complement cascade are beyond the scope of this thesis and here only a brief summary of the main features will be given. The complement system consist of more than 30 different complement components that could be activated via three different canonical pathways namely the classical, the lectin and the alternative pathway ADDIN EN.CITE <EndNote><Cite><Author>Nonaka</Author><Year>2014</Year><RecNum>287</RecNum><DisplayText>(301)</DisplayText><record><rec-number>287</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581689160">287</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nonaka, M.</author></authors></contributors><auth-address>Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan, mnonaka@biol.s.u-tokyo.ac.jp.</auth-address><titles><title>Evolution of the complement system</title><secondary-title>Subcell Biochem</secondary-title></titles><periodical><full-title>Subcell Biochem</full-title></periodical><pages>31-43</pages><volume>80</volume><edition>2014/05/07</edition><keywords><keyword>Animals</keyword><keyword>Complement Factor B/genetics</keyword><keyword>Complement System Proteins/*classification/*genetics</keyword><keyword>*Evolution, Molecular</keyword><keyword>Fibrinogen/genetics</keyword><keyword>Humans</keyword><keyword>Insect Proteins/genetics</keyword><keyword>Mannose-Binding Protein-Associated Serine Proteases/genetics</keyword><keyword>Multigene Family</keyword><keyword>Phylogeny</keyword></keywords><dates><year>2014</year></dates><isbn>0306-0225 (Print)&#xD;0306-0225 (Linking)</isbn><accession-num>24798006</accession-num><urls><related-urls><url>;(301). In the cross road of all these different trails stands complement component 3 (C3), and further cleavage of C3 by different C3 convertase enzymes will drive the cascade and the inflammatory response onwards.The classical pathway recognizes antibodies (IgG and IgM) and pentraxins (for instance CRP) that bind to C1q and form a C1 complex. This will lead to cleavage of C4 and C2 which then will form C4b2a, that is the C3 convertase of the classical pathway. The lectin pathway is initiated by mannose-binding lectin (MBL) that recognize pathogenic factors, eventually forming the C4b2a or C3 convertase via activation of MBL-associated proteases (MASP-1 and MASP-2). In the alternative pathway, PAMPS and DAMPS trigger a hydrolyzation of C3 that together, with other factors (most predominantly factor B) eventually will form C3 convertase, although of another kind than in the classical or lectin pathway (namely C3bBb).When C3 is cleaved, C3a and C3b are formed, where C3a , one of the anaphylatoxins that via different mechanisms promotes recruitment of neutrophils and other immune cells, and hence boost an immune response PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbG9zPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (304). Furthermore, C3b will function as a very potent opsonin ADDIN EN.CITE <EndNote><Cite><Author>Joiner</Author><Year>1984</Year><RecNum>289</RecNum><DisplayText>(305)</DisplayText><record><rec-number>289</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581719624">289</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joiner, K. A.</author><author>Brown, E. J.</author><author>Frank, M. M.</author></authors></contributors><titles><title>Complement and bacteria: chemistry and biology in host defense</title><secondary-title>Annu Rev Immunol</secondary-title></titles><periodical><full-title>Annu Rev Immunol</full-title></periodical><pages>461-91</pages><volume>2</volume><edition>1984/01/01</edition><keywords><keyword>Animals</keyword><keyword>Bacteria/*immunology</keyword><keyword>Blood Bactericidal Activity</keyword><keyword>Cell Wall/immunology</keyword><keyword>*Complement Activation</keyword><keyword>Complement Membrane Attack Complex</keyword><keyword>Complement System Proteins/metabolism/*physiology</keyword><keyword>Gram-Negative Bacteria/immunology</keyword><keyword>Gram-Positive Bacteria/immunology</keyword><keyword>Humans</keyword><keyword>Lipopolysaccharides/immunology</keyword><keyword>Phagocytosis</keyword><keyword>Polysaccharides, Bacterial/immunology</keyword></keywords><dates><year>1984</year></dates><isbn>0732-0582 (Print)&#xD;0732-0582 (Linking)</isbn><accession-num>6399850</accession-num><urls><related-urls><url>;(305), that will opsonize a pathogen and hence make it recognizable for complement receptor 1 (CR1) on neutrophils and other phagocytes. This will eventually lead to phagocytosis of the pathogen, or formation of NETs ADDIN EN.CITE <EndNote><Cite><Author>Palmer</Author><Year>2016</Year><RecNum>288</RecNum><DisplayText>(306)</DisplayText><record><rec-number>288</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581719457">288</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palmer, L. J.</author><author>Damgaard, C.</author><author>Holmstrup, P.</author><author>Nielsen, C. H.</author></authors></contributors><auth-address>Section for Periodontology, Microbiology and Community Dentistry, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.&#xD;Department of Infectious Diseases and Rheumatology, Institute for Inflammation Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Influence of complement on neutrophil extracellular trap release induced by bacteria</title><secondary-title>J Periodontal Res</secondary-title></titles><periodical><full-title>J Periodontal Res</full-title></periodical><pages>70-6</pages><volume>51</volume><number>1</number><edition>2015/04/23</edition><keywords><keyword>Complement System Proteins</keyword><keyword>*Extracellular Traps</keyword><keyword>Macrophage-1 Antigen</keyword><keyword>Neutrophils</keyword><keyword>Receptors, Complement 3b</keyword><keyword>Staphylococcus aureus</keyword><keyword>biofilm</keyword><keyword>complement</keyword><keyword>inflammation</keyword><keyword>neutrophil extracellular traps</keyword><keyword>periodontal disease</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1600-0765 (Electronic)&#xD;0022-3484 (Linking)</isbn><accession-num>25900429</accession-num><urls><related-urls><url>;(306).Complement component 3 could also be activated via a fourth, non-canonical extrinsic pathway, where coagulation factors, elastase or trypsin cleaves C3 and initiate the cascade ADDIN EN.CITE <EndNote><Cite><Author>Bettac</Author><Year>2017</Year><RecNum>283</RecNum><DisplayText>(307)</DisplayText><record><rec-number>283</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581672276">283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bettac, L.</author><author>Denk, S.</author><author>Seufferlein, T.</author><author>Huber-Lang, M.</author></authors></contributors><auth-address>Department of Internal Medicine I, University Hospital of Ulm , Ulm , Germany.&#xD;Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm , Ulm , Germany.</auth-address><titles><title>Complement in Pancreatic Disease-Perpetrator or Savior?</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>15</pages><volume>8</volume><edition>2017/02/02</edition><keywords><keyword>acinar cells</keyword><keyword>complement</keyword><keyword>multiple organ failure</keyword><keyword>pancreas</keyword><keyword>pancreatic ductal adenocarcinomas</keyword><keyword>pancreatitis</keyword></keywords><dates><year>2017</year></dates><isbn>1664-3224 (Print)&#xD;1664-3224 (Linking)</isbn><accession-num>28144242</accession-num><urls><related-urls><url>;(307). It has already been noted that proteases such as trypsin cleaves C3 and in the case of AP this is naturally a very interesting mechanism.Due to the potency of the complement cascade, it is tightly regulated in order to protect the hosts cells. This is done by many mechanisms and inhibiting proteins, so called complement regulatory proteins (CRegs) where Factor H and Factor I acts as inhibitors of C3 convertase and thus is in control of the very center of the cascade. Disturbances in the balance between activation of complements and counter activation of CRegs is thought to be involved in the development of several diseases, especially in conditions with massive release of proteases such as Lyell?s syndrome and Steven-Johnson?s syndrome of the skin ADDIN EN.CITE <EndNote><Cite><Author>Perl</Author><Year>2012</Year><RecNum>292</RecNum><DisplayText>(308)</DisplayText><record><rec-number>292</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581784017">292</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Perl, M.</author><author>Denk, S.</author><author>Kalbitz, M.</author><author>Huber-Lang, M.</author></authors></contributors><auth-address>Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Hospital of Ulm, Steinhoevelstr. 9, 89075 Ulm, Germany. mario.perl@uniklinik-ulm.de</auth-address><titles><title>Granzyme B: a new crossroad of complement and apoptosis</title><secondary-title>Adv Exp Med Biol</secondary-title></titles><periodical><full-title>Adv Exp Med Biol</full-title></periodical><pages>135-46</pages><volume>946</volume><edition>2011/09/29</edition><keywords><keyword>Apoptosis/*immunology</keyword><keyword>Complement System Proteins/*immunology</keyword><keyword>Granzymes/*immunology</keyword><keyword>Humans</keyword><keyword>Multiple Trauma/*immunology</keyword><keyword>Signal Transduction/*immunology</keyword></keywords><dates><year>2012</year></dates><isbn>0065-2598 (Print)&#xD;0065-2598 (Linking)</isbn><accession-num>21948366</accession-num><urls><related-urls><url>;(308), Multiple organ dysfunction syndrome (MODS) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbHRzaHVsZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

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ADDIN EN.CITE.DATA (309), multi trauma ADDIN EN.CITE <EndNote><Cite><Author>Kanse</Author><Year>2012</Year><RecNum>294</RecNum><DisplayText>(310)</DisplayText><record><rec-number>294</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581784412">294</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kanse, S. M.</author><author>Gallenmueller, A.</author><author>Zeerleder, S.</author><author>Stephan, F.</author><author>Rannou, O.</author><author>Denk, S.</author><author>Etscheid, M.</author><author>Lochnit, G.</author><author>Krueger, M.</author><author>Huber-Lang, M.</author></authors></contributors><auth-address>Department of Medicine, Institute for Biochemistry, Justus Liebig University, D-35392 Giessen, Germany. sandip.kanse@biochemie.med.uni-giessen.de</auth-address><titles><title>Factor VII-activating protease is activated in multiple trauma patients and generates anaphylatoxin C5a</title><secondary-title>J Immunol</secondary-title></titles><periodical><full-title>J Immunol</full-title></periodical><pages>2858-65</pages><volume>188</volume><number>6</number><edition>2012/02/07</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Blotting, Western</keyword><keyword>Complement C5a/*immunology/metabolism</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Immunoprecipitation</keyword><keyword>Male</keyword><keyword>Mass Spectrometry</keyword><keyword>Middle Aged</keyword><keyword>Multiple Trauma/blood/*immunology</keyword><keyword>Serine Endopeptidases/blood/*immunology</keyword><keyword>Young Adult</keyword></keywords><dates><year>2012</year><pub-dates><date>Mar 15</date></pub-dates></dates><isbn>1550-6606 (Electronic)&#xD;0022-1767 (Linking)</isbn><accession-num>22308306</accession-num><urls><related-urls><url>;(310) and AP ADDIN EN.CITE <EndNote><Cite><Author>Sah</Author><Year>2013</Year><RecNum>77</RecNum><DisplayText>(117)</DisplayText><record><rec-number>77</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579733208">77</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sah, R. P.</author><author>Dawra, R. K.</author><author>Saluja, A. K.</author></authors></contributors><auth-address>Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.</auth-address><titles><title>New insights into the pathogenesis of pancreatitis</title><secondary-title>Curr Opin Gastroenterol</secondary-title></titles><periodical><full-title>Curr Opin Gastroenterol</full-title></periodical><pages>523-30</pages><volume>29</volume><number>5</number><edition>2013/07/31</edition><keywords><keyword>Acute Disease</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Mutation</keyword><keyword>NF-kappa B/metabolism</keyword><keyword>Pancreatitis/*etiology/genetics/metabolism</keyword><keyword>Pancreatitis, Chronic/etiology/genetics/metabolism</keyword><keyword>Signal Transduction/physiology</keyword><keyword>Systemic Inflammatory Response Syndrome/etiology/physiopathology</keyword><keyword>Trypsin/physiology</keyword><keyword>Trypsinogen/metabolism</keyword></keywords><dates><year>2013</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1531-7056 (Electronic)&#xD;0267-1379 (Linking)</isbn><accession-num>23892538</accession-num><urls><related-urls><url>;(117).The complement system and the coagulative cascade are to a large extent intertwingled when it comes to protease release and could be seen as parts of a global protease system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWJlci1MYW5nPC9BdXRob3I+PFllYXI+MjAwNjwvWWVh

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ADDIN EN.CITE.DATA (311). The details in this complex interplay is however beyond the scope of this thesis.In AP the complement system has been proposed to play a part in the pathogenesis since the 70s ADDIN EN.CITE <EndNote><Cite><Author>Seelig</Author><Year>1975</Year><RecNum>296</RecNum><DisplayText>(312)</DisplayText><record><rec-number>296</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581786763">296</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Seelig, R.</author><author>Ehemann, V.</author><author>Tschahargane, C.</author><author>Seelig, H. P.</author></authors></contributors><titles><title>The serum complement system--a mediator of acute pancreatitis</title><secondary-title>Virchows Arch A Pathol Anat Histol</secondary-title></titles><periodical><full-title>Virchows Arch A Pathol Anat Histol</full-title></periodical><pages>193-9</pages><volume>365</volume><number>3</number><edition>1975/01/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Complement System Proteins/*analysis</keyword><keyword>Deoxycholic Acid</keyword><keyword>Male</keyword><keyword>Pancreatitis/*blood/chemically induced</keyword><keyword>Rats</keyword><keyword>Snakes</keyword><keyword>Time Factors</keyword><keyword>Venoms</keyword></keywords><dates><year>1975</year></dates><isbn>0340-1227 (Print)&#xD;0340-1227 (Linking)</isbn><accession-num>804750</accession-num><urls><related-urls><url>;(312).This has later been confirmed in several studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZWVsaWc8L0F1dGhvcj48WWVhcj4xOTc2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (307, 313, 314). Even though all details are still unknown, and a few studies show contradictive results ADDIN EN.CITE <EndNote><Cite><Author>Kyriakides</Author><Year>2001</Year><RecNum>299</RecNum><DisplayText>(315)</DisplayText><record><rec-number>299</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581969098">299</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kyriakides, C.</author><author>Jasleen, J.</author><author>Wang, Y.</author><author>Moore, F. D., Jr.</author><author>Ashley, S. W.</author><author>Hechtman, H. B.</author></authors></contributors><auth-address>Department of Surgery, Brigham and Women&apos;s Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.</auth-address><titles><title>Neutrophils, not complement, mediate the mortality of experimental hemorrhagic pancreatitis</title><secondary-title>Pancreas</secondary-title></titles><periodical><full-title>Pancreas</full-title></periodical><pages>40-6</pages><volume>22</volume><number>1</number><edition>2001/01/04</edition><keywords><keyword>Acute Disease</keyword><keyword>Alanine Transaminase/metabolism</keyword><keyword>Amylases/blood</keyword><keyword>Animals</keyword><keyword>Complement Activation/physiology</keyword><keyword>Complement System Proteins/*physiology</keyword><keyword>Female</keyword><keyword>Hemorrhage/etiology/*mortality/physiopathology</keyword><keyword>Mice</keyword><keyword>Mice, Inbred ICR</keyword><keyword>Neutropenia/complications</keyword><keyword>Neutrophil Activation/physiology</keyword><keyword>Neutrophils/*physiology</keyword><keyword>Pancreatitis/etiology/*mortality/physiopathology</keyword><keyword>Peroxidase/metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0885-3177 (Print)&#xD;0885-3177 (Linking)</isbn><accession-num>11138969</accession-num><urls><related-urls><url>;(315), some general assumptions seems to be valid. It seems that the complement system could be activated both through the classical and the alternative pathway, but to a lesser extent via the lectin pathway in AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZvdmljPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

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ADDIN EN.CITE.DATA (316). Since trypsin cleaves C3, the extrinsic pathway is also activated and possibly constitutes the main road of the pathogenesis ADDIN EN.CITE <EndNote><Cite><Author>Roxvall</Author><Year>1991</Year><RecNum>298</RecNum><DisplayText>(314)</DisplayText><record><rec-number>298</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581968171">298</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Roxvall, L.</author><author>Bengtson, A.</author><author>Sennerby, L.</author><author>Heideman, M.</author></authors></contributors><auth-address>Dept. of Surgery, University of Gothenburg, Sweden.</auth-address><titles><title>Activation of the complement cascade by trypsin</title><secondary-title>Biol Chem Hoppe Seyler</secondary-title></titles><periodical><full-title>Biol Chem Hoppe Seyler</full-title></periodical><pages>273-8</pages><volume>372</volume><number>4</number><edition>1991/04/01</edition><keywords><keyword>Acute Disease</keyword><keyword>*Complement Activation</keyword><keyword>Complement C3a/metabolism</keyword><keyword>Complement C5a/metabolism</keyword><keyword>Humans</keyword><keyword>Luminescent Measurements</keyword><keyword>Neutrophils/metabolism</keyword><keyword>Pancreatitis/enzymology/*immunology</keyword><keyword>Trypsin/blood/*metabolism</keyword></keywords><dates><year>1991</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0177-3593 (Print)&#xD;0177-3593 (Linking)</isbn><accession-num>2059336</accession-num><urls><related-urls><url>;(314). Elevated levels of C3a and C5a, which is downstream from C3 in the complement cascade, is observed in patients with AP, and has been proposed as a predictor of severity ADDIN EN.CITE <EndNote><Cite><Author>Gloor</Author><Year>2003</Year><RecNum>302</RecNum><DisplayText>(317)</DisplayText><record><rec-number>302</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581974219">302</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gloor, B.</author><author>Stahel, P. F.</author><author>Muller, C. A.</author><author>Schmidt, O. I.</author><author>Buchler, M. W.</author><author>Uhl, W.</author></authors></contributors><auth-address>Dept. of Visceral and Transplantation Surgery, University of Bern, Switzerland.</auth-address><titles><title>Predictive value of complement activation fragments C3a and sC5b-9 for development of severe disease in patients with acute pancreatitis</title><secondary-title>Scand J Gastroenterol</secondary-title></titles><periodical><full-title>Scand J Gastroenterol</full-title></periodical><pages>1078-82</pages><volume>38</volume><number>10</number><edition>2003/11/19</edition><keywords><keyword>Acute Disease</keyword><keyword>Complement C3a/*analysis</keyword><keyword>Complement Membrane Attack Complex/*analysis</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/blood/*diagnosis/immunology</keyword><keyword>Predictive Value of Tests</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2003</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0036-5521 (Print)&#xD;0036-5521 (Linking)</isbn><accession-num>14621284</accession-num><urls><related-urls><url>;(317). Both C3a and especially C5a are very strong anaphylatoxins promoting neutrophil recruitment, which has already been stated is the hallmark of inflammation in AP. It has been proposed that C5a is the main driver behind both local and systemic inflammation and especially for neutrophil recruitment to the lungs in ARDS ADDIN EN.CITE <EndNote><Cite><Author>Solomkin</Author><Year>1985</Year><RecNum>303</RecNum><DisplayText>(318)</DisplayText><record><rec-number>303</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582061020">303</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Solomkin, J. S.</author><author>Cotta, L. A.</author><author>Satoh, P. S.</author><author>Hurst, J. M.</author><author>Nelson, R. D.</author></authors></contributors><titles><title>Complement activation and clearance in acute illness and injury: evidence for C5a as a cell-directed mediator of the adult respiratory distress syndrome in man</title><secondary-title>Surgery</secondary-title></titles><periodical><full-title>Surgery</full-title></periodical><pages>668-78</pages><volume>97</volume><number>6</number><edition>1985/06/01</edition><keywords><keyword>*Chemotaxis, Leukocyte/drug effects</keyword><keyword>Complement Activation</keyword><keyword>Complement C3/analogs &amp; derivatives/metabolism</keyword><keyword>*Complement C3a/*analogs &amp; derivatives</keyword><keyword>Complement C5/analogs &amp; derivatives/metabolism/pharmacology/*physiology</keyword><keyword>Complement C5a</keyword><keyword>Complement C5a, des-Arginine</keyword><keyword>Humans</keyword><keyword>N-Formylmethionine Leucyl-Phenylalanine/pharmacology</keyword><keyword>Neutrophils</keyword><keyword>Respiratory Distress Syndrome, Adult/immunology/*physiopathology</keyword></keywords><dates><year>1985</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0039-6060 (Print)&#xD;0039-6060 (Linking)</isbn><accession-num>4002115</accession-num><urls><related-urls><url>;(318). 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ADDIN EN.CITE.DATA (183), and the powerful opsonizing effect of C3b is strongly involved in NETosis ADDIN EN.CITE <EndNote><Cite><Author>Palmer</Author><Year>2016</Year><RecNum>288</RecNum><DisplayText>(306)</DisplayText><record><rec-number>288</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581719457">288</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palmer, L. J.</author><author>Damgaard, C.</author><author>Holmstrup, P.</author><author>Nielsen, C. H.</author></authors></contributors><auth-address>Section for Periodontology, Microbiology and Community Dentistry, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.&#xD;Department of Infectious Diseases and Rheumatology, Institute for Inflammation Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Influence of complement on neutrophil extracellular trap release induced by bacteria</title><secondary-title>J Periodontal Res</secondary-title></titles><periodical><full-title>J Periodontal Res</full-title></periodical><pages>70-6</pages><volume>51</volume><number>1</number><edition>2015/04/23</edition><keywords><keyword>Complement System Proteins</keyword><keyword>*Extracellular Traps</keyword><keyword>Macrophage-1 Antigen</keyword><keyword>Neutrophils</keyword><keyword>Receptors, Complement 3b</keyword><keyword>Staphylococcus aureus</keyword><keyword>biofilm</keyword><keyword>complement</keyword><keyword>inflammation</keyword><keyword>neutrophil extracellular traps</keyword><keyword>periodontal disease</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1600-0765 (Electronic)&#xD;0022-3484 (Linking)</isbn><accession-num>25900429</accession-num><urls><related-urls><url>;(306), and hence AP. On the other hand NETs itself have been showed to activate both the classical PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWZmbGVyPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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b3RlPgB=

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b3RlPgB=

ADDIN EN.CITE.DATA (321), and thus complements and NETs can promote each other in a self-amplifying loop. The mechanisms at play here are still elusive, but some plausible explanations have been suggested. On PMA-induced NETs all the three components needed for the production of C3bBb convertase have been found, namely C3, Factor B and properdin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (320-322), and thus theoretically NETs hold the ability to cleave C3. It is also conceivable that the elastase present on the NETs could cleave C3 ADDIN EN.CITE <EndNote><Cite><Author>Maison</Author><Year>1991</Year><RecNum>311</RecNum><DisplayText>(323)</DisplayText><record><rec-number>311</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582359171">311</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Maison, C. M.</author><author>Villiers, C. L.</author><author>Colomb, M. G.</author></authors></contributors><auth-address>Department de Biologie, Moleculaire et Structural/Laboratoire d&apos;Immunochimie, Unite INSERM 238, Grenoble, France.</auth-address><titles><title>Proteolysis of C3 on U937 cell plasma membranes. Purification of cathepsin G</title><secondary-title>J Immunol</secondary-title></titles><periodical><full-title>J Immunol</full-title></periodical><pages>921-6</pages><volume>147</volume><number>3</number><edition>1991/08/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Cathepsin G</keyword><keyword>Cathepsins/*isolation &amp; purification</keyword><keyword>Cell Line</keyword><keyword>Cell Membrane/*enzymology</keyword><keyword>Chromatography, Ion Exchange</keyword><keyword>Complement C3/*metabolism</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Flow Cytometry</keyword><keyword>Molecular Sequence Data</keyword><keyword>Pancreatic Elastase/isolation &amp; purification</keyword><keyword>Serine Endopeptidases</keyword></keywords><dates><year>1991</year><pub-dates><date>Aug 1</date></pub-dates></dates><isbn>0022-1767 (Print)&#xD;0022-1767 (Linking)</isbn><accession-num>1861080</accession-num><urls><related-urls><url>;(323). Furthermore MPO have been showed to directly by itself cleave C5 and in this way could start of the complement cascade further downstream ADDIN EN.CITE <EndNote><Cite><Author>Vogt</Author><Year>1996</Year><RecNum>312</RecNum><DisplayText>(324)</DisplayText><record><rec-number>312</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582359563">312</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vogt, W.</author></authors></contributors><auth-address>Max Planck Institute for Experimental Medicine, Gottingen, Germany.</auth-address><titles><title>Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes</title><secondary-title>Immunobiology</secondary-title></titles><periodical><full-title>Immunobiology</full-title></periodical><pages>334-46</pages><volume>195</volume><number>3</number><edition>1996/08/01</edition><keywords><keyword>Complement Activation/*drug effects</keyword><keyword>Complement C5/biosynthesis/drug effects</keyword><keyword>Humans</keyword><keyword>Neutrophils/*metabolism</keyword><keyword>Peroxidase/*biosynthesis/classification/*pharmacology</keyword><keyword>Taurine/pharmacology</keyword></keywords><dates><year>1996</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0171-2985 (Print)&#xD;0171-2985 (Linking)</isbn><accession-num>8877407</accession-num><urls><related-urls><url>(96)80050-7</electronic-resource-num></record></Cite></EndNote>(324). Since MPO could bind to properdin of NETs, it is consequently possible that NETs could act as a scaffold on which activation of complements could occur PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PJmFwb3M7Rmx5bm48L0F1dGhvcj48WWVhcj4yMDE0PC9Z

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ADDIN EN.CITE.DATA (326). Cytokines, ChemokinesCytokines constitutes a broad and loose category of polypeptides that functions as transducers in cellular signaling during inflammatory conditions, such as AP ADDIN EN.CITE <EndNote><Cite><Author>Makhija</Author><Year>2002</Year><RecNum>225</RecNum><DisplayText>(327)</DisplayText><record><rec-number>225</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581373541">225</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Makhija, R.</author><author>Kingsnorth, A. N.</author></authors></contributors><auth-address>University of Plymouth, Level 07, Derriford Hospital, Derriford Road, Plymouth, PL6 8DH, UK.</auth-address><titles><title>Cytokine storm in acute pancreatitis</title><secondary-title>J Hepatobiliary Pancreat Surg</secondary-title></titles><periodical><full-title>J Hepatobiliary Pancreat Surg</full-title></periodical><pages>401-10</pages><volume>9</volume><number>4</number><edition>2002/12/17</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Antibody Formation/physiology</keyword><keyword>Apoptosis/physiology</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Immunity, Cellular/physiology</keyword><keyword>Interleukin-1/physiology</keyword><keyword>Interleukin-10/physiology</keyword><keyword>Interleukin-6/physiology</keyword><keyword>Interleukins/*physiology</keyword><keyword>Pancreatitis/immunology/*physiopathology</keyword><keyword>Platelet Activating Factor/physiology</keyword><keyword>Systemic Inflammatory Response Syndrome/physiopathology</keyword><keyword>Tumor Necrosis Factor-alpha/*physiology</keyword></keywords><dates><year>2002</year></dates><isbn>0944-1166 (Print)&#xD;0944-1166 (Linking)</isbn><accession-num>12483260</accession-num><urls><related-urls><url>;(327). They are produced by many types of cells including immune cells, stroma cells, fibroblasts, platelets and epithelial cells, and the production of a specific cytokine is not restricted to just one cell type. The response to a specific cytokine could also differ depending on what cell type receiving the stimuli,It has been difficult to find a robust classification system for cytokines due to their redundancy and pleomorphism, but broadly they can be classified as either pro- or anti-inflammatory ADDIN EN.CITE <EndNote><Cite><Author>Opal</Author><Year>2000</Year><RecNum>226</RecNum><DisplayText>(328)</DisplayText><record><rec-number>226</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581423161">226</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Opal, S. M.</author><author>DePalo, V. A.</author></authors></contributors><auth-address>Infectious Disease Division, Brown University School of Medicine, Providence, RI, USA. Steven_Opal@brown.edu</auth-address><titles><title>Anti-inflammatory cytokines</title><secondary-title>Chest</secondary-title></titles><periodical><full-title>Chest</full-title></periodical><pages>1162-72</pages><volume>117</volume><number>4</number><edition>2000/04/18</edition><keywords><keyword>Adjuvants, Immunologic/pharmacology</keyword><keyword>Animals</keyword><keyword>*Cytokines/antagonists &amp; inhibitors/pharmacology/physiology</keyword><keyword>Humans</keyword><keyword>Immune System/drug effects/immunology/*metabolism</keyword><keyword>Inflammation/immunology/*metabolism/therapy</keyword><keyword>Receptors, Cytokine/metabolism</keyword></keywords><dates><year>2000</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0012-3692 (Print)&#xD;0012-3692 (Linking)</isbn><accession-num>10767254</accession-num><urls><related-urls><url>;(328). Among the pro-inflammatory cytokines, that hence are involved in the innate immune system, are Tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-2 and IL-6, that mediate a classical acute phase response, including signs such as fever or nausea, but also, synthesis of acute phase reactants in the liver ADDIN EN.CITE <EndNote><Cite><Author>Bauer</Author><Year>2013</Year><RecNum>229</RecNum><DisplayText>(329)</DisplayText><record><rec-number>229</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581425624">229</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bauer, M.</author><author>Press, A. T.</author><author>Trauner, M.</author></authors></contributors><auth-address>Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany. michael.bauer@med.uni-jena.de</auth-address><titles><title>The liver in sepsis: patterns of response and injury</title><secondary-title>Curr Opin Crit Care</secondary-title></titles><periodical><full-title>Curr Opin Crit Care</full-title></periodical><pages>123-7</pages><volume>19</volume><number>2</number><edition>2013/03/02</edition><keywords><keyword>Acute-Phase Proteins/*metabolism</keyword><keyword>Critical Care</keyword><keyword>End Stage Liver Disease/immunology/*metabolism/physiopathology</keyword><keyword>Female</keyword><keyword>Gene Expression Regulation</keyword><keyword>Humans</keyword><keyword>Intensive Care Units</keyword><keyword>Interleukin-6/*metabolism</keyword><keyword>Liver/*metabolism/pathology</keyword><keyword>Liver Diseases/immunology/*metabolism/physiopathology</keyword><keyword>Liver Function Tests</keyword><keyword>Male</keyword><keyword>Prognosis</keyword><keyword>Sepsis/immunology/*metabolism/physiopathology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1531-7072 (Electronic)&#xD;1070-5295 (Linking)</isbn><accession-num>23448974</accession-num><urls><related-urls><url>;(329) and release of neutrophils PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW5hcmVsbG88L0F1dGhvcj48WWVhcj4xOTg2PC9ZZWFy

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ADDIN EN.CITE.DATA (332). Cytokines from one of these subgroups tends to inhibit the effect of cytokines from the other subgroup ADDIN EN.CITE <EndNote><Cite><Author>van der Poll</Author><Year>2001</Year><RecNum>233</RecNum><DisplayText>(333)</DisplayText><record><rec-number>233</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581427357">233</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van der Poll, T.</author><author>de Jonge, E.</author><author>Levi, M.</author></authors></contributors><auth-address>Laboratory of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. T.vanderPoll@amc.uva.nl</auth-address><titles><title>Regulatory role of cytokines in disseminated intravascular coagulation</title><secondary-title>Semin Thromb Hemost</secondary-title></titles><periodical><full-title>Semin Thromb Hemost</full-title></periodical><pages>639-51</pages><volume>27</volume><number>6</number><edition>2001/12/12</edition><keywords><keyword>Animals</keyword><keyword>Blood Coagulation</keyword><keyword>Cytokines/blood/*physiology</keyword><keyword>Disseminated Intravascular Coagulation/*blood/etiology/physiopathology</keyword><keyword>Humans</keyword><keyword>Sepsis/blood/complications</keyword></keywords><dates><year>2001</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0094-6176 (Print)&#xD;0094-6176 (Linking)</isbn><accession-num>11740687</accession-num><urls><related-urls><url>;(333). This is very delicately moderated and dysregulation is believed to be involved in the pathogenesis of autoimmunity ADDIN EN.CITE <EndNote><Cite><Author>Karin</Author><Year>2018</Year><RecNum>234</RecNum><DisplayText>(334)</DisplayText><record><rec-number>234</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581427615">234</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Karin, N.</author></authors></contributors><auth-address>Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.</auth-address><titles><title>Autoantibodies to Chemokines and Cytokines Participate in the Regulation of Cancer and Autoimmunity</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>623</pages><volume>9</volume><edition>2018/04/14</edition><keywords><keyword>Animals</keyword><keyword>Antibody Affinity</keyword><keyword>Autoantibodies/*metabolism</keyword><keyword>Autoimmune Diseases/*immunology</keyword><keyword>Autoimmunity</keyword><keyword>B-Lymphocytes/*physiology</keyword><keyword>Chemokines/metabolism</keyword><keyword>Humans</keyword><keyword>Immune Tolerance</keyword><keyword>Immunologic Tests</keyword><keyword>Neoplasms/*immunology</keyword><keyword>T-Lymphocytes/*immunology</keyword><keyword>*autoantibodies</keyword><keyword>*cancer</keyword><keyword>*chemokines</keyword><keyword>*cytokines</keyword><keyword>*experimental autoimmune encephalomyelitis</keyword><keyword>*tolerance</keyword><keyword>*type I diabetes</keyword></keywords><dates><year>2018</year></dates><isbn>1664-3224 (Print)&#xD;1664-3224 (Linking)</isbn><accession-num>29651292</accession-num><urls><related-urls><url>;(334).Cytokines are secreted upon mediation of specific stimuli, this could be a ligand binding to a TLR, leading to transcription factors such as NF-κB translocating to the nucleus where it will facilitate the expression of a specific cytokine gene PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWNjYW5pPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48

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ADDIN EN.CITE.DATA (335, 336). Other stimuli that could yield a cytokine release are ROS PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WbGFob3BvdWxvczwvQXV0aG9yPjxZZWFyPjE5OTk8L1ll

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ADDIN EN.CITE.DATA (338). Storage and secretion is also heterogenous among cytokines, were a few are produced continuously ADDIN EN.CITE <EndNote><Cite><Author>Makhija</Author><Year>2002</Year><RecNum>225</RecNum><DisplayText>(327)</DisplayText><record><rec-number>225</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581373541">225</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Makhija, R.</author><author>Kingsnorth, A. N.</author></authors></contributors><auth-address>University of Plymouth, Level 07, Derriford Hospital, Derriford Road, Plymouth, PL6 8DH, UK.</auth-address><titles><title>Cytokine storm in acute pancreatitis</title><secondary-title>J Hepatobiliary Pancreat Surg</secondary-title></titles><periodical><full-title>J Hepatobiliary Pancreat Surg</full-title></periodical><pages>401-10</pages><volume>9</volume><number>4</number><edition>2002/12/17</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Antibody Formation/physiology</keyword><keyword>Apoptosis/physiology</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Immunity, Cellular/physiology</keyword><keyword>Interleukin-1/physiology</keyword><keyword>Interleukin-10/physiology</keyword><keyword>Interleukin-6/physiology</keyword><keyword>Interleukins/*physiology</keyword><keyword>Pancreatitis/immunology/*physiopathology</keyword><keyword>Platelet Activating Factor/physiology</keyword><keyword>Systemic Inflammatory Response Syndrome/physiopathology</keyword><keyword>Tumor Necrosis Factor-alpha/*physiology</keyword></keywords><dates><year>2002</year></dates><isbn>0944-1166 (Print)&#xD;0944-1166 (Linking)</isbn><accession-num>12483260</accession-num><urls><related-urls><url>;(327), others like IL-1 are stored in monocytes and release passively and some, like IL-6 are synthesized and released upon stimulation ADDIN EN.CITE <EndNote><Cite><Author>Rubartelli</Author><Year>1990</Year><RecNum>238</RecNum><DisplayText>(339)</DisplayText><record><rec-number>238</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581435180">238</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rubartelli, A.</author><author>Cozzolino, F.</author><author>Talio, M.</author><author>Sitia, R.</author></authors></contributors><auth-address>Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.</auth-address><titles><title>A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence</title><secondary-title>EMBO J</secondary-title></titles><periodical><full-title>EMBO J</full-title></periodical><pages>1503-10</pages><volume>9</volume><number>5</number><edition>1990/05/01</edition><keywords><keyword>Brefeldin A</keyword><keyword>Cyclopentanes/pharmacology</keyword><keyword>Hot Temperature</keyword><keyword>Humans</keyword><keyword>Interleukin-1/*metabolism</keyword><keyword>Kinetics</keyword><keyword>Lipopolysaccharides/pharmacology</keyword><keyword>Methylamines/pharmacology</keyword><keyword>Monensin/pharmacology</keyword><keyword>Monocytes/drug effects/*metabolism</keyword><keyword>Protein Processing, Post-Translational/drug effects</keyword><keyword>Subcellular Fractions/analysis</keyword></keywords><dates><year>1990</year><pub-dates><date>May</date></pub-dates></dates><isbn>0261-4189 (Print)&#xD;0261-4189 (Linking)</isbn><accession-num>2328723</accession-num><urls><related-urls><url>;(339). Chemokines are a family within the cytokine group, consisting of small signalling proteins with the task to act as a chemoattractant to guide the migration of leukocytes ADDIN EN.CITE <EndNote><Cite><Author>Luster</Author><Year>1998</Year><RecNum>239</RecNum><DisplayText>(340)</DisplayText><record><rec-number>239</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581436499">239</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Luster, A. D.</author></authors></contributors><auth-address>Partners AIDS Research Center, Massachusetts General Hospital, and the Department of Medicine, Harvard Medical School, Boston, USA.</auth-address><titles><title>Chemokines--chemotactic cytokines that mediate inflammation</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>436-45</pages><volume>338</volume><number>7</number><edition>1998/02/12</edition><keywords><keyword>Animals</keyword><keyword>Chemokines/chemistry/*physiology</keyword><keyword>Humans</keyword><keyword>Infections/physiopathology</keyword><keyword>Inflammation/*immunology</keyword><keyword>Leukocytes/physiology</keyword><keyword>Neovascularization, Pathologic/physiopathology</keyword><keyword>Receptors, Chemokine/*physiology</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb 12</date></pub-dates></dates><isbn>0028-4793 (Print)&#xD;0028-4793 (Linking)</isbn><accession-num>9459648</accession-num><urls><related-urls><url>;(340). All chemokines structurally consist of four cysteine residues, and depending of the spacing of their first two residues they are classified into four groups namely; C, CC, CXC and CX3C ADDIN EN.CITE <EndNote><Cite><Author>Melik-Parsadaniantz</Author><Year>2008</Year><RecNum>240</RecNum><DisplayText>(341)</DisplayText><record><rec-number>240</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581437261">240</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Melik-Parsadaniantz, S.</author><author>Rostene, W.</author></authors></contributors><auth-address>Unite mixte 732 INSERM, UPMC Paris 06, Hopital Saint-Antoine, Paris, France. parsadan@st-antoine.inserm.fr</auth-address><titles><title>Chemokines and neuromodulation</title><secondary-title>J Neuroimmunol</secondary-title></titles><periodical><full-title>J Neuroimmunol</full-title></periodical><pages>62-8</pages><volume>198</volume><number>1-2</number><edition>2008/06/10</edition><keywords><keyword>Animals</keyword><keyword>Brain/cytology</keyword><keyword>Chemokine CCL2/*physiology</keyword><keyword>Chemokine CXCL2/*physiology</keyword><keyword>Humans</keyword><keyword>Neuroglia/drug effects/physiology</keyword><keyword>Neurons/drug effects/physiology</keyword><keyword>Neurotransmitter Agents/classification/pharmacology/*physiology</keyword><keyword>Receptors, CCR2/*physiology</keyword><keyword>Receptors, CXCR4/*physiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul 31</date></pub-dates></dates><isbn>0165-5728 (Print)&#xD;0165-5728 (Linking)</isbn><accession-num>18538863</accession-num><urls><related-urls><url>;(341). 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ADDIN EN.CITE.DATA (342). The nomenclature when it comes to cytokines and chemokines is a bit complex were the same substance could have alternative names, that also differ depending on specie, for instance, the murine chemokine MIP-2 is also termed CXCL-2, but its counterpart in humans is called IL-8.Several cytokines and chemokines have been demonstrated to play a role in the pathophysiology of AP. For instance, it has been demonstrated that IL-6 is elevated in serum samples from patients early in the course of AP ADDIN EN.CITE <EndNote><Cite><Author>Leser</Author><Year>1991</Year><RecNum>243</RecNum><DisplayText>(343)</DisplayText><record><rec-number>243</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581457865">243</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leser, H. G.</author><author>Gross, V.</author><author>Scheibenbogen, C.</author><author>Heinisch, A.</author><author>Salm, R.</author><author>Lausen, M.</author><author>Ruckauer, K.</author><author>Andreesen, R.</author><author>Farthmann, E. H.</author><author>Scholmerich, J.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Freiburg, Germany.</auth-address><titles><title>Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>782-5</pages><volume>101</volume><number>3</number><edition>1991/09/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Acute-Phase Reaction/*etiology</keyword><keyword>C-Reactive Protein/analysis</keyword><keyword>Humans</keyword><keyword>Interleukin-6/*blood</keyword><keyword>Pancreatitis/*blood/complications/mortality</keyword><keyword>Predictive Value of Tests</keyword><keyword>Prognosis</keyword><keyword>Time Factors</keyword></keywords><dates><year>1991</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0016-5085 (Print)&#xD;0016-5085 (Linking)</isbn><accession-num>1907253</accession-num><urls><related-urls><url>(91)90539-w</electronic-resource-num></record></Cite></EndNote>(343) and that IL-6 leukocytes via Janus Kinase (JAK)-2performes phosphorylation of the protein; Signal Transducer and Activator of Transcription (STAT)-3 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWlucmljaDwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+

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ADDIN EN.CITE.DATA (346).Furthermore, MIP-2 (i.e. CXCL2 and/or IL-8) have been demonstrated to regulate both activation and migration of leukocytes in AP ADDIN EN.CITE <EndNote><Cite><Author>Gross</Author><Year>1992</Year><RecNum>244</RecNum><DisplayText>(347)</DisplayText><record><rec-number>244</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581458043">244</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gross, V.</author><author>Andreesen, R.</author><author>Leser, H. G.</author><author>Ceska, M.</author><author>Liehl, E.</author><author>Lausen, M.</author><author>Farthmann, E. H.</author><author>Scholmerich, J.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Freiburg, Germany.</auth-address><titles><title>Interleukin-8 and neutrophil activation in acute pancreatitis</title><secondary-title>Eur J Clin Invest</secondary-title></titles><periodical><full-title>Eur J Clin Invest</full-title></periodical><pages>200-3</pages><volume>22</volume><number>3</number><edition>1992/03/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Interleukin-8/*blood</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neutrophils/enzymology/*immunology</keyword><keyword>Pancreatic Elastase/blood</keyword><keyword>Pancreatitis/complications/enzymology/*immunology</keyword></keywords><dates><year>1992</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0014-2972 (Print)&#xD;0014-2972 (Linking)</isbn><accession-num>1582445</accession-num><urls><related-urls><url>;(347) and that inhibition of MIP-2 reduced the severity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXN0b3I8L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (172). The high affinity receptor for CXCL2 is CXCR2, and it has been shown to be critical in supporting the infiltration of neutrophils into the pancreatic tissue during AP ADDIN EN.CITE <EndNote><Cite><Author>Bhatia</Author><Year>2007</Year><RecNum>245</RecNum><DisplayText>(298)</DisplayText><record><rec-number>245</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581458587">245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bhatia, M.</author><author>Hegde, A.</author></authors></contributors><auth-address>Department of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Bldg MD2, 18 Medical Drive, Singapore 117597, Singapore. mbhatia@nus.edu.sg</auth-address><titles><title>Treatment with antileukinate, a CXCR2 chemokine receptor antagonist, protects mice against acute pancreatitis and associated lung injury</title><secondary-title>Regul Pept</secondary-title></titles><periodical><full-title>Regul Pept</full-title></periodical><pages>40-8</pages><volume>138</volume><number>1</number><edition>2006/10/04</edition><keywords><keyword>Amylases/blood</keyword><keyword>Animals</keyword><keyword>Chemokine CXCL2</keyword><keyword>Chemokines/blood</keyword><keyword>Lung/metabolism/pathology</keyword><keyword>Lung Diseases/*prevention &amp; control</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Oligopeptides/*therapeutic use</keyword><keyword>Pancreas/enzymology/metabolism/pathology</keyword><keyword>Pancreatitis/chemically induced/*prevention &amp; control</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Receptors, Interleukin-8B/*antagonists &amp; inhibitors</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan 10</date></pub-dates></dates><isbn>0167-0115 (Print)&#xD;0167-0115 (Linking)</isbn><accession-num>17014919</accession-num><urls><related-urls><url>;(298). On the other hand, IL-10 has been demonstrated to have a protective role in an experimental model, in according to its anti-inflammatory nature. However it did not ameliorate the symptoms in the clinical setting ADDIN EN.CITE <EndNote><Cite><Author>Fantini</Author><Year>2006</Year><RecNum>246</RecNum><DisplayText>(348)</DisplayText><record><rec-number>246</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581459239">246</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fantini, L.</author><author>Tomassetti, P.</author><author>Pezzilli, R.</author></authors></contributors><auth-address>Department of Internal Medicine, Sant&apos;Orsola-Malpighi Hospital, Bologna, Italy. pezzilli@aosp.bo.it.</auth-address><titles><title>Management of acute pancreatitis: current knowledge and future perspectives</title><secondary-title>World J Emerg Surg</secondary-title></titles><periodical><full-title>World J Emerg Surg</full-title></periodical><pages>16</pages><volume>1</volume><edition>2006/06/09</edition><dates><year>2006</year><pub-dates><date>May 23</date></pub-dates></dates><isbn>1749-7922 (Electronic)&#xD;1749-7922 (Linking)</isbn><accession-num>16759369</accession-num><urls><related-urls><url>;(348). Even though much is still elusive, taken together it is clear that cytokines and chemokines are key-player in the regulation and orchestration of inflammation, not at least in AP.Chromatin changes and Nuclear proteins In order to survive under stressful conditions such as infections, starvation or trauma the cells have to be adoptable and adjust their nature in accordion with the demands. This is achieved through coordination of the gene transcription in aspect of time and cellular context ADDIN EN.CITE <EndNote><Cite><Author>Bannister</Author><Year>2011</Year><RecNum>251</RecNum><DisplayText>(349)</DisplayText><record><rec-number>251</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581591964">251</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bannister, A. J.</author><author>Kouzarides, T.</author></authors></contributors><auth-address>The Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge CB2 1QN, UK.</auth-address><titles><title>Regulation of chromatin by histone modifications</title><secondary-title>Cell Res</secondary-title></titles><periodical><full-title>Cell Res</full-title></periodical><pages>381-95</pages><volume>21</volume><number>3</number><edition>2011/02/16</edition><keywords><keyword>Chromatin/*metabolism</keyword><keyword>Heterochromatin/chemistry</keyword><keyword>Histone Demethylases/metabolism</keyword><keyword>Histones/*metabolism</keyword><keyword>Protein Processing, Post-Translational</keyword></keywords><dates><year>2011</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1748-7838 (Electronic)&#xD;1001-0602 (Linking)</isbn><accession-num>21321607</accession-num><urls><related-urls><url>;(349). 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ADDIN EN.CITE.DATA (350). The primary protein components of the chromatin are the histones, H2A, H2B, H3 and H4 that are arranged duplicable to form a histone octamer. This octamer acts as a spool around which 146 or 147 base pairs of DNA curves to form a nucleosome ADDIN EN.CITE <EndNote><Cite><Author>Luger</Author><Year>1997</Year><RecNum>248</RecNum><DisplayText>(351)</DisplayText><record><rec-number>248</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581541418">248</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Luger, K.</author><author>Mader, A. W.</author><author>Richmond, R. K.</author><author>Sargent, D. F.</author><author>Richmond, T. J.</author></authors></contributors><auth-address>Institut fur Molekularbiologie und Biophysik, Zurich, Switzerland.</auth-address><titles><title>Crystal structure of the nucleosome core particle at 2.8 A resolution</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>251-60</pages><volume>389</volume><number>6648</number><edition>1997/09/26</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Base Composition</keyword><keyword>Crystallography, X-Ray</keyword><keyword>DNA/*chemistry</keyword><keyword>DNA, Superhelical/chemistry</keyword><keyword>Histones/chemistry</keyword><keyword>Humans</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Nucleic Acid Conformation</keyword><keyword>Nucleosomes/*chemistry</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Protein Folding</keyword></keywords><dates><year>1997</year><pub-dates><date>Sep 18</date></pub-dates></dates><isbn>0028-0836 (Print)&#xD;0028-0836 (Linking)</isbn><accession-num>9305837</accession-num><urls><related-urls><url>;(351). For gene transcription to occur, the nucleosome structure must be relaxed by modification of histone elements, thus allowing recruitment of transcript factors in to the affected DNA elements ADDIN EN.CITE <EndNote><Cite><Author>Wu</Author><Year>1997</Year><RecNum>249</RecNum><DisplayText>(352)</DisplayText><record><rec-number>249</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581542659">249</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wu, C.</author></authors></contributors><auth-address>Laboratory of Molecular Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, USA. carlwu@helix.</auth-address><titles><title>Chromatin remodeling and the control of gene expression</title><secondary-title>J Biol Chem</secondary-title></titles><periodical><full-title>J Biol Chem</full-title></periodical><pages>28171-4</pages><volume>272</volume><number>45</number><edition>1997/11/14</edition><keywords><keyword>Acetyltransferases/metabolism</keyword><keyword>Adenosine Triphosphate/metabolism</keyword><keyword>Animals</keyword><keyword>Chromatin/*physiology</keyword><keyword>*Gene Expression Regulation</keyword><keyword>Histone Acetyltransferases</keyword><keyword>Histone Deacetylases/metabolism</keyword><keyword>Humans</keyword><keyword>Nucleosomes/physiology</keyword><keyword>Saccharomyces cerevisiae</keyword><keyword>*Saccharomyces cerevisiae Proteins</keyword><keyword>Tetrahymena</keyword><keyword>Transcription Factors, TFII/physiology</keyword></keywords><dates><year>1997</year><pub-dates><date>Nov 7</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>9353261</accession-num><urls><related-urls><url>;(352). The RNA formed in the transcription process is transferred to the ribosomes where they are translated into polypeptide chains of amino acids that will undergo modifications in order to finally become mature protein products. These changes of the amino acids occurring after the translation is thus termed post-translational ADDIN EN.CITE <EndNote><Cite><Author>Pombo</Author><Year>2015</Year><RecNum>250</RecNum><DisplayText>(353)</DisplayText><record><rec-number>250</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581591495">250</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pombo, A.</author><author>Dillon, N.</author></authors></contributors><auth-address>Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max Delbruck Center for Molecular Medicine, Robert Roessle Strasse, 13125 Berlin-Buch, Germany.&#xD;Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.</auth-address><titles><title>Three-dimensional genome architecture: players and mechanisms</title><secondary-title>Nat Rev Mol Cell Biol</secondary-title></titles><periodical><full-title>Nat Rev Mol Cell Biol</full-title></periodical><pages>245-57</pages><volume>16</volume><number>4</number><edition>2015/03/12</edition><keywords><keyword>Animals</keyword><keyword>Chromatin/*chemistry</keyword><keyword>Chromosomes/*chemistry</keyword><keyword>Genome/*genetics</keyword><keyword>Humans</keyword><keyword>*Models, Biological</keyword><keyword>Protein Folding</keyword></keywords><dates><year>2015</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1471-0080 (Electronic)&#xD;1471-0072 (Linking)</isbn><accession-num>25757416</accession-num><urls><related-urls><url>;(353). The post translational modifications of histones, occurs predominantly at the N-terminal tail and there are at least eight distinct different changes known ADDIN EN.CITE <EndNote><Cite><Author>Kouzarides</Author><Year>2003</Year><RecNum>252</RecNum><DisplayText>(354)</DisplayText><record><rec-number>252</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581594533">252</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kouzarides, T.</author></authors></contributors><auth-address>Wellcome Trust/Cancer Research UK Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QR, UK. tk106@mole.bio.ca.ac.uk</auth-address><titles><title>Wellcome Trust Award Lecture. Chromatin-modifying enzymes in transcription and cancer</title><secondary-title>Biochem Soc Trans</secondary-title></titles><periodical><full-title>Biochem Soc Trans</full-title></periodical><pages>741-3</pages><volume>31</volume><number>Pt 4</number><edition>2003/07/31</edition><keywords><keyword>Acetylesterase/genetics/metabolism</keyword><keyword>Animals</keyword><keyword>Chromatin/*metabolism</keyword><keyword>Chromosomal Proteins, Non-Histone/metabolism</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Enzyme Inhibitors/pharmacology</keyword><keyword>Gene Silencing</keyword><keyword>Histone Deacetylase Inhibitors</keyword><keyword>Histone Deacetylases/metabolism</keyword><keyword>Humans</keyword><keyword>Methyltransferases/metabolism</keyword><keyword>Neoplasms/*enzymology/*genetics</keyword><keyword>Phosphotransferases/metabolism</keyword><keyword>Transcription, Genetic</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0300-5127 (Print)&#xD;0300-5127 (Linking)</isbn><accession-num>12887294</accession-num><urls><related-urls><url>;(354), for instance acetylation of lysine ADDIN EN.CITE <EndNote><Cite><Author>Vidali</Author><Year>1968</Year><RecNum>253</RecNum><DisplayText>(355)</DisplayText><record><rec-number>253</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581597502">253</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vidali, G.</author><author>Gershey, E. L.</author><author>Allfrey, V. G.</author></authors></contributors><titles><title>Chemical studies of histone acetylation. The distribution of epsilon-N-acetyllysine in calf thymus histones</title><secondary-title>J Biol Chem</secondary-title></titles><periodical><full-title>J Biol Chem</full-title></periodical><pages>6361-6</pages><volume>243</volume><number>24</number><edition>1968/12/25</edition><keywords><keyword>Acetates/*analysis</keyword><keyword>Animals</keyword><keyword>Arginine/analysis</keyword><keyword>Carbon Isotopes</keyword><keyword>Cattle</keyword><keyword>Chromatography, Gel</keyword><keyword>Chromatography, Ion Exchange</keyword><keyword>Histones/*analysis</keyword><keyword>Hydroxylamines</keyword><keyword>Lysine/*analysis</keyword><keyword>Peptide Hydrolases</keyword><keyword>Thymus Gland/analysis</keyword><keyword>Trypsin</keyword></keywords><dates><year>1968</year><pub-dates><date>Dec 25</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>5726891</accession-num><urls><related-urls><url>;(355), methylation and citrullination of arginine ADDIN EN.CITE <EndNote><Cite><Author>Tessarz</Author><Year>2014</Year><RecNum>254</RecNum><DisplayText>(356)</DisplayText><record><rec-number>254</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581597592">254</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tessarz, P.</author><author>Kouzarides, T.</author></authors></contributors><auth-address>Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge, CB2 1QN, UK; and the Max Planck Research Group &apos;Chromatin and Ageing&apos;, Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931 Cologne, Germany.&#xD;Gurdon Institute and Department of Pathology, Tennis Court Road, Cambridge, CB2 1QN, UK.</auth-address><titles><title>Histone core modifications regulating nucleosome structure and dynamics</title><secondary-title>Nat Rev Mol Cell Biol</secondary-title></titles><periodical><full-title>Nat Rev Mol Cell Biol</full-title></periodical><pages>703-8</pages><volume>15</volume><number>11</number><edition>2014/10/16</edition><keywords><keyword>Acetylation</keyword><keyword>Citrulline/metabolism</keyword><keyword>DNA/*metabolism</keyword><keyword>*DNA Repair</keyword><keyword>DNA Replication</keyword><keyword>Histones/genetics/*metabolism</keyword><keyword>Humans</keyword><keyword>Methylation</keyword><keyword>Molecular Chaperones/genetics/*metabolism</keyword><keyword>Nucleosomes/chemistry/genetics/*metabolism</keyword><keyword>Phosphorylation</keyword><keyword>*Protein Processing, Post-Translational</keyword><keyword>Transcription, Genetic</keyword></keywords><dates><year>2014</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1471-0080 (Electronic)&#xD;1471-0072 (Linking)</isbn><accession-num>25315270</accession-num><urls><related-urls><url>;(356) and phosphorylation of serein and threonine residues ADDIN EN.CITE <EndNote><Cite><Author>Davie</Author><Year>1999</Year><RecNum>255</RecNum><DisplayText>(357)</DisplayText><record><rec-number>255</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581597699">255</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Davie, J. R.</author><author>Spencer, V. A.</author></authors></contributors><auth-address>Manitoba Institute of Cell Biology and the Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba R3E 0V9 Canada. Davie@cc.umanitoba.ca</auth-address><titles><title>Control of histone modifications</title><secondary-title>J Cell Biochem</secondary-title></titles><periodical><full-title>J Cell Biochem</full-title></periodical><pages>141-8</pages><volume>Suppl 32-33</volume><edition>2000/01/11</edition><keywords><keyword>Acetylation</keyword><keyword>Acetyltransferases/metabolism</keyword><keyword>Animals</keyword><keyword>*Gene Expression Regulation</keyword><keyword>Histone Acetyltransferases</keyword><keyword>Histone Deacetylases/metabolism</keyword><keyword>Histones/*chemistry/*metabolism</keyword><keyword>Humans</keyword><keyword>Nucleosomes/chemistry/metabolism</keyword><keyword>Phosphorylation</keyword><keyword>*Saccharomyces cerevisiae Proteins</keyword><keyword>Transcription, Genetic/genetics</keyword></keywords><dates><year>1999</year></dates><isbn>0730-2312 (Print)&#xD;0730-2312 (Linking)</isbn><accession-num>10629113</accession-num><urls><related-urls><url>(sici)1097-4644(1999)75:32+&lt;141::aid-jcb17&gt;3.0.co;2-a</electronic-resource-num></record></Cite></EndNote>(357). The importance of citrullination of histone has already been dealt with in the NETs chapter. The process of adding methyl groups at the N-terminus of lysine residues is catalysed by the enzyme histone acetylase (HAT), and removal of methyl groups by enzymes of the histone deacetylase (HDAC)-family ADDIN EN.CITE <EndNote><Cite><Author>Peserico</Author><Year>2011</Year><RecNum>256</RecNum><DisplayText>(358)</DisplayText><record><rec-number>256</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581598890">256</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Peserico, A.</author><author>Simone, C.</author></authors></contributors><auth-address>Laboratory of Signal-Dependent Transcription, Department of Translational Pharmacology (DTP), Consorzio Mario Negri Sud, Santa Maria Imbaro, 66030 Chieti, Italy.</auth-address><titles><title>Physical and functional HAT/HDAC interplay regulates protein acetylation balance</title><secondary-title>J Biomed Biotechnol</secondary-title></titles><periodical><full-title>J Biomed Biotechnol</full-title></periodical><pages>371832</pages><volume>2011</volume><edition>2010/12/15</edition><keywords><keyword>Acetylation</keyword><keyword>Animals</keyword><keyword>Histone Acetyltransferases/*metabolism</keyword><keyword>Histone Deacetylases/*metabolism</keyword><keyword>Humans</keyword><keyword>Proteins/chemistry/*metabolism</keyword></keywords><dates><year>2011</year></dates><isbn>1110-7251 (Electronic)&#xD;1110-7243 (Linking)</isbn><accession-num>21151613</accession-num><urls><related-urls><url>;(358). 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ADDIN EN.CITE.DATA (360), intracellular transduction ADDIN EN.CITE <EndNote><Cite><Author>Lang</Author><Year>2006</Year><RecNum>259</RecNum><DisplayText>(361)</DisplayText><record><rec-number>259</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581599654">259</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lang, R.</author><author>Hammer, M.</author><author>Mages, J.</author></authors></contributors><auth-address>Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Immunology and Hygiene, Trogerstrasse 30, Munich 81675, Germany. Roland.Lang@lrz.tum.de</auth-address><titles><title>DUSP meet immunology: dual specificity MAPK phosphatases in control of the inflammatory response</title><secondary-title>J Immunol</secondary-title></titles><periodical><full-title>J Immunol</full-title></periodical><pages>7497-504</pages><volume>177</volume><number>11</number><edition>2006/11/23</edition><keywords><keyword>Animals</keyword><keyword>Dual Specificity Phosphatase 1</keyword><keyword>Gene Expression/*immunology</keyword><keyword>Humans</keyword><keyword>Inflammation</keyword><keyword>Macrophage Activation/*immunology</keyword><keyword>Mice</keyword><keyword>Protein Phosphatase 1</keyword><keyword>*Protein Tyrosine Phosphatases/genetics/immunology/metabolism</keyword><keyword>Signal Transduction/*immunology</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec 1</date></pub-dates></dates><isbn>0022-1767 (Print)&#xD;0022-1767 (Linking)</isbn><accession-num>17114416</accession-num><urls><related-urls><url>;(361) and even transcription . Since these are all processes concerning regulation of cell survival and growth, it is not surprising that HDAC have been shown to be involved in the development of several types of cancer ADDIN EN.CITE <EndNote><Cite><Author>Yoon</Author><Year>2016</Year><RecNum>260</RecNum><DisplayText>(362)</DisplayText><record><rec-number>260</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581600898">260</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yoon, S.</author><author>Eom, G. H.</author></authors></contributors><auth-address>Department of Pharmacology, Chonnam National University Medical School, Gwangju, Korea.</auth-address><titles><title>HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases</title><secondary-title>Chonnam Med J</secondary-title></titles><periodical><full-title>Chonnam Med J</full-title></periodical><pages>1-11</pages><volume>52</volume><number>1</number><edition>2016/02/13</edition><keywords><keyword>Cardiovascular diseases</keyword><keyword>Histone deacetylase inhibitors</keyword><keyword>Histone deacetylases</keyword><keyword>Neoplasms</keyword></keywords><dates><year>2016</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>2233-7385 (Print)&#xD;2233-7393 (Linking)</isbn><accession-num>26865995</accession-num><urls><related-urls><url>;(362), but also in many inflammatory conditions including AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJ0bWFuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA (364). Attached to the nucleosome are other proteins than histones such as High- Mobility Group Box 1 (HMGB1) ADDIN EN.CITE <EndNote><Cite><Author>Goodwin</Author><Year>1973</Year><RecNum>263</RecNum><DisplayText>(365)</DisplayText><record><rec-number>263</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581606280">263</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goodwin, G. H.</author><author>Sanders, C.</author><author>Johns, E. W.</author></authors></contributors><titles><title>A new group of chromatin-associated proteins with a high content of acidic and basic amino acids</title><secondary-title>Eur J Biochem</secondary-title></titles><periodical><full-title>Eur J Biochem</full-title></periodical><pages>14-9</pages><volume>38</volume><number>1</number><edition>1973/09/21</edition><keywords><keyword>Amino Acids/analysis</keyword><keyword>Animals</keyword><keyword>Cattle</keyword><keyword>Chemical Precipitation</keyword><keyword>Chromatin/*analysis</keyword><keyword>Chromatography, Gel</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Proteins/analysis/*isolation &amp; purification</keyword><keyword>Sodium Chloride</keyword><keyword>Solubility</keyword><keyword>Thymus Gland/*analysis</keyword><keyword>Trichloroacetic Acid</keyword><keyword>Urea</keyword></keywords><dates><year>1973</year><pub-dates><date>Sep 21</date></pub-dates></dates><isbn>0014-2956 (Print)&#xD;0014-2956 (Linking)</isbn><accession-num>4774120</accession-num><urls><related-urls><url>;(365) and Cold-Inducible RNA-binding Protein (CIRP) ADDIN EN.CITE <EndNote><Cite><Author>Nishiyama</Author><Year>1997</Year><RecNum>264</RecNum><DisplayText>(366)</DisplayText><record><rec-number>264</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581606494">264</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nishiyama, H.</author><author>Higashitsuji, H.</author><author>Yokoi, H.</author><author>Itoh, K.</author><author>Danno, S.</author><author>Matsuda, T.</author><author>Fujita, J.</author></authors></contributors><auth-address>Department of Clinical Molecular Biology, Faculty of Medicine, Kyoto University, Japan.</auth-address><titles><title>Cloning and characterization of human CIRP (cold-inducible RNA-binding protein) cDNA and chromosomal assignment of the gene</title><secondary-title>Gene</secondary-title></titles><periodical><full-title>Gene</full-title></periodical><pages>115-20</pages><volume>204</volume><number>1-2</number><edition>1998/01/20</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Base Sequence</keyword><keyword>Chromosome Mapping</keyword><keyword>*Chromosomes, Human, Pair 19</keyword><keyword>Cloning, Molecular</keyword><keyword>DNA, Complementary</keyword><keyword>HeLa Cells</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Molecular Sequence Data</keyword><keyword>RNA, Messenger</keyword><keyword>RNA-Binding Proteins/*genetics/metabolism</keyword><keyword>Sequence Homology, Amino Acid</keyword><keyword>Tumor Cells, Cultured</keyword></keywords><dates><year>1997</year><pub-dates><date>Dec 19</date></pub-dates></dates><isbn>0378-1119 (Print)&#xD;0378-1119 (Linking)</isbn><accession-num>9434172</accession-num><urls><related-urls><url>(97)00530-1</electronic-resource-num></record></Cite></EndNote>(366). Upon stimulation and stress such as ROS; histones, HMGB1 and CIRP can detach from the nucleosome, thus allowing transcription to occur and eventually translocate from the nucleus of the cell to the surface, where they will act as DAMPs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA (367-369) thus initiating inflammation and complement activation. HMGB1contain three structural domains, two DNA binding boxes (box A and box B) and one histone binding C-terminal end. The C-terminal end could interact with the A and B boxes inducing changes in the internal protein structure of HMGB1 ADDIN EN.CITE <EndNote><Cite><Author>Stros</Author><Year>2010</Year><RecNum>268</RecNum><DisplayText>(370)</DisplayText><record><rec-number>268</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581609501">268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stros, M.</author></authors></contributors><auth-address>Laboratory of Analysis of Chromosomal Proteins, Academy of Sciences of the Czech Republic, Institute of Biophysics, Kralovopolska 135, 612 65 Brno, Czech Republic. stros@ibp.cz</auth-address><titles><title>HMGB proteins: interactions with DNA and chromatin</title><secondary-title>Biochim Biophys Acta</secondary-title></titles><periodical><full-title>Biochim Biophys Acta</full-title></periodical><pages>101-13</pages><volume>1799</volume><number>1-2</number><edition>2010/02/04</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Chromatin/*metabolism</keyword><keyword>DNA/*metabolism</keyword><keyword>Gene Expression Regulation</keyword><keyword>HMGB Proteins/chemistry/genetics/*metabolism</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword><keyword>Protein Binding</keyword><keyword>Protein Processing, Post-Translational</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>0006-3002 (Print)&#xD;0006-3002 (Linking)</isbn><accession-num>20123072</accession-num><urls><related-urls><url>;(370) this together with the fact that deacetylation through action of HDAC regulates the affinity of the protein to the nucleosome ADDIN EN.CITE <EndNote><Cite><Author>Scaffidi</Author><Year>2002</Year><RecNum>269</RecNum><DisplayText>(371)</DisplayText><record><rec-number>269</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581609826">269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scaffidi, P.</author><author>Misteli, T.</author><author>Bianchi, M. E.</author></authors></contributors><auth-address>DIBIT, Istituto Scientifico San Raffaele, 20132 Milano, Italy.</auth-address><titles><title>Release of chromatin protein HMGB1 by necrotic cells triggers inflammation</title><secondary-title>Nature</secondary-title></titles><periodical><full-title>Nature</full-title></periodical><pages>191-5</pages><volume>418</volume><number>6894</number><edition>2002/07/12</edition><keywords><keyword>Acetylation</keyword><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Cell Survival</keyword><keyword>Chromatin/*metabolism</keyword><keyword>Gene Deletion</keyword><keyword>HMGB1 Protein/genetics/*metabolism</keyword><keyword>HeLa Cells</keyword><keyword>Humans</keyword><keyword>Inflammation/genetics/*metabolism/pathology</keyword><keyword>*Necrosis</keyword><keyword>Protein Binding</keyword><keyword>Rats</keyword></keywords><dates><year>2002</year><pub-dates><date>Jul 11</date></pub-dates></dates><isbn>0028-0836 (Print)&#xD;0028-0836 (Linking)</isbn><accession-num>12110890</accession-num><urls><related-urls><url>;(371), enable rapid detachment from the chromatin and hence permitting transcription. After detachment HMGB1 could translocate to the cytoplasm via post-translational modifications (acetylation) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb25hbGRpPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48

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ADDIN EN.CITE.DATA (374), indicating the protective purpose of intracellular HMGB1 during oxidative stress PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW5nPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYW5nPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (375). Furthermore, release of HMGB1 has also been observed to induce NETosis via TLR-4 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYWRpZTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (376) in accordance with many other known DAMPS. Originally CIRP was recognized as a protein that promotes cell differentiation and suppresses mitosis during hypothermia ADDIN EN.CITE <EndNote><Cite><Author>Ward</Author><Year>2013</Year><RecNum>275</RecNum><DisplayText>(377)</DisplayText><record><rec-number>275</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581614924">275</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ward, P. A.</author></authors></contributors><auth-address>Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.</auth-address><titles><title>An endogenous factor mediates shock-induced injury</title><secondary-title>Nat Med</secondary-title></titles><periodical><full-title>Nat Med</full-title></periodical><pages>1368-9</pages><volume>19</volume><number>11</number><edition>2013/11/10</edition><keywords><keyword>Animals</keyword><keyword>Cold Shock Proteins and Peptides/*blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>RNA-Binding Proteins/*blood</keyword><keyword>Sepsis/*blood</keyword><keyword>Shock, Hemorrhagic/*blood</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1546-170X (Electronic)&#xD;1078-8956 (Linking)</isbn><accession-num>24202382</accession-num><urls><related-urls><url>;(377), hence its name. Now several other stress factors such as ROS, hypoxia and UV-radiation have been shown to upregulate the expression, and release of CIRP, from the nucleus. Within the cytoplasm it is referred to as iCIRP (where "i" stands for intracellular) and here it regulates several stress coping strategies favourable for the cell including; mRNA stability, cell proliferation, cell survival, telomerase maintenance and stress adaptation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaG9uZzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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AG==

ADDIN EN.CITE.DATA (378). Intracellularly the iCIRP is stored in stress granules that upon further stimulation could be gradually released to the extracellular space where it will be referred to as eCIRP (here "e" consequently stands for extracellular), and here it will act as a DAMP ADDIN EN.CITE <EndNote><Cite><Author>Aziz</Author><Year>2019</Year><RecNum>278</RecNum><DisplayText>(379)</DisplayText><record><rec-number>278</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581616476">278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aziz, M.</author><author>Brenner, M.</author><author>Wang, P.</author></authors></contributors><auth-address>Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA.&#xD;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA.</auth-address><titles><title>Extracellular CIRP (eCIRP) and inflammation</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>133-146</pages><volume>106</volume><number>1</number><edition>2019/01/16</edition><keywords><keyword>Ali</keyword><keyword>Cirp</keyword><keyword>Damp</keyword><keyword>eCIRP</keyword><keyword>hemorrhage</keyword><keyword>inflammation</keyword><keyword>ischemia/reperfusion</keyword><keyword>macrophage</keyword><keyword>neutrophils</keyword><keyword>sepsis</keyword></keywords><dates><year>2019</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>30645013</accession-num><urls><related-urls><url>;(379). In the extracellular context eCIRP will bind to TLR4-MD2 receptor, activating NF-κB leading to release of TNF-α and HMBG1 and further proinflammatory effects PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5RaWFuZzwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (369). Via this NF-κB pathway eCIRP has also been shown to activate NETosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PZGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (271). The platelet-produced enzyme IP6K1 could possibly be involved in this process since it has been reported that it regulates aggregation of platelets and neutrophils in lung inflammation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3U8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (292). The aim of this paper was to investigate whether platelets and neutrophils interaction are involved in NETs release and possible NETs-MP formation, if such occurs, in AP; and more specifically what role, if any, IP6K1 play in these processes and hence in the development of APPaper IIICold-induced RNA-binding protein (CIRP) is a nuclear protein that during stress could be expelled to the extracellular space and here function as a Damage-Associated-Molecular-Pattern protein called eCIRP ADDIN EN.CITE <EndNote><Cite><Author>Aziz</Author><Year>2019</Year><RecNum>278</RecNum><DisplayText>(379)</DisplayText><record><rec-number>278</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581616476">278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aziz, M.</author><author>Brenner, M.</author><author>Wang, P.</author></authors></contributors><auth-address>Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA.&#xD;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA.</auth-address><titles><title>Extracellular CIRP (eCIRP) and inflammation</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>133-146</pages><volume>106</volume><number>1</number><edition>2019/01/16</edition><keywords><keyword>Ali</keyword><keyword>Cirp</keyword><keyword>Damp</keyword><keyword>eCIRP</keyword><keyword>hemorrhage</keyword><keyword>inflammation</keyword><keyword>ischemia/reperfusion</keyword><keyword>macrophage</keyword><keyword>neutrophils</keyword><keyword>sepsis</keyword></keywords><dates><year>2019</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>30645013</accession-num><urls><related-urls><url>;(379). It has been shown that eCIRP induce NETs formation in sepsis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PZGU8L0F1dGhvcj48WWVhcj4yMDE4PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (183), the aim with this paper was to examine whether eCIRP is involved in NETs formation in AP.Paper IVPremature activation of trypsinogen into trypsin is consider a key step in the pathogenesis of AP ADDIN EN.CITE <EndNote><Cite><Author>Regner</Author><Year>2008</Year><RecNum>42</RecNum><DisplayText>(80)</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579511400">42</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Regner, S.</author><author>Manjer, J.</author><author>Appelros, S.</author><author>Hjalmarsson, C.</author><author>Sadic, J.</author><author>Borgstrom, A.</author></authors></contributors><auth-address>Department of Surgery, Malmo University Hospital, Lund University, Lund, Sweden. sara.regner@med.lu.se</auth-address><titles><title>Protease activation, pancreatic leakage, and inflammation in acute pancreatitis: differences between mild and severe cases and changes over the first three days</title><secondary-title>Pancreatology</secondary-title></titles><periodical><full-title>Pancreatology</full-title></periodical><pages>600-7</pages><volume>8</volume><number>6</number><edition>2008/10/14</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Amylases/blood</keyword><keyword>C-Reactive Protein/metabolism</keyword><keyword>Carboxypeptidase B/blood</keyword><keyword>Chemokine CCL2/blood/urine</keyword><keyword>Enzyme Activation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>*Inflammation</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/*classification/*enzymology/physiopathology</keyword><keyword>Peptide Hydrolases/*blood</keyword><keyword>Trypsin/blood</keyword><keyword>Trypsinogen/blood</keyword></keywords><dates><year>2008</year></dates><isbn>1424-3911 (Electronic)&#xD;1424-3903 (Linking)</isbn><accession-num>18849642</accession-num><urls><related-urls><url>;(80). Trypsin is known to cleave, and thus activate complement component 3 (C3), and hence the complement cascade ADDIN EN.CITE <EndNote><Cite><Author>Bettac</Author><Year>2017</Year><RecNum>283</RecNum><DisplayText>(307)</DisplayText><record><rec-number>283</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581672276">283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bettac, L.</author><author>Denk, S.</author><author>Seufferlein, T.</author><author>Huber-Lang, M.</author></authors></contributors><auth-address>Department of Internal Medicine I, University Hospital of Ulm , Ulm , Germany.&#xD;Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm , Ulm , Germany.</auth-address><titles><title>Complement in Pancreatic Disease-Perpetrator or Savior?</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>15</pages><volume>8</volume><edition>2017/02/02</edition><keywords><keyword>acinar cells</keyword><keyword>complement</keyword><keyword>multiple organ failure</keyword><keyword>pancreas</keyword><keyword>pancreatic ductal adenocarcinomas</keyword><keyword>pancreatitis</keyword></keywords><dates><year>2017</year></dates><isbn>1664-3224 (Print)&#xD;1664-3224 (Linking)</isbn><accession-num>28144242</accession-num><urls><related-urls><url>;(307). Activation of C3 has been demonstrated to induce NETs ADDIN EN.CITE <EndNote><Cite><Author>Palmer</Author><Year>2016</Year><RecNum>288</RecNum><DisplayText>(306)</DisplayText><record><rec-number>288</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581719457">288</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palmer, L. J.</author><author>Damgaard, C.</author><author>Holmstrup, P.</author><author>Nielsen, C. H.</author></authors></contributors><auth-address>Section for Periodontology, Microbiology and Community Dentistry, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.&#xD;Department of Infectious Diseases and Rheumatology, Institute for Inflammation Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Influence of complement on neutrophil extracellular trap release induced by bacteria</title><secondary-title>J Periodontal Res</secondary-title></titles><periodical><full-title>J Periodontal Res</full-title></periodical><pages>70-6</pages><volume>51</volume><number>1</number><edition>2015/04/23</edition><keywords><keyword>Complement System Proteins</keyword><keyword>*Extracellular Traps</keyword><keyword>Macrophage-1 Antigen</keyword><keyword>Neutrophils</keyword><keyword>Receptors, Complement 3b</keyword><keyword>Staphylococcus aureus</keyword><keyword>biofilm</keyword><keyword>complement</keyword><keyword>inflammation</keyword><keyword>neutrophil extracellular traps</keyword><keyword>periodontal disease</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1600-0765 (Electronic)&#xD;0022-3484 (Linking)</isbn><accession-num>25900429</accession-num><urls><related-urls><url>;(306), which in turn has the ability to activate the complement cascade PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWZmbGVyPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA (320, 321). Since formation of NETs is of great importance in AP, the aim of this study was thus to investigate whether C3 affects the formation of NETs in AP.Material and methods:Animals In all experiments male C57BL/6 mice (Taconic Europe, Bomholt Denmark (paper I), Janvier Labs, Leof Genest-Sant-Isle, France (paper II, III, IV)), (20-25 g, 8-9 weeks old), were used as wild type. In paper II, male IP6K1 deficient mice (21-25g, 8-9 weeks old), and in paper IV, C3 deficient mice were used (21-27 g, 8-9 weeks old). (Jackson laboratories, Farmington, CT, USA) The animals were kept on a 12–12 h light dark cycle with access to laboratory diet and water ad libitum. For in vivo studies involving animals, the ARRIVE guidelines ADDIN EN.CITE <EndNote><Cite><Author>Kilkenny</Author><Year>2011</Year><RecNum>413</RecNum><DisplayText>(382)</DisplayText><record><rec-number>413</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583756177">413</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kilkenny, C.</author><author>Browne, W.</author><author>Cuthill, I. C.</author><author>Emerson, M.</author><author>Altman, D. G.</author><author>National Centre for the Replacement, Refinement</author><author>Reduction of Amimals in, Research</author></authors></contributors><titles><title>Animal research: reporting in vivo experiments--the ARRIVE guidelines</title><secondary-title>J Cereb Blood Flow Metab</secondary-title></titles><periodical><full-title>J Cereb Blood Flow Metab</full-title></periodical><pages>991-3</pages><volume>31</volume><number>4</number><edition>2011/01/06</edition><keywords><keyword>Animal Experimentation/ethics/*standards/statistics &amp; numerical data</keyword><keyword>Animal Husbandry/standards</keyword><keyword>Animals</keyword><keyword>Checklist</keyword><keyword>Data Interpretation, Statistical</keyword><keyword>Periodicals as Topic</keyword><keyword>Publishing/standards</keyword><keyword>Quality Control</keyword><keyword>Research Design/*standards</keyword></keywords><dates><year>2011</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1559-7016 (Electronic)&#xD;0271-678X (Linking)</isbn><accession-num>21206507</accession-num><urls><related-urls><url>;(382) and an editorial on the application of ARRIVE guidelines to pharmacological studies ADDIN EN.CITE <EndNote><Cite><Author>McGrath</Author><Year>2010</Year><RecNum>414</RecNum><DisplayText>(383)</DisplayText><record><rec-number>414</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583756325">414</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McGrath, J. C.</author><author>Drummond, G. B.</author><author>McLachlan, E. M.</author><author>Kilkenny, C.</author><author>Wainwright, C. L.</author></authors></contributors><titles><title>Guidelines for reporting experiments involving animals: the ARRIVE guidelines</title><secondary-title>Br J Pharmacol</secondary-title></titles><periodical><full-title>Br J Pharmacol</full-title></periodical><pages>1573-6</pages><volume>160</volume><number>7</number><edition>2010/07/24</edition><keywords><keyword>Animal Experimentation/*standards/statistics &amp; numerical data</keyword><keyword>Animals</keyword><keyword>Biomedical Research/standards</keyword><keyword>*Editorial Policies</keyword><keyword>*Guidelines as Topic</keyword><keyword>Pharmacology/standards</keyword><keyword>United Kingdom</keyword></keywords><dates><year>2010</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1476-5381 (Electronic)&#xD;0007-1188 (Linking)</isbn><accession-num>20649560</accession-num><urls><related-urls><url>;(383) were consulted. All experiments were approved by the Regional Ethics Committee for animal experimentation at Lund University, Sweden. Before all procedures, the mice were anesthetized by intraperitoneal (i.p.) administration of 75 mg of ketamine hydrochloride (Hoffman-La Roche, Basel, Switzerland) and 25 mg of xylazine (Janssen Pharmaceutica, Beerse, Belgium) per kg body weight.Study designPaper I. In order to examine the role of CXCL4, wild-type mice were treated with ip PBS (vehicle) or with 10 ?l of the monoclonal antibody against murine CXCL4 (clone 140910) (R&D Systems, Europe, Abingdon, Oxon, UK) or 4mg/kg of the CXCR2 antagonist SB225002 (Calbiochem, Merck, Darmstadt, Germany) prior induction of pancreatitis. To study the role of platelet, 1.0 mg/kg of a platelet-depleted antibody against murine CD42b (anti-GP1bα) (Emfret Analytics GmbH& Co, Wurzburg, Germany) or 1.0 mg/kg of an isotype control antibody (clone R3-34) (BD Bioscience Pharmigen, San Jose, CA, USA) was given i.p. before the challenge with taurocholate. Animals were sacrificed 24 hours after induction, and blood and samples collected.Paper II. In order to examine the role of platelets, platelet-neutrophil aggregation and the role of IP6K1, wild-type and IP6K1-/- mice were treated with ip injection of either: PBS (vehicle), 5 mg/kg of DNase-1 (Pulomzyne, Roche, Grenzach-Wyhlen, Germany), 1mg/kg of anti-GP1bα (Emfret Analytics GmbH& Co, Wurzburg, Germany), 2 mg/kg of an anti-P-selectin antibody (clone RB40.43, rat IgG)(BD Bioscience Pharmigen, San Jose, CA, USA), 1.0 mg/kg of a control antibody (rat IgG)( Emfret Analytics GmbH& Co, Wurzburg, Germany) or 20 mg/kg of the IP6K1 inhibitor TNP (2N-(m-Trifluorobenzyl),N6-(p-nitrobenzyl)purine) (Tocris bioscience, Bristol, UK), prior to induction of pancreatitis. Animals were sacrificed 24 hours after induction, and blood and samples collected.Paper III. To investigate the role of CIRP, wild-type mice received iv. injection of vehicle (saline) or 8 mg/kg of the CIRP antagonist C23 one hour prior to induction of pancreatitis. 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ADDIN EN.CITE.DATA (384). One group of animals received C23 alone without sodium taurocholate. Animals were sacrificed 24 hours after induction, and blood and samples collectedPaper IV. In order to examine the role of C3; wild type or C3-/- mice were challenged with taurocholate. Animals were sacrificed 24 hours after induction, and blood and samples collected.Experimental models of induction of pancreatitis. Taurocholate induced pancreatitis The main method for inducing pancreatitis in all papers (Paper I-IV) was by controlled retrograde infusion of the bile salt taurocholate. This is a well described method in rodents. With this procedure extensive necrosis develops in the head of the pancreas, but not in the body and tail, since the infusion does not reach so far up the pancreatic duct ADDIN EN.CITE <EndNote><Cite><Author>Perides</Author><Year>2010</Year><RecNum>415</RecNum><DisplayText>(385)</DisplayText><record><rec-number>415</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583762407">415</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Perides, G.</author><author>van Acker, G. J.</author><author>Laukkarinen, J. M.</author><author>Steer, M. L.</author></authors></contributors><auth-address>Department of Surgery, Tufts Medical Center, Boston, Massachusetts, USA. gperides@</auth-address><titles><title>Experimental acute biliary pancreatitis induced by retrograde infusion of bile acids into the mouse pancreatic duct</title><secondary-title>Nat Protoc</secondary-title></titles><periodical><full-title>Nat Protoc</full-title></periodical><pages>335-41</pages><volume>5</volume><number>2</number><edition>2010/02/06</edition><keywords><keyword>Animals</keyword><keyword>Bile Acids and Salts/administration &amp; dosage/*toxicity</keyword><keyword>Disease Models, Animal</keyword><keyword>Infusions, Parenteral</keyword><keyword>Mice</keyword><keyword>Pancreatic Ducts/drug effects/*pathology</keyword><keyword>Pancreatitis/*chemically induced/pathology/surgery</keyword><keyword>Reference Values</keyword><keyword>Taurocholic Acid/toxicity</keyword><keyword>Taurolithocholic Acid/analogs &amp; derivatives/toxicity</keyword></keywords><dates><year>2010</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1750-2799 (Electronic)&#xD;1750-2799 (Linking)</isbn><accession-num>20134432</accession-num><urls><related-urls><url>;(385). Briefly, anesthetized mice underwent a midline incision into the abdominal cavity and the second part of duodenum and papilla of Vater were identified. Traction sutures (7.0 Prolene) were placed one cm proximally and one cm distally of the papilla for immobilization A small puncture was made through the duodenal wall (23 G needle) opposite to and parallel with the papilla of Vater in accordion with the described method ADDIN EN.CITE <EndNote><Cite><Author>Laukkarinen</Author><Year>2007</Year><RecNum>416</RecNum><DisplayText>(386)</DisplayText><record><rec-number>416</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583762630">416</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laukkarinen, J. M.</author><author>Van Acker, G. J.</author><author>Weiss, E. R.</author><author>Steer, M. L.</author><author>Perides, G.</author></authors></contributors><auth-address>Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland.</auth-address><titles><title>A mouse model of acute biliary pancreatitis induced by retrograde pancreatic duct infusion of Na-taurocholate</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>1590-8</pages><volume>56</volume><number>11</number><edition>2007/06/27</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Biliary Tract Diseases/*chemically induced</keyword><keyword>*Cholagogues and Choleretics</keyword><keyword>*Disease Models, Animal</keyword><keyword>Female</keyword><keyword>Interleukin-6/metabolism</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred BALB C</keyword><keyword>Pancreatic Ducts</keyword><keyword>Pancreatitis/*chemically induced</keyword><keyword>Pneumonia/chemically induced</keyword><keyword>Reproducibility of Results</keyword><keyword>*Taurocholic Acid</keyword></keywords><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1468-3288 (Electronic)&#xD;0017-5749 (Linking)</isbn><accession-num>17591621</accession-num><urls><related-urls><url>;(386). A polyethylene catheter connected to a micro-infusion pump (CMA/100, Carnegie Medical, Stockholm, Sweden) was inserted through the punctured hole in the duodenum and one mm into the common bile duct. A micro clamp was temporarily placed on the common hepatic duct at the liver hilum to prevent hepatic reflux. Ten ?l of 5% sodium taurocholate (Sigma, St. Louis, MO, USA) were infused into the pancreatic duct for 10 min, after which the catheter and the clamp on the common hepatic duct were removed and the duodenal puncture was closed with a 7.0 purse-string suture. Traction sutures were removed and the abdomen was closed with sutures in two layers. Sham mice underwent the exact same procedure except that the pancreatic duct was infused with 10 ?l of 0.9% sodium chloride. The mice all received Temgesic subcutaneously at the end of the surgery for pain relief. The mice were sacrificed under anaesthesia by cervical dislocation 24 h after induction of AP, and blood and tissue samples were collected.Courtesy of Dr H HartmannFigure 1. L-arginine induced pancreatitis Given i.p. the essential amino acid L-arginine causes pancreatitis in mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXdyYTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (387). The reason for this is not totally known, but might be related to the fact that nitric oxide synthase has been known to metabolize L-arginine intra acinar, and hence yield an accumulation of nitric oxide and inflammatory mediators in the acinar cells ADDIN EN.CITE <EndNote><Cite><Author>Wu</Author><Year>1998</Year><RecNum>421</RecNum><DisplayText>(388)</DisplayText><record><rec-number>421</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583764542">421</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wu, G.</author><author>Morris, S. M., Jr.</author></authors></contributors><auth-address>Departments of Animal Science, Medical Physiology, and Veterinary Anatomy and Public Health, and Faculty of Nutrition, Texas A&amp;M University, College Station, TX 77843, USA. g-wu@tamu.edu</auth-address><titles><title>Arginine metabolism: nitric oxide and beyond</title><secondary-title>Biochem J</secondary-title></titles><periodical><full-title>Biochem J</full-title></periodical><pages>1-17</pages><volume>336 ( Pt 1)</volume><edition>1998/11/10</edition><keywords><keyword>Amidinotransferases/metabolism</keyword><keyword>Animals</keyword><keyword>Arginase/metabolism</keyword><keyword>Arginine/biosynthesis/*metabolism</keyword><keyword>Biological Transport</keyword><keyword>Carboxy-Lyases/metabolism</keyword><keyword>Intestinal Mucosa/metabolism</keyword><keyword>Kidney/metabolism</keyword><keyword>Liver/metabolism</keyword><keyword>Nitric Oxide/*metabolism</keyword><keyword>Nitric Oxide Synthase/metabolism</keyword></keywords><dates><year>1998</year><pub-dates><date>Nov 15</date></pub-dates></dates><isbn>0264-6021 (Print)&#xD;0264-6021 (Linking)</isbn><accession-num>9806879</accession-num><urls><related-urls><url>;(388), that will induce oxidative stress that provokes necrosis and apoptosis of the acinar cells. L-arginine induced pancreatitis was used as a control in paper I and II. Pancreatitis was thus induced by giving L-arginine hydrochloride (4g/kg, 8% diluted in saline, Sigma-Aldrich) i.p. twice with an interwall of one hour as previously described PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXdyYTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (387). Sham mice were given i.p. saline infusion twice and served as negative control. All mice were sacrificed 72 hours after induction of AP through cervical dislocation under anaesthesia, and blood and tissue were procured.Amylase levels Amylase levels were quantified in blood obtained from the tail vein (diluted using a commercially available assay (Reflotron, Roche Diagnostics GmbH, Mannheim, Germany)Preparation of Neutrophils and PlateletsNeutrophils were isolated from bone marrow in femur and tibia of mice as described previously in the literature ADDIN EN.CITE <EndNote><Cite><Author>Swamydas</Author><Year>2013</Year><RecNum>427</RecNum><DisplayText>(389)</DisplayText><record><rec-number>427</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583930486">427</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Swamydas, M.</author><author>Lionakis, M. S.</author></authors></contributors><auth-address>Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, USA.</auth-address><titles><title>Isolation, purification and labeling of mouse bone marrow neutrophils for functional studies and adoptive transfer experiments</title><secondary-title>J Vis Exp</secondary-title></titles><periodical><full-title>J Vis Exp</full-title></periodical><pages>e50586</pages><number>77</number><edition>2013/07/31</edition><keywords><keyword>Adoptive Transfer/*methods</keyword><keyword>Animals</keyword><keyword>Bone Marrow Cells/*cytology</keyword><keyword>Centrifugation, Density Gradient/methods</keyword><keyword>Cytological Techniques/*methods</keyword><keyword>Flow Cytometry</keyword><keyword>Mice</keyword><keyword>Neutrophils/*cytology</keyword><keyword>Staining and Labeling/methods</keyword></keywords><dates><year>2013</year><pub-dates><date>Jul 10</date></pub-dates></dates><isbn>1940-087X (Electronic)&#xD;1940-087X (Linking)</isbn><accession-num>23892876</accession-num><urls><related-urls><url>;(389) by density gradient centrifugation using a Ficoll-Paque gradient (GE healthcare, Uppsala, Sweden) (paper I-IV).For isolation of platelets (paper II), blood from the vena cava was collected and 1:10 acid citrate dextrose anticoagulant added. Blood was then immidiately diluted with equal volumes of modified Tyrode sollution (1?g/ml prostaglandin E1 and 0.1 U/ml apyrase) and centriguged at 200 g for 5minutes. The resulting platelet-rich plasma was the collected and further centrifuged at 800 g for 15 minutes. After the supranatent was removed the paltelet pellet weas washed with modified Tyrode solution twice, and instantly used for s generation in vitro In papers II, III and IV, freshly isolated neutrophils were incubated with 500 nM phorbol myristate acetate (PMA)(Sigma-Aldrich, Stockholm, Sweden) for 3 hours at 37°C in 6-well plate in RPMI medium, this have been demostrated to trigger NETs formation ADDIN EN.CITE <EndNote><Cite><Author>Meng</Author><Year>2012</Year><RecNum>429</RecNum><DisplayText>(390)</DisplayText><record><rec-number>429</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583968009">429</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meng, W.</author><author>Paunel-Gorgulu, A.</author><author>Flohe, S.</author><author>Hoffmann, A.</author><author>Witte, I.</author><author>MacKenzie, C.</author><author>Baldus, S. E.</author><author>Windolf, J.</author><author>Logters, T. T.</author></authors></contributors><titles><title>Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice</title><secondary-title>Crit Care</secondary-title></titles><periodical><full-title>Crit Care</full-title></periodical><pages>R137</pages><volume>16</volume><number>4</number><edition>2012/07/28</edition><keywords><keyword>Animals</keyword><keyword>Bacterial Load</keyword><keyword>Deoxyribonuclease I/*pharmacology</keyword><keyword>Disease Models, Animal</keyword><keyword>Disease Progression</keyword><keyword>Disease Susceptibility</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Fluorescent Antibody Technique</keyword><keyword>Interleukin-6/metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Infiltration/*immunology</keyword><keyword>Neutrophils/*immunology</keyword><keyword>Prospective Studies</keyword><keyword>Recombinant Proteins/pharmacology</keyword><keyword>Sepsis/*drug therapy/*immunology/microbiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Jul 26</date></pub-dates></dates><isbn>1466-609X (Electronic)&#xD;1364-8535 (Linking)</isbn><accession-num>22835277</accession-num><urls><related-urls><url>;(390). 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ADDIN EN.CITE.DATA (257), Supernatants were discharged and fresh media was added to isolate NETs. Residual neutrophils and NETs were collected through extensive pipetting. The mixture was centrifuged at 200 g for 5 min to remove cellular components and NETs containing supernatants were collected. Supernatants were further centrifuged at 19,000 g for 10 min to pellet the NETs for collection (paper II, III and IV). For MP preparation (paper II), the supernatants were exposed to high centrifugation (21000 g for 1 h at 4?C), afterwhich the supernatants were removed and the pellets resuspended in phosphate buffer saline (PBS).Pancreatic Acinar CellsPancreatic acinar cells were prepared by collagenase digestion as previously described in the literature PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXJpZGVzPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48

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ADDIN EN.CITE.DATA (391) HEPES-ringer buffer containing collagenase from Clostridium histolyticum type 1 (2.5 ml, 1%, Sigma-Aldrich, Stockholm, Sweden) was gently infused into the pancreatic duct of male C57BL/6 mice. The animals were sacrificed through cervical dislocation and pancreatic tissue was collected. In order to achieve maximal exposure to collagenase, the pancreas was minced, gently shaken and incubated at 37°C for 15 minutes. The solute was then centrifuged and washed three times in cold HEPES-Ringer buffer, pH 7.4 to stop digestion and remove the collagenase. Next, the acinar cells were suspended in cold HEPES-Ringer buffer and the solute was passed through a 150 ?m cell strainer (Partec, G?rlitz, Germany). Trypan blue was used to check the viability of pancreatic acinar cells which was higher than 95%. The cell suspension was then aliquoted into Eppendorf tubes and kept on ice until subsequent in vitro experiments and determination of amylase secretion assay. In paper I, isolated cells were then, stimulated with either cerulein or murine CXCL4 (100, 500 or 1000 ng/mL) in duplicates at 37?C for 30 minutes.In paper II, isolated acinar cells were exposed to NETs, NETs depleted of MPs (calpain/caspase treated), NETs treated with DNase-1 and/or neutrophil-derived MPs, for 1 h at 37?C.In paper III, the isolated acinar cells were instead exposed to taurocholate or NETs for 1 hour at 37°C, either in the presence or absence of C23. The pellets of isolated acinar cells were used for western blot (STAT-3 phosphorylation) (paper II) and flow cytometry (paper III).Chemotaxis assayIn paper I, neutrophil chemotaxis was performed in accordance with a previously described protocol ADDIN EN.CITE <EndNote><Cite><Author>Smith</Author><Year>1991</Year><RecNum>428</RecNum><DisplayText>(392)</DisplayText><record><rec-number>428</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583933362">428</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Smith, W. B.</author><author>Gamble, J. R.</author><author>Clark-Lewis, I.</author><author>Vadas, M. A.</author></authors></contributors><auth-address>Division of Human Immunology, Institute of Medical and Veterinary Sciences, Adelaide, South Australia.</auth-address><titles><title>Interleukin-8 induces neutrophil transendothelial migration</title><secondary-title>Immunology</secondary-title></titles><periodical><full-title>Immunology</full-title></periodical><pages>65-72</pages><volume>72</volume><number>1</number><edition>1991/01/01</edition><keywords><keyword>Capillary Permeability</keyword><keyword>Cell Adhesion</keyword><keyword>Cell Movement</keyword><keyword>Chemotactic Factors/*physiology</keyword><keyword>Endothelium, Vascular/metabolism</keyword><keyword>Humans</keyword><keyword>Interleukin-8/*physiology</keyword><keyword>Neutrophils/*physiology</keyword><keyword>Polystyrenes</keyword><keyword>Tumor Necrosis Factor-alpha/physiology</keyword><keyword>Umbilical Veins/metabolism</keyword></keywords><dates><year>1991</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0019-2805 (Print)&#xD;0019-2805 (Linking)</isbn><accession-num>1997402</accession-num><urls><related-urls><url>;(392). Isolated neutrophils (1,5x106), were placed in the upper chamber of the 5?m pore size transwell inserts (Corning Costar, Corning, NY, USA). The inserts were then placed in wells containing medium alone (control), medium with murine CXCL2 (100ng/mL) (R&D systems, Europe, Abingdon, Oxon, UK) or medium plus murine CXCL4 (100, 500, 1000 ng/ml) (R&D systems, Europe, Abingdon, Oxon, UK). After 120 minutes the inserts were removed, the migrated neutrophils were stained with Turks solution and counted in a Burker chamber in order to determine the chemotaxisMyeloperoxidase levelsMyeloperoxidase (MPO) was analysed in pancreas and lung in all four papers as a measurement of infiltration of neutrophils and hence systemic inflammation. All samples of pancreas and lung tissue were snap frozen in liquid nitrogen, and before analysis, thawed and weighed and then homogenized in 1 ml mixture (4:1) of PBS and aprotinin (10,000 kallikrein inactivator units per ml; Trasylol) (Bayer HealthCare AG, Leverkusen, Germany) for one min. Homogenates were centrifuged for 10 min (15,300 g, 4°C), and supernatants were frozen to -20°C, and stored for other analysis. MPO activity was determined in the remaining pellets in obedience with a well-established protocol PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdW88L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA (393). Pellets were resuspended in 0.2M PB pH7.4. After another round of centrifugation, the samples were suspended with one ml of 0.5% hexadecyl-trimethylammonium bromide. The dissolved samples were frozen for 24h, thawed, sonicated for 90 sec and put in a water bath (60°C, 2h). Enzyme activity was determined spectrophotometrically as the MPO-catalysed change in absorbance in the redox reaction of H2O2 (450 nm, with a reference filter 540 nm, 25°C). Data are expressed as MPO units per gram tissue.Flow cytometryFor flowcytometry, blood from the vena cava was collected into syringes pre-filled with 1:10 acid citrate dextrose. Immediately after collection, blood samples were incubated for 10 minutes at room temperature with an anti-CD16/CD32 antibody blocking Fcγ III/II receptors to reduce non-specific labellingIn paper I and II, blood collected from the vena cava 24 hours after induction of AP was used to determine expression of mac-1 on circulating neutrophils (paper I) or the presence of platelet-neutrophil aggregates (PNA) (Ly6G+= neutrophils, CD41+=platelets) and the percentage of platelets and different leukocyte subtypes (paper II).In paper III, isolated pancreatic acinar cells from pancreatic mice were used to quantify expression of TLR-4-. The acinar cells were incubated for 10 minutes at room temperature with an anti-CD16/CD32 antibody blocking Fcγ III/II receptors to reduce non-specific labelling, immediately after isolation.In paper IV isolated neutrophils from bone marrow of mice with pancreatitis were used to determine MPO and citrullinated H3 on neutrophils. The isolated neutrophils were also immediately after isolation incubated for 10 minutes at room temperature with an anti-CD16/CD32 antibody blocking Fcγ III/II receptors in order to reduce non-specific labelling, In paper I, the blood samples after blocking were incubated with phycoerythrin-conjugated anti-Gr-1 (clone RB6-8C5 rat IgG2b) (eBioscience, Frankfurt, Germany) and fluorescein isothiocyanate anti-mac-1 antigen (clone M1/70, rat IgG2bκ) (BD Bioscience Pharmigen, San Jose, CA, USA) antibodies. After fixation in 2% formaldehyde solution, the erythrocytes were lysed using ACK lysing buffer (Thermo Fisher Scientific, Somerset, NJ, USA), the sample was centrifuged and the neutrophils recovered. In paper II, the blood samples were incubated after blocking with phycoerythrin-conjugated anti-Ly6G (clone 1A8) (BD Pharmingen, San Jose, CA, USA) and fluorescein isothiocyanate-conjugated anti-CD41 (clone MWReg30) (BD Pharmingen, San Jose, USA) antibodies. Cells were fixed with 2% formaldehyde solution, erythrocytes were lysed using ACK lysing buffer (Thermo Fisher Scientific, Somerset, NJ, USA) and neutrophils were recovered following centrifugation. Samples were then incubated with PerCP-Cy5.5-conjugated anti-CD45 (clone 30-F11) (Biolegend, San Diego, CA, USA) and an APC-conjugated antiCD4 (clone GK 1.5) (eBioscience, San Diego, CA, USA) antibody at 4°C for 20 minutes. Cells were fixed with 2% formaldehyde; erythrocytes were lysed and cells were recovered following centrifugation. Furthermore, in paper II, comparison of leukocytes subtypes and platelets, in blood of both wild-type and IP6K-/- mice were performed. Blocking was performed as previously described and the blood samples were incubated for 20 minutes in 4?, with different antibodies: PerCP-Cy5.5-conjugated anti CD45 (clone 30-F11) (Biolegend, San Diego; CA, USA )antibody, phycoerythrin-conjugated antiLy6G (clone 1A8, BD Pharmingen, San Jose, CA, USA) antibody, APC-conjugated anti-CD4 (clone GK 1.5, eBioscience, San Diego, CA, USA) antibody and FITC-conjugated anti CD41 (clone eBioMWReg30) (eBioscience, San Diego, CA, USA) antibody. After this the cells were fixed with 2% formaldehyde; ACK lysing buffer (Thermo Fisher Scientific, Somerset, NJ, USA) was used to lyse erythrocytes and the cells were centrifuged and recovered. In paper III, after blocking, the acinar cells were incubated with biotinylated peanut agglutinin (B-1075-5, Vector, UK), APC conjugated anti-TLR-4 Ab (clone MTS510) (Thermo Fisher Scientific, Somerset,?NJ,?USA) or APC conjugated IgG2a Ab (clone RTK2758) (Biolegend, San Diego, CA, USA) at 4°C for 20 min. After two washes, the acinar cells were incubated with a secondary phycoerythrin-conjugated anti-biotin antibody (clone BK-1/39) (Thermo Fisher Scientific, Somerset,?NJ,?USA) at 4°C for 20 min. In paper IV, the neutrophils after stimulation with PMA (a total of 1 x 106 neutrophils) and blocking, were incubated with primary antibodies: phycoerythrin-conjugated anti-Ly6G (clone 1A8)(BD Pharmingen, San Jose, CA, USA), fluorescein isothiocyanate-conjugated anti-MPO antibody (mouse: ab90812)( Abcam, Cambridge, MA, USA) and rabbit anti-citH3 (citrulline 2,8,17, ab5103)(Abcam, Cambridge, MA, USA) in PBS containing 5% donkey serum. After washing two times, cells were incubated with rat anti-rabbit APC conjugated secondary antibody (A-21038) (Thermo Fisher Scientific, Rockford, IL, USA). Flow cytometric analysis was performed according to standard settings on a Cytoflex flow cytometer (Beckman Coulter, Indianapolis, IN, USA), and viability gate was used to exclude dead and fragmented cells. 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ADDIN EN.CITE.DATA (394) see table.Tabel 1. Local tissue injury in pancreatic tissue samples analyzed in light microscope, magnification x100, in a blinded manner. Paraffin embedded samples cut in 6 ?m sections and stained with hematoxylin and eosin. Hemorrhage and oedema were graded 0-4 (0=absent, 4=extensive). Necrosis and neutrophil infiltration were assessed in 10 random high-power fields (HPF) per sample.Histopathologic scoring criteria 0-4:Oedema0Absent0,5focal expansion of the interlobar space1diffuse expansion of the interlobar space1,51+ focal expansion of the interlobar space21+ diffuse expansion of the interlobar space2,52+ focal expansion of the interlobar space32+ diffuse expansion of the interlobar space3,53+ focal expansion of the interlobar space43+ diffuse expansion of the interlobar spaceAcinar cell necrosis0Absent0,5Focal occurrence of 1-4 necrotic cells/HPF1Diffuse occurrence of 1-4 necrotic cells/HPF1,5Focal occurrence of 5-10necrotic cells/HPF2Diffuse occurrence of 5-10 necrotic cells/HPF2,5Focal occurrence of 11-16 necrotic cells/HPF3Diffuse occurrence of 11-16 necrotic cells/HPF3,5Focal occurrence of >16 necrotic cells/HPF4Extensive confluent necrosis/HPFHemorrhage0Absent0,51 focus12 foci1,53 foci24 foci2,55 foci36 foci3,57 foci4 >7 fociExtravascular leukocytes00-1 interlobar or perivascular leucocyte/HPF0,52-5 interlobar or perivascular leucocytes/HPF16-10 interlobar or perivascular leucocytes/HPF1,511-15 interlobar or perivascular leucocytes/HPF216-20 interlobar or perivascular leucocytes/HPF2,521-25 interlobar or perivascular leucocytes/HPF326-30 interlobar or perivascular leucocytes/HPF3,5>30 leukocytes/HPF or focal micro abscess4>30 leukocytes/HPF or confluent micro abscessElectron microscopyFor examination of NETs in tissue samples, in paper II, III, IV, high resolution scanning electron microscopy was performed, using paraffin embedded pancreatic tissue samples. The specimens on coverslips were deparaffinized and the pancreatic tissue samples were fixed in 2.5% glutaraldehyde in 0.15 mol/l sodium cacodylate, pH7.4 (cacodylate buffer) for 30 min at room temperature. Specimens were then washed with cacodylate buffer and dehydrated with an ascending ethanol series from 50% (vol/vol) to absolute ethanol (10 min/step). Specimens were subjected to critical-point drying in carbon dioxide with absolute ethanol as intermediate solvent, mounted on aluminium holders, and finally sputtered with 20 nm palladium/gold. Specimens were examined using a Jeol/FEI XL 30 FEG scanning electron microscope at the Core facility for Integrated Microscopy at the Panum Institute (University of Copenhagen, Denmark).Location of individual target molecules in tissue NETs were analysed at high resolution by ultrathin sectioning and transmission immunoelectron microscopy. Specimens on coverslips were embedded in Epon 812 and sectioned into 50-nm–thick ultrathin sections with a diamond knife in an ultramicrotome. For immunohistochemistry, sections were incubated overnight at 4°C with primary antibodies against elastase (paper II, III and IV), histone 4, mac-1, CD41(paper II) and citrullinated histone 3 (paper III and IV) (Abcam, Cambridge, MA, USA).In paper III, transmission electron microscopy was used in order to detect eCIRP in NETs generated from PMA-stimulated bone marrow neutrophils, samples were incubated overnight at 4°C with a primary antibody against CIRP (Proteintech, Rosemont, IL, USA). Controls without primary antibodies were included. The grids were incubated with species-specific, gold-conjugated secondary antibodies (Electron Microscopy Sciences, Fort Washington, MD, USA). The sections were then post-fixed in 2% glutaraldehyde and post-stained with 2% uranyl acetate and lead citrate. Specimens were observed in a Jeol/FEI CM100 transmission electron microscope operated at 80-kV accelerating voltage at the Core Facility for Integrated Microscopy at the Panum Institute. Confocal imagingIn paper II, confocal imaging was performed to confirm the deficiency of Poly-P in platelets. Isolated platelets from both wild type mice and IP6K1-/- mice were fixed in 4% paraformaldehyde in PBS in room temperature for 30 minutes, after which they were washed with PBS. The pellet of platelets was then dissolved in water and 1 mg/ml of 4’,6-diamidino-2-phenylindole (DAPI) was added. DAPI emits higher wavelengths light after binding to Poly-P, and thus induce a higher fluorescence intensity if Poly-P is present ADDIN EN.CITE <EndNote><Cite><Author>Aschar-Sobbi</Author><Year>2008</Year><RecNum>430</RecNum><DisplayText>(395)</DisplayText><record><rec-number>430</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1584014901">430</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aschar-Sobbi, R.</author><author>Abramov, A. Y.</author><author>Diao, C.</author><author>Kargacin, M. E.</author><author>Kargacin, G. J.</author><author>French, R. J.</author><author>Pavlov, E.</author></authors></contributors><auth-address>Department of Physiology and Biophysics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.</auth-address><titles><title>High sensitivity, quantitative measurements of polyphosphate using a new DAPI-based approach</title><secondary-title>J Fluoresc</secondary-title></titles><periodical><full-title>J Fluoresc</full-title></periodical><pages>859-66</pages><volume>18</volume><number>5</number><edition>2008/01/23</edition><keywords><keyword>Fluorescent Dyes/chemistry/*metabolism</keyword><keyword>Fluorometry</keyword><keyword>Indoles/*metabolism</keyword><keyword>Kinetics</keyword><keyword>Polyphosphates/*chemistry</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Spectrometry, Fluorescence</keyword></keywords><dates><year>2008</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1053-0509 (Print)&#xD;1053-0509 (Linking)</isbn><accession-num>18210191</accession-num><urls><related-urls><url>;(395). The samples were then mounted on slides, and confocal microscopy was performed.In another experiment in paper II, isolated neutrophils were co- incubated with wild-type or IP6K1-/- platelets, together with or without Poly-P (100?M) and/or with or without thrombin (0.2 U/ml) for three hours in 37?C .The neutrophils were then challenged with PMA, fixed with 2% formaldehyde and permeabilized with 1% Triton-X-100 for 10 minutes, after which they were washed twice with PBS containing 2% fetal bovine serum. Following this, the cells were incubated in PBS with 5% donkey serum and with primary antibodies; Fluorescein isothiocyanate conjugated anti-MPO (mouse ab90812) (Abcam, Cambridge, MA, USA) and rabbit anti-H3cit (citrulline 2,8,17, ab5103) (Abcam, Cambridge, MA, USA). After washing twice, incubation with rat anti-rabbit allophycocyanin conjugated secondary antibody (A-21038) (Thermo Scientific, Rockford, IL, USA). When the immunostaining was completed the cells were counterstained with Hoechst 33342 in order to stain DNA. The cells were then mounted and confocal microscopy performed.The microscope used was Zeiss LSM 800 (Carl Zeiss, Jena, Germany), and the images were processed using ZEN2012 software.Enzyme-linked immunosorbent assay (ELISA)Pancreatic and plasma levels of CXCL2 and IL-6 were quantified (paper I-IV) using double-antibody, enzyme-linked immunosorbent assay kits (R&D Systems Europe, Abingdon, Oxon, UK) according to the manufacturers’ instructions. The same assay kit was used to determine plasma CXCL 1 (paper II, III and IV), pancreatic CXCL 1 (paper II and III) CXCL4 (paper I), MMP-9 (paper II, III and IV) and pancreatic histone 3 and 4 (Paper II). In paper III, CIRP was quantified using another double-antibody ELISA kit (Cusabio Biotech, Houston, TX, USA). Supernatants were collected from homogenized pancreatic tissue and stored at -20°C until used, blood collected from the inferior vena cava was diluted (1:10) in acid citrate dextrose, centrifuged (15,300 g for 5 min at 4°C), and stored at -20°C until use. DNA-histone complexes were determined in blood obtained from the inferior vena cava (Paper II-IV). Blood was diluted (1:10) in acid citrate dextrose and centrifuged for 5 min (15,300 g, 4°C). In order to quantify DNA-histone complexes, a Cell Death Detection Elisa Plus kit (Roche Diagnostics, Mannheim, Germany) was used, according to the manufacturers’ instructions. DNA histone-complexes were also determined, in paper II the same way as described above, in supernatants from co-incubated isolated platelets and neutrophils (see section on confocal microscopy for details).In paper III, plasma levels of CIRP in humans with AP were quantified using double-antibody enzyme-linked immunosorbent assay kits (Wuhan Fine Biotech Co., Ltd, Wuhan, China) according to the manufacturers’ instructions. In paper IV, DNA-histone complexes were determined in the supernatants of in vitro experiments, neutrophils were here isolated from bone marrow as previously described. A total of 1 x 106 neutrophils was stimulated with 0.3 μg/ml PMA (Sigma-Aldrich, Stockholm, Sweden) or 1.0 μg/ml mouse recombinant C3a (R&D Systems Europe, Abingdon, Oxon, UK) in suspension. Samples were centrifuged (400 g, 5 min) and supernatants were collected for analysis of DNA-histone as described above.Western blotIn paper II, collected pellets of isolated acinar cell were incubated with NETs, NETs depleted of MPs (i.e. pre-treated with calpain/caspase), DNase1.treated NETs or neutrophil derived MPs and homogenized in ice-cold RIPA buffer (Pierce RIPA Buffer, Thermo Scientific?, USA) containing protease inhibitors (Halt Protease Inhibitor Cocktail; Pierce Biotechnology, Rockford, IL). Samples were kept 20 min on ice and sonicated and centrifuged for 15 min (16,000 g, 4°C).In paper III, pancreatic tissue samples (30-40 mg) were homogenized and treated in exactly the same way as in paper II. In both paper II and III supernatants were stored at -20°C and their protein concentration were determined using the Pierce BCA Protein Assay Reagent (Pierce Biotechnology). Proteins (20 μg per lane) were separated by 8-16% SDS-PAGE gels and transferred to polyvinylidene fluoride membranes (Novex, San Diego, Calif., USA). Prior to blotting, a total protein gel image was taken using Bio-Rad’s stain-free gel chemistry. Membranes were blocked in TPBS/Tween 20 buffer containing 5% non-fat dry milk powder. Immunoblots were then generated using specific antibodies:In paper II this was done using antibodies against phosphotyrosin (Tyr 705)-STAT-3 and STAT-3 (Cat. #9131 and Cat. #4904, Cell Signalling Technology, Beverly, MA, USA). In paper III, this was performed by use of an anti-histone H3 antibody (citrulline R2+R8+R17; AB5103, Abcam, Cambridge, MA, USA). Membranes (both in paper II and III) were then incubated with peroxidase conjugated secondary antibodies. Protein bands were developed using the Bio-Rad ChemiDoc MP imaging system. The Image Lab software (version 5.2.1) was used to normalize the band against the total protein in respective lane. In Paper IV, for confirmation of the C3 deficiency in protein level, liver homogenate samples were used and run on a 10% SDS-PAGE, transferred to PVDF membranes and blotted for C3 using goat anti-mouse C3 (catalog number 55500) (ICN Biomedicals Eire, PA, USA), then detected using rabbit anti-goat HRP-labeled secondary antibody (DAKO, ST Clara, CA, USA), and developed using enhanced chemiluminescence reagent (Millipore) and imaged using a Bio-Rad Chemidoc CCD camera. Loading control of beta-actin was detected with anti-beta-actin monoclonal antibody (Abcam, Cambridge, MA, USA.) Quantitative Reverse Transcription-polymerase chain reaction (qRT-PCR)In Paper I, total RNA was isolated from isolated acinar cells by use of an RNeasy Mini Kit (Qiagen, West Sussex, UK) and treated with RNase-free DNase (DNase I; Amersham Pharmacia Biotech, Sollentuna, Sweden) to remove potential genomic DNA contaminants. By measuring the absorbance at 260?nm, RNA concentrations were determined, by reverse transcription from 10?μg of the total RNA Each complementary DNA was synthesized by use of the SuperScript First-Strand Synthesis System and random hexamer primers (Stratagene) (AH diagnostics, Stockholm, Sweden). Real-time polymerase chain reaction (PCR) was performed using a Brilliant SYBR Green QPCR master mix and MX 3000P detection system (Stratagene, AH diagnostics, Stockholm, Sweden). The primer sequences were: for CXCL2: (forward) 5′-CGC CCA GAC AGA AGT CAT AG-3′ (reverse) 5′-CCT CCT TTC CAG GTC AGT TAG -3′ for CXCL4 (forward) 5′-CTC ATA GCC ACC CTG AAG AAT G-3′ (reverse) 5′-AGG CAG CTG ATA CCT AAC TCT-3′ and for β-actin (forward) 5′-TGT GAT GGT GGG AAT GGG TCA GAA-3′ (reverse) 5′-TGT GGT GCC AGA TCT TCT CCA TGT-3′. Standard PCR curves were generated for each PCR product to establish linearity of the reverse transcription-polymerase chain reaction. PCR amplifications were performed in a total volume of 50?μL, containing 25?μL of SYBR Green PCR 2× Master Mix, 2?μL of 0.15-μM each primer, 0.75?μL of reference dye, and 1 1-μL complementary DNA as a template adjusted up to 50?μL with water. PCR reactions were started with 10?minutes denaturing temperature of 95°C, followed by a total of 40 cycles (95°C for 30?seconds and 55°C for 1?minute) and 1?minute of elongation at 72°C. The relative differences in expression between groups were expressed by using cycling time values. Cycling time values for the specific target genes were first normalized with that of β-actin in the same sample, and then relative differences between groups were expressed as percentage of control.In paper II, isolated acinar cells were incubated with NETs, NETs depleted of MPs (calpain/caspase treatment), DNase I-treated NETs and neutrophil-derived MPs, then cell pellets were collected and expression of IL-6 mRNA and TGFB1 mRNA were analyzed by RT-qPCR. Briefly, RNA samples were extracted using Direct-zol RNA extraction kit (Zymo Research, Irvine, CA, USA) kit according to manufacturer’s recommendations. Total RNA concentration was determined using Nanodrop spectrophotometer at 260 nm absorbance and cDNA was synthesized using Revert Aid First Strand cDNA synthesis kit (Thermo Fisher Scientific) in a final reaction volume of 10 μL according to the manufacturer’s instructions. qRT-PCR was conducted in a final volume of 25 μL using SYBR Green dye (Takara Bio, Mountain View, CA, USA) for relative expression of IL-6 mRNA and TGFB1 mRNA. The PCR primers used were as follows;IL-6 (forward); 5'-GAGGATACCACTCCCAACAGACC-3', (reverse) 5'- AAGTGCATCATCGTTGTTCATACA-3' TGFB1 (forward); 5′- TCCCGTGGCTTCTAGTGCTG-3′, (reverse); 5′-ATTTTAATCTCTGCAAGCGCA-3′,GAPDH 6 (forward); 5′-GTCCCAGCTTAGGTTCATAG-3′, (reverse); 5′- GATGGCAACAATCTCCACTTTG-3′. IL-6 mRNA and TGFB1 mRNA relative to housekeeping gene GADPH were determined using 2- ΔΔ CT method.Genotyping by polymerase chain reaction (PCR)In paper IV in order to confirm that the C3 gene was really knocked out, genotyping PCR was carried out on RNA from C3-deficient mice using common forward primer ATCTTGAGTGCACCAAGCC and either Wild Type-specific reverse primer GGTTGCAGCAGTCTATGAAGG or Knocked Out-specific reverse primer GCCAGAGGCCACTTGTGTAG, in combination with RedTaq PCR readymix (Sigma Aldrich, Stockholm, Sweden), according to reagent instructions. Bands were confirmed using UV light.Patients SamplesAnalyses on blood from human patients with AP were performed in Paper I and Paper IV. Informed consent (oral and written) was obtained from all participants included, and the study was approved by the regional ethics committee at Lund University (2009/413). Patients age over 18 years with AP admitted to the Department of Surgery, Sk?ne University Hospital, Malm?, Sweden, from January 2010 to September 2013 were prospectively and consecutively included. To fulfil the diagnosis of AP, three criteria were used: 1) acute characteristic?upper abdominal pain, 2) serum?amylase?≥3 times the upper limit or 3) characteristic findings of AP on?CT scan, abdominal ultrasound or?MRI. Blood samples were drawn at 24-48 hours after admission, placed in plasma separator tubes and centrifuged (2000g, 25°C, 10 minutes) before plasma was frozen at-80°C. Retrospectively the patients were then classified as having mild, moderately severe or severe AP according to the revised Atlanta classification of 2012? ADDIN EN.CITE <EndNote><Cite><Author>Banks</Author><Year>2013</Year><RecNum>318</RecNum><DisplayText>(47)</DisplayText><record><rec-number>318</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582629793">318</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Banks, P. A.</author><author>Bollen, T. L.</author><author>Dervenis, C.</author><author>Gooszen, H. G.</author><author>Johnson, C. D.</author><author>Sarr, M. G.</author><author>Tsiotos, G. G.</author><author>Vege, S. S.</author><author>Acute Pancreatitis Classification Working, Group</author></authors></contributors><auth-address>Division of Gastroenterology, Hepatology, and Endoscopy, Harvard Medical School, Brigham and Women&apos;s Hospital, Boston, Massachusetts, USA.</auth-address><titles><title>Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>102-11</pages><volume>62</volume><number>1</number><edition>2012/10/27</edition><keywords><keyword>Acute Disease</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Pancreatitis/*classification/complications/diagnosis/diagnostic imaging</keyword><keyword>Severity of Illness Index</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1468-3288 (Electronic)&#xD;0017-5749 (Linking)</isbn><accession-num>23100216</accession-num><urls><related-urls><url>;(47). Samples from healthy persons were included as controls, and handled the same way as patient samples.In paper 1, CXCL4 was determined with an ELISA Kit (see section Enzyme-link immunosorbent assay).In paper III, eCIRP was determined with an ELISA-kit (see section Enzyme-link immunosorbent assay.Statistical analysis. Paper I Data are presented as mean values?±?standard error of the mean. Statistical evaluations were performed by using nonparametric tests Kruskal-Wallis 1-way analysis of variance on ranks followed by multiple comparisons. P?<?0.05 was considered significant, and n representing the number of animals or patients.Paper II, III and IV Graphpad Prism 7 was used for data analysis. Data are presented in box plot (25-75 percentiles) where horizontal line indicates median of the group; whiskers extend from the minimum to the maximum values. Statistical comparisons were performed using non-parametrical tests (Mann-Whitney (paper II, III, IV) or ANOVA on ranks followed by Dunnett’s multiple comparisons (paper II, IV). P < 0.05 was considered significant and n representing the number of animals or experiments.Results and DiscussionsPaper 1In paper I the purpose was to examine whether CXCL4 the most abundant chemokines in the platelets are involved in neutrophil recruitment in AP.After challenge with taurocholate there was a 6-fold increase in the plasma levels of CXCL4 (figure 1). Sham animals showed low but detectable plasma levels. Figure 1. Levels of CXCL4 in plasma in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an antiCXCL4 Ab, Anti-GP1ba, and the CXCR2 antagonist SB225002. The same elevation of CXCL4 was seen in the plasma of human patients both with mild and sever AP, compared with healthy controls (Figure 2). Figure 2. CXCL4 levels in patients with AP. Plasma was drawn at admission and 24 h after admission from patients with mild and severe AP. Plasma levels of CXCL4 were determined by use of ELISA. Healthy individuals served as controlsWhen the antibody anti-GP1bα was given prior to induction of AP, an 85 % depletion of platelets was observed, combined with a reduction of CXCL4 to levels in parity with sham animals (Figure 1). This strongly indicates that platelets are the main source of CXCL4 in AP. Also, when an anti-CXCL4 antibody was given before Taurocholate was infused, the plasma levels of CXCL4 decreased significantly, something that was not observed when a control antibody was administrated instead. Furthermore, a 4-fold increase of CXCL4 was seen in the inflamed pancreas after challenge with taurocholate, but when platelets were depleted, a significant decrease in the pancreatic levels of CXCL4 was observed (Figure3). A corresponding decrease was seen when CXCL4 was reduced through immunoneutralization (Figure 3).Figure 3. Levels of CXCL4 in pancreas in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an antiCXCL4 Ab, Anti-GP1bα, and the CXCR2 antagonist SB225002..Another finding was that induction of AP dramatically increased the plasma levels of Il-6, an important marker of systemic inflammation ADDIN EN.CITE <EndNote><Cite><Author>Damas</Author><Year>1992</Year><RecNum>432</RecNum><DisplayText>(396)</DisplayText><record><rec-number>432</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1584140963">432</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Damas, P.</author><author>Ledoux, D.</author><author>Nys, M.</author><author>Vrindts, Y.</author><author>De Groote, D.</author><author>Franchimont, P.</author><author>Lamy, M.</author></authors></contributors><auth-address>Department of Anesthesiology, University of Liege, Belgium.</auth-address><titles><title>Cytokine serum level during severe sepsis in human IL-6 as a marker of severity</title><secondary-title>Ann Surg</secondary-title></titles><periodical><full-title>Ann Surg</full-title></periodical><pages>356-62</pages><volume>215</volume><number>4</number><edition>1992/04/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Bacteremia/*blood</keyword><keyword>C-Reactive Protein/analysis</keyword><keyword>Cause of Death</keyword><keyword>*Critical Illness</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Interleukin-1/*analysis</keyword><keyword>Interleukin-6/*analysis</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Severity of Illness Index</keyword><keyword>Shock/blood</keyword><keyword>Shock, Septic/*blood</keyword><keyword>Survival Rate</keyword><keyword>Tumor Necrosis Factor-alpha/*analysis</keyword></keywords><dates><year>1992</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0003-4932 (Print)&#xD;0003-4932 (Linking)</isbn><accession-num>1558416</accession-num><urls><related-urls><url>;(396). If antibodies against platelets (anti-GP1bα) or CXCL4 were given aforehand, no such increase of plasma Il-6 was observed (figure 4)Figure 4. Levels of Il-6 in plasma in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an antiCXCL4 Ab, Anti-GP1bα, and the CXCR2 antagonist SB225002 mean.When AP was induced by retrograde infusion of taurocholate a 7-fold increase in plasma amylase levels were noted. However, when an antibody against CXCL 4 was given before induction of AP the elevation of plasma amylase was 44 % lower (figure 5). This decrease in amylase was not observed if a control antibody was given instead. Figure 5. Levels of Amylas in blood in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an anti-CXCL4 Ab, Anti-GP1bα, and the CXCR2 antagonist SB225002.Changes in the histology of the pancreas were correlated to elevation of plasma amylase, where sham mice had normal microarchitecture, whereas challenge with taurocholate induced significant destruction of the morphology, typified by haemorrhage, oedema, acinar cell necrosis and neutrophil accumulation. When depletion of platelets or immunoneutralization of CXCL4 were performed, more moderate alternations of the morphology was observed as could be noted in figures 6. The same patterns concerning plasma amylase and histology, together with increased recruitment of neutrophils in both pancreas and lung, was also demonstrated if AP was induced with another model using L-arginine instead of taurocholate,736600AABCADAAABCADAFigure 6. (A) edema (B) hemorrhage (C) acinar necrosis, and (D) extravascular leukocytes in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an anti-CXCL4 Ab, and AntiGP1bαNext the role of CXCL4 concerning neutrophil infiltration in AP was examined. As an indicator of infiltration of neutrophils, MPO levels were measured, and taurocholate challenge rendered a 4-fold increase in pancreatic MPO. Pre-treatment with the anti-CXCL4 antibody decreased the taurocholate-induced MPO levels with 77%. A similar reduction in MPO was also seen when the platelets were depleted (Figure 7A).Figure 7A. MPO activity in the pancreas in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an anti-CXCL4 Ab, Anti-GP1bα, and the CXCR2 antagonist SB225002.MPO was also measured in lungs as an indicator of systemic response to severe AP, and indeed, retrograde infusion of taurocholate generated a significant elevation of lung MPO. The increase in MPO activity was markedly reduced when platelets or CXCL 4 were eliminated, all in accordance with earlier studies ADDIN EN.CITE <EndNote><Cite><Author>Abdulla</Author><Year>2011</Year><RecNum>391</RecNum><DisplayText>(294)</DisplayText><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583078179">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdulla, A.</author><author>Awla, D.</author><author>Hartman, H.</author><author>Rahman, M.</author><author>Jeppsson, B.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Section for Surgery, Malmo University Hospital, Lund University, S-205 02 Malmo, Sweden.</auth-address><titles><title>Role of platelets in experimental acute pancreatitis</title><secondary-title>Br J Surg</secondary-title></titles><periodical><full-title>Br J Surg</full-title></periodical><pages>93-103</pages><volume>98</volume><number>1</number><edition>2010/10/01</edition><keywords><keyword>Amylases/blood</keyword><keyword>Animals</keyword><keyword>Antibodies/blood</keyword><keyword>Arginine/adverse effects</keyword><keyword>Blood Platelets/*physiology</keyword><keyword>Ceruletide/adverse effects</keyword><keyword>Chemokine CXCL2/biosynthesis/metabolism</keyword><keyword>Flow Cytometry</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Activation/physiology</keyword><keyword>Pancreatitis/*blood/chemically induced/pathology</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Platelet Aggregation/physiology</keyword><keyword>Platelet Glycoprotein GPIb-IX Complex/immunology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1365-2168 (Electronic)&#xD;0007-1323 (Linking)</isbn><accession-num>20882560</accession-num><urls><related-urls><url>;(294) (Figure 7B).Figure 7B. MPO activity in the lung in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an anti-CXCL4 Ab, Anti-GP1bα, and the CXCR2 antagonist SB225002.In order to check the activation of peripheral neutrophils in mice with AP, the expression of mac-1 was check with flowcytometry. Even though the expression of mac-1 was increased on circulating neutrophils in the animals with AP, no change in mac-1 expression was noticed when immunoneutralization of CXCL4 was performed (figure 8A)Figures 8A. Mac-1 expression on neutrophils in sham (saline) animals and taurocholate-exposed mice pretreated with saline or an anti-CXCL4 AbIn correspondence with this it was noted that in vitro incubation of isolated neutrophils with CXCL2 increased the expression of mac-1, whereas co-stimulation with CXCL4 did not (figure 8B).Figures 8B. Mac-1 expression on isolated neutrophils stimulated with CXCL2 and CXCL4.In vitro, CXCL2 was found to trigger a marked chemotactic effect on isolated neutrophils, whereas no effect induced by CXCL4 was seen on neutrophil migration (Figure 9A). In accordance with this notion, no effect on gene expression of CXCL4 was observed when acinar cells were incubated with cerulein, while on the contrary a marked increase in mRNA levels of CXCL2 was obvious (Figure 9B)AABAABFigure 9. (A) Neutrophil chemotaxis provoked by CXCL2 or different concentrations of CXCL4. (B) Gene expression of CXCL2 and CXCL4 in acinar cells stimulated with cerulein.To summarize, these observations indicate that even though CXCL4 patently triggers accumulation of neutrophils in the inflamed pancreas, this is due to some kind of indirect effect of CXCL4, and not a direct action on the neutrophils.When AP was induced a 5-fold increase in CXCL2 was seen in both plasma and pancreatic tissue, whereas it was low but detectable in sham mice. If CXCL4 was immunoblocked prior challenge with taurocholate the plasma levels of CXCL2 was reduced with 40% and pancreatic CXCL2 with 80%. A correlative pattern was noticed if an antibody towards platelets was given before induction of AP (figures10A and 10B).AABAABFigures 10. CXCL2 levels in the (A) pancreas and (B) plasma in sham (saline) animals and taurocholate-exposed mice pretreated with saline, control antibody (Ab), an anti-CXCL4 Ab, Anti-GP1bα, and the CXCR2 antagonist SB225002Taken together this indicate that the indirect CXCL4-effect of neutrophil recruitment in AP in some way is related to CXCL2 formation, since it, as mentioned above, triggered a massive neutrophil migration. In order to examine this, the CXCL2 receptor CXCR2 was targeted by the specific antagonist SB225002, which resulted in reduced Il-6 levels (Figure 4), lower amylase levels (Figure 5) and less neutrophil recruitment to both pancreas (Figure7A) and lung (Figure 7B), indicated by lower MPO levels. However, it did not influence the levels of CXCL4 in neither plasma nor pancreas in mice with AP (Figures 4 and 5).The fact that platelets play a role in AP through its impact on neutrophil recruitment and activation is a well-established notion ADDIN EN.CITE <EndNote><Cite><Author>Abdulla</Author><Year>2011</Year><RecNum>386</RecNum><DisplayText>(294)</DisplayText><record><rec-number>386</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583075280">386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abdulla, A.</author><author>Awla, D.</author><author>Hartman, H.</author><author>Rahman, M.</author><author>Jeppsson, B.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Section for Surgery, Malmo University Hospital, Lund University, S-205 02 Malmo, Sweden.</auth-address><titles><title>Role of platelets in experimental acute pancreatitis</title><secondary-title>Br J Surg</secondary-title></titles><periodical><full-title>Br J Surg</full-title></periodical><pages>93-103</pages><volume>98</volume><number>1</number><edition>2010/10/01</edition><keywords><keyword>Amylases/blood</keyword><keyword>Animals</keyword><keyword>Antibodies/blood</keyword><keyword>Arginine/adverse effects</keyword><keyword>Blood Platelets/*physiology</keyword><keyword>Ceruletide/adverse effects</keyword><keyword>Chemokine CXCL2/biosynthesis/metabolism</keyword><keyword>Flow Cytometry</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Neutrophil Activation/physiology</keyword><keyword>Pancreatitis/*blood/chemically induced/pathology</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Platelet Aggregation/physiology</keyword><keyword>Platelet Glycoprotein GPIb-IX Complex/immunology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1365-2168 (Electronic)&#xD;0007-1323 (Linking)</isbn><accession-num>20882560</accession-num><urls><related-urls><url>;(294). For instance it has been demonstrated that, platelet-derived P-selectin regulate neutrophil activation in AP, but also activation and tissue recruitment of neutrophils in the lung and thus systemic inflammation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJ0bWFuPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA (398). In line with these findings it was also noted that taurocholate infusion generated elevated levels of CXCL 4, but if the animals were immune-depleted of platelets, the plasma levels and also the pancreatic tissue levels of CXCL 4 was greatly reduced. This finding thus indicates that the main source of CXCL 4 must be the platelets. Since pancreatic mice that had their CXCL 4 immunoneutralized, showed much less microscopic tissue damage, and lower blood amylase levels, the role of CXCL 4 and hence platelets in the development of AP was further underlined. On top of this, Il-6, a cytokine identified as a key link between local and systemic inflammation was markedly elevated in AP. If, however the animals were depleted of platelets or CXCL 4, the plasma levels of Il-6 significantly decreased, indicating that CXCL 4 from the platelets acts as a potent inducer of systemic inflammation in AP.Since the accumulation of neutrophils in the tissues are the rate-limiting step in regulating the tissue damage in AP, and MPO levels are used to measure just the neutrophil infiltration, it was not surprising that challenging the pancreas with taurocholate elevated the number of neutrophils, but also the levels of MPO in the inflamed pancreatic tissue. Both these levels were however markedly decreased when CXCL 4 as well as Platelets were depleted, suggesting that CXCL 4 plays a specific role in the recruitment of neutrophils to the inflamed pancreas. Since this is such an important component of the pathophysiology of AP, this could help to explain why inhibition of CXCL 4 either direct via depletion or indirect through depletion of platelets, generates less tissue damage.The same pattern was noted in the lungs were the enhanced MPO activity that were produced by taurocholate were attenuated when CXCL 4 was neutralized. This confirms the previously stated notion that CXCL 4 regulates the systemic recruitment of neutrophils and hence the systemic inflammation itself.This raises the question, how comes that CXCL 4, that is not a potent activator of neutrophils itself, yet seems to be so important in the process of neutrophil accumulation? Neutrophil migration from the circulation to extracellular sites of inflammation is a multistep action, mediated by several substances, where mac-1 is one of the more important ADDIN EN.CITE <EndNote><Cite><Author>Asaduzzaman</Author><Year>2008</Year><RecNum>439</RecNum><DisplayText>(399)</DisplayText><record><rec-number>439</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1585174383">439</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Asaduzzaman, M.</author><author>Zhang, S.</author><author>Lavasani, S.</author><author>Wang, Y.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Surgery, Malmo University Hospital, Lund University, Malmo, Sweden.</auth-address><titles><title>LFA-1 and MAC-1 mediate pulmonary recruitment of neutrophils and tissue damage in abdominal sepsis</title><secondary-title>Shock</secondary-title></titles><periodical><full-title>Shock</full-title></periodical><pages>254-9</pages><volume>30</volume><number>3</number><edition>2008/01/17</edition><keywords><keyword>Animals</keyword><keyword>Chemokines/*metabolism</keyword><keyword>Edema/immunology</keyword><keyword>*Gene Expression Regulation</keyword><keyword>Humans</keyword><keyword>Leukocytes/microbiology</keyword><keyword>Lung/immunology/*metabolism</keyword><keyword>Lung Injury</keyword><keyword>Lymphocyte Function-Associated Antigen-1/*biosynthesis</keyword><keyword>Macrophage-1 Antigen/*biosynthesis</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Models, Biological</keyword><keyword>Neutrophils/immunology/*metabolism</keyword><keyword>Sepsis/*blood/metabolism</keyword></keywords><dates><year>2008</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1540-0514 (Electronic)&#xD;1073-2322 (Linking)</isbn><accession-num>18197144</accession-num><urls><related-urls><url>;(399). However, CXCL 4 turned out to have no effect on mac-1-expression in neutrophils of mice with AP. The same was also found on isolated neutrophils in vitro. Contrariwise to this, it was demonstrated that CXCL 2 highly up-regulated mac-1-expression in vitro. CXCL 2 was also found to exert a strong chemotactic effect on neutrophils in vitro, in opposition to CXCL 4 that did not promote any such effect. When CXCL 4 was depleted in animals with AP, both the plasma and pancreas levels of CXCL 2 were however markedly decreased. Taken together this suggest that the noted CXCL 4-induced recruitment of neutrophils to the pancreatic tissue in AP is not due to a direct action of CXCL 4 on neutrophils, but might be mediated via generation of CXCL 2 and thus upregulation of mac-1. The importance of CXCL 2 was further strengthened by the fact that blocking the main receptor of CXCL 2, namely CXCR 2, in animals challenged with taurocholate, gave rise to much lower levels of neutrophils within both the pancreas and the lungs, and also lower blood amylase levels and less tissue damage. However, since it was demonstrated that CXCL 4 not by itself upregulate CXCL 2 in isolated acinar cells, the cellular mechanisms behind the CXCL 4-induced secretion of CXCL 2 is still shrouded in darkness.Since the pathology of AP could be divided into two phases, namely, trypsinogen activation into trypsin, and neutrophil recruitment, it was important to rule out in which of these phases CXCL 4 perform its action. When isolated acinar cells were challenged with CXCL 4, no trypsinogen activation was noted, thus showing that CXCL 4 acts downstream of trypsin activation, strengthening the idea that CXCL 4 plays its role in the neutrophil accumulation.The observed findings were not dependent of taurocholate but could be verified in an alternative model for inducing AP, using i.p. L-arginine instead. In comparison, human patients with AP were also observed to have elevated levels of CXCL 4, but no difference was noted between patients that developed mild AP compared to the group that developed severe disease. CXCL 4 is thus not responsible for aggravation of the disease but is rather involved in a broad spectrum of disease activity in AP. Taken together these finding implies that targeting CXCL 4 could be a beneficial strategy when it comes to ameliorate the clinical course of all types of AP. Paper IIThe purpose of paper II was to examine whether NETs and microparticles are interplay in the pathophysiology of Ap. Furthermore, the intention was to study whether neutrophils and Platelets form complexes with each other in AP and if these complexes affect NETs formation. Finally, it was studied whether the enzyme IP6K1 that is derived from the platelets, somehow affects the above mention processes.With scanning electron microscopy formation of extracellular fibrillar, web-like structures in the pancreas compatible with NETs could be found after mice had been challenge with retrograde taurocholate infusion. Moreover, transmission immunoelectron microscopy showed that co-localized with these extracellular fibrillar and web-like structures were the neutrophil-derived granule proteins elastase, and histone 4, found. In the normal pancreas however no such findings were observed When platelets were depleted using the antibody directed against GP1ba a significant decreased in the taurocholate-induced NETs formation was noted in the inflamed pancreas. This effect was as expected, abolished when mice were pre-treated with DNase I.Furthermore, challenge with taurocholate enhanced plasma levels of DNA-histone complexes by 3-fold, whereas depletion of platelets in animals with AP, reduced DNA-histone complexes in plasma by 86% (Figure 1A). A similar pattern as in plasma was observed within the pancreas itself, were taurocholate infusion increased pancreatic levels of histone 3 and histone 4 by 3-fold and 4-fold, respectively. The levels of histone 3 and histone 4 in the inflamed pancreas were however greatly attenuated when platelets were depletion (Figures 1B-C). Figures 1. (A)Plasma levels of DNA-histone complexes, (B) pancreatic levels of histone 3 and (C) pancreatic levels of histone 4, after retrograde infusion of taurocholate or saline (sham) into the pancreatic duct. Mice were pre-treated with i.p. injection of PBS, DNase-1, a control antibody or an antibody against GP1bα (depletion of platelets).Furthermore, in scanning electron microscopy, it was found that taurocholate-induced NETs in the pancreas contained numerous round structures compatible with MPs, and transmission electron microscopy revealed that these MPs probably were of both platelet and neutrophil origin, since they expressed both CD41 or Mac-1 respectively (CD41 from platelets and mac-1 from neutrophils). Platelet depletion with an anti-GP1bα antibody, reduced tissue damage and also NETs formation in the inflamed pancreas. On the remaining NETs, decreased numbers of MPs was also seen. If DNase I was given to mice when AP was induced, formation of NETs was eliminated and consequently of the MP on the NETs as well. (Figure 2) Figure 2 Formation of NET-MP complexes, after retrograde infusion of taurocholate or saline (sham) into the pancreatic duct. Mice were pre-treated with i.p. injection of PBS, a control antibody, an anti-GP1bα antibody (depletion of platelets) or DNase-1Since formation of leukocyte-platelet aggregates (PNAs) is a common feature in many inflammatory conditions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWxhdDwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (283, 400) it was hypothesized that such complex formation also influence neutrophil activation and NETs formation in AP. Indeed, it was found that taurocholate-induced AP markedly increased formation of PNA in the circulation of mice (Figure 3). Furthermore, it was noted that immunoneutralization of P-selectin significantly reduced the taurocholate-induced formation of PNA (Figure 3), which lead to the assumption that the P-selectin-mediated contact between platelets and neutrophils could be of importance also for NETs formation. Figure 3. Aggregate data on platelet-neutrophil aggregates, after retrograde infusion of taurocholate or saline (sham) into the pancreatic duct. Mice were pre-treated with iv injection of a control antibody or an antibody against P-selectin. One notion was that thrombin stimulation of co-incubated platelets and neutrophils increased formation of DNA-histone complexes (Figure 4). In vitro it was also demonstrated that inhibition of P-selection abolished thrombin-induced formation of DNA-histone complexes under the same conditions, strengthening the idea that P-selectin-mediated contact between neutrophils and platelets plays a key role in this NETs formation (Figure 4). Figure 4 Formation of DNA- histone complexes. In vitro mixtures of neutrophils and platelets were stimulated with thrombin and treated with a control antibody or an anti-P-selectin antibody. PMA-stimulated neutrophils served as positive control.In vivo experiments further demonstrated that immunoneutralization of P-selectin in taurocholate-induced AP showed markedly reduced NETosis in the inflamed pancreas, alongside reduced plasma levels of DNA-histone complexes and also lower levels of histone 3 and histone 4 in the pancreas of these animals. As a consequence, less inflammation and tissue damage were observed in the pancreas of these pancreatic animals (Figures 5A-D). Figures 5. Histological quantification of (A) edema, (B) hemorrhage, (C) acinar cell necrosis and (D) leukocyte infiltration after retrograde infusion of Taurocholate or saline (sham) into the pancreas duct. Mice were pre-treated with i.p. injection of a control antibody or an antibody against P-selectinPMA stimulation of neutrophils triggered not only formation of NETs but these NETs also contained numerous MPs. Since such NET-MP complexes in other studies have been showed to regulate trypsin activation in acinar cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (346). When the cells were co-incubation with DNase I a complete reduction of NET-induced phosphorylation of STAT-3 was seen (Figure 7) Notably, co-incubation with caspase and calpain inhibitors (known to reduce MPs), decreased NET-induced STAT-3 phosphorylation by 44%, but had no effect on the levels of PMA-induced DNA-histone complex levels or NETs content of histone 4. Co-incubation of acinar cells only with neutrophil-derived MPs did not have any effect on neither amylase secretion nor STAT-3 phosphorylation (Figure 7). Figure 7. Aggregated data showing phosphorylated STAT-3 normalized to total STAT-3 in acinar cells stimulated with: NETs formed in presence of a vehicle, NETs depleted of microparticles (with a combination of caspase and calpain inhibitors), NETs formed in presence of DNase or microparticles derived from isolated neutrophils.This indicates that both NETs and MPs together in complex are involved in the STAT-3 phosphorylation and inflammatory response in AP, maybe through STAT-3 targeting genes for IL-6 and TGFβ1. As an indication of this notion being valid NETs challenge greatly enhanced acinar cell mRNA levels of IL-6 and TGFβ1, whereas co-incubation with DNase I or calpain and caspase inhibitors (i.e. neither NETs nor MPs respectively) significantly reduced NET-provoked gene expression of IL-6 and TGFβ1 in acinar cells. Incubation of acinar cells with MPs alone had no effect on mRNA levels of neither IL-6 nor TGFβ1.The platelet derived enzyme IP6K1 has been shown to regulate formation of PNA and theoretically thus indirectly regulate NETs and NETs-MP formation. Indeed, NETs formation, revealed by use of electron microscope was also markedly reduced in the pancreas of IP6K1-deficient mice exposed to taurocholate. In parallel with this, taurocholate challenge increased DNA histone complexes in plasma by more than 7-fold (Figure 8 A). Whereas plasma levels of DNA-histone complexes were decreased by 81% in animals lacking IP6K1 when triggered by taurocholate. The levels of histone 3 and histone 4 in the pancreas were enhanced 52-fold and 25-fold, respectively when challenged with taurocholate, whilst the levels were low in sham animals. In IP6K1 gene-deficient mice, the increases in histone 3 and histone 4 levels provoked by AP were respectively 97% and 87%, lower than in wild-type mice (Figures 8 B-C). No differences in the number of leukocyte subtypes or platelets was observed between wild-type and IP6K1-deficienct animals. Figures 8 A-C. (A) Plasma levels of DNA-histone complexes, (B) pancreatic levels of histone 3 and (C) Pancreatic levels of histone 4, after retrograde infusion of saline (sham) or taurocholate into the pancreatic duct of wild-type (WT) and IP6K1 gene-deficient (IP6K1-/-) miceChallenge with taurocholate enhanced the amylase level, which was assessed as an indicator of tissue damage in AP, nearly 21-fold. In IP6K1-deficient-animals taurocholate-induced increase in amylase was decreased by 65% (Figure 9A). The tissue levels of MPO in the pancreas were used as an indicator of neutrophil infiltration and taurocholate increased pancreatic MPO activity by 12-fold. In mice lacking IP6K1, taurocholate-provoked pancreatic levels of MPO were however decreased by 86% (Figure 9B). Taurocholate not only increased amylase-expression but also formation of the chemokine CXCL1, and in parity with amylase the levels of CXCL1 significantly lower in IP6K1 gene-deficient animals after AP was induced (Figure 9C). Figures 9 A-C. (A) Blood amylase levels, (B) pancreatic MPO levels and (C) pancreatic CXCL1 levels, after retrograde infusion of saline (sham) or taurocholate into the pancreatic duct of wild-type (WT) and IP6K1 gene-deficient (IP6K1-/-) miceWhen the histology of control animals was examined normal microarchitecture in pancreas tissue from found, whereas taurocholate challenge caused severe destruction of the pancreatic tissue structure characterized by extensive edema, acinar cell necrosis, hemorrhage in the interstitial tissue along with massive infiltration of neutrophils (Figures 10 A-D). This taurocholate-provoked destruction of the tissue architecture was not seen in IP6K1 knock-out mice, instead, compared with wild-type mice the edema, acinar cell necrosis, hemorrhage and leukocyte accumulation caused by taurocholate were reduced by 64%, 61%, 63% and 62%, respectively, in IP6K1-deficient mice (Figures 10A-D). Figure 10A-D. Histological quantification of (A) Edema, (B) Hemorrhage, (C) acinar cell necrosis and (D) leukocyte infiltration, after retrograde infusion of saline (sham) or taurocholate into the pancreatic duct of wild-type (WT) and IP6K1 gene-deficient (IP6K1-/-) miceFurthermore, activated neutrophils accumulate in the lung and MMP-9 and IL-6 levels increase in the circulation in severe AP as part of a systemic inflammatory response (Figures 11A-C). When IP6K1 knock-out mice were exposed to taurocholate, MPO levels in the lung was attenuated by 66% (Figure 11A), plasma levels of MMP-9 by 80% (Figure 11B) and IL-6 by 90% (Figure 11C) compared with wild-type. Figures 11A-C. (A)Lung levels of MPO, (B)Plasma levels of MMP-9 and plasma levels of IL-6, after retrograde infusion of saline (sham) or taurocholate into the pancreatic duct of wild-type (WT) and IP6K1 gene-deficient (IP6K1-/-) miceSimilar pattern as in the IP6K1 deficient mice, i.e. decreases NET formation, inflammation and tissue injury in AP, were seen when the IP6K1 inhibitor TNP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWRtYW5hYmhhbjwvQXV0aG9yPjxZZWFyPjIwMDk8L1ll

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ADDIN EN.CITE.DATA (401) was used. More specifically TNP treatment markedly generated less NETs in the inflamed pancreas after Taurocholate-challenge compared to untreated mice.In parallel administration of TNP in animals exposed to taurocholate were shown to reduce the levels of DNA-histone complex in the plasma by 63% and histone 3 and 4 levels in the pancreas by 68% and 67%, respectively, (Figures 12A-C). Figures 12A-C. (A)Plasma levels of DNA-histone complexes, (B) pancreatic histone 3 and (C) pancreatic levels of histone 4, after retrograde infusion of saline (sham) or taurocholate into the pancreatic duct. The animals were pre-treated with either vehicle (PBS) or TNP (an IP6K1 inhibitor).Furthermore, administration of TNP attenuated amylase by 48%, pancreatic MPO activity by 75% and CXCL1 levels by 67% in comparison with untreated mice with AP. Since the pattern so far is in line with the result seen in the IP6K1- deficient animals, hardly surprising, mice treated with TNP also exhibited less taurocholate-induced damage to the tissue of the inflamed pancreas, in terms of decreased edema, hemorrhage, acinar cell necrosis and leukocyte infiltration (Figures 13A-D).Figures 13 A-D. Histological quantification of (A) edema, (B) hemorrhage, (C) acinar cell necrosis and (D) leukocyte infiltration, after retrograde infusion of saline (sham) or taurocholate into the pancreatic duct. The animals were pre-treated with either vehicle (PBS) or TNP (an IP6K1 inhibitor).Since IP6K1 is known to regulate platelet homeostasis of polyphosphate formation (27) it was hypothesized that polyphosphates play a role in the formation of NETs. As expected, in the experiments it was first noted that reduction of IP6K1 led to lower number of polyphosphates in platelets.Furthermore, stimulation of platelets and neutrophils from wild-type mice together with thrombin resulted in significantly more DNA-histone complexes formation, in contrary to thrombin stimulation of IP6K1-deficient platelets co-incubated with wild-type neutrophils. Here a 59% reduction in DNA-histone complexes was observed. However, if, polyphosphate was added to the mixture of thrombin stimulated IP6K1-deficient platelets and wild-type neutrophils, formation of DNA-histone-complexes were restored, in a direct dose-dependent manner, further underlining that polyphosphates are involved in this process (Figure 14).Figures 14. DNA-histone complex formation (measured by ELISA). Wild type neutrophils were co-incubated with isolated wild-type or IP6K1-/- platelets together with or without Thrombin with or without PolyP (two different concentrations (10?M or 100?M)Stimulation of wild-type platelets and neutrophils with thrombin also resulted in the confocal microscope findings of expulsion of DNA co-localizing with MPO and citrullinated histone 3, well matching the picture of NETs formation. No such expulsion was seen when IP6K1-deficient platelets and wild-type neutrophils were stimulated with thrombin, but when polyphosphate was added to the mixture, NETs formation reoccurred. However, even if IP6K1 affect NETosis it is not an absolute necessity.Much of the same patterns were seen if AP was induced by i.p. injection of L-arginine, which was used as an alternative experimental model to taurocholate, in order to confirm the findings.In much the same way as when taurocholate was used, L-arginine exposure increased NET formation in the pancreas, plasma levels of DNA-histone complexes and pancreatic levels of citrullinated histone 3 formation, furthermore, L-arginine challenge increased blood amylase levels as well as pancreatic and plasma markers of inflammation. Blocking IP6K1 in animals exposed to L-arginine with TNP significantly decreased NET formation, as well as levels of blood amylase and levels of MPO and other pro-inflammatory compounds in the pancreas and plasma. Finally, administration of TNP attenuated the pathological microscopy-findings: edema, hemorrhage, acinar cell necrosis and leukocyte infiltration in the pancreas.The role of platelets in the pathophysiology of AP was thus further outlined in paper II since several mechanisms involving platelets were at play. Convincing evidence in the literature suggest that the formation of NETs is a process which is central in the development of AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJ6YTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (183, 402). Since it is a well establish fact, also pointed out in paper I, that platelets are involved in the recruitment of neutrophils PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYWhtYW48L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (183) and also of their own power cause epithelial damage ADDIN EN.CITE <EndNote><Cite><Author>Saffarzadeh</Author><Year>2012</Year><RecNum>443</RecNum><DisplayText>(405)</DisplayText><record><rec-number>443</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1585260831">443</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Saffarzadeh, M.</author><author>Juenemann, C.</author><author>Queisser, M. A.</author><author>Lochnit, G.</author><author>Barreto, G.</author><author>Galuska, S. P.</author><author>Lohmeyer, J.</author><author>Preissner, K. T.</author></authors></contributors><auth-address>School of Medicine, Institute of Biochemistry, Justus-Liebig-University, Giessen, Germany.</auth-address><titles><title>Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e32366</pages><volume>7</volume><number>2</number><edition>2012/03/06</edition><keywords><keyword>Animals</keyword><keyword>Bronchoalveolar Lavage Fluid</keyword><keyword>Cell Death/drug effects/physiology</keyword><keyword>Cell Line, Tumor</keyword><keyword>Cells, Cultured</keyword><keyword>Endothelial Cells/*cytology/drug effects</keyword><keyword>Epithelial Cells/*cytology/drug effects</keyword><keyword>Histones/*metabolism/pharmacology</keyword><keyword>Humans</keyword><keyword>Leukocyte Elastase/chemistry/pharmacology</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Microscopy, Fluorescence</keyword><keyword>Neutrophils/chemistry/*metabolism</keyword></keywords><dates><year>2012</year></dates><isbn>1932-6203 (Electronic)&#xD;1932-6203 (Linking)</isbn><accession-num>22389696</accession-num><urls><related-urls><url>;(405), elevated amount of histones must be considered harmful, and consequently a reduction is something desirable. The precise trail by which platelets exert its action in the NETosis of AP is still elusive, but since TLR 4 have been reported to be involved in platelet induced NETs formation in conjunction with endotoxemia, and also as a key player in neutrophil recruitment of AP, it is rather possible, that TLR 4 is involved also in the platelet mediated NETosis of AP. This is however still just theories, and must be proven in future studies.In the concept of NETs, another important phenomenon is the fact that NETs could interact with MPs and form so called NET-MP complexes, which are known to be of importance for thrombin generation in sepsis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (257). In paper II, it was found that there were indeed increased numbers of NET-MP complexes in the inflamed pancreas after AP had been induced, and also that the amount was diminished if platelets were depleted. The MPs in these complexes could be derived as to be of both neutrophil and platelet origin. It turned out that the NET-MP complexes were much more potent then NETs alone, depleted of MPs, when it came to elevating blood amylase levels or the gene expression of Il-6, alongside with STAT-3 phosphorylation and expression of TGFβ1. Since neither the amount of NETs nor the content of histones on the NETs were diminished, but only the MPs, this indicates that the formation of NET-MP complexes is of importance in the pathophysiology of AP, in that it seems that the NETs function as a scaffold on which the MPs could be assembled. Since the MPs on the NETs expelled from activated neutrophils came from both neutrophils and platelets, together with the fact that neutrophils and platelets them self are known to form complexes with one another in many inflammatory conditions such as abdominal sepsis ADDIN EN.CITE <EndNote><Cite><Author>Salat</Author><Year>1999</Year><RecNum>382</RecNum><DisplayText>(283)</DisplayText><record><rec-number>382</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583074365">382</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Salat, A.</author><author>Bodingbauer, G.</author><author>Boehm, D.</author><author>Murabito, M.</author><author>Tochkow, E.</author><author>Sautner, T.</author><author>Mueller, M. R.</author><author>Fuegger, R.</author></authors></contributors><auth-address>Department of General Surgery, University of Vienna, Austria. andreas.salat@univie.ac.at</auth-address><titles><title>Changes of platelet surface antigens in patients suffering from abdominal septic shock</title><secondary-title>Thromb Res</secondary-title></titles><periodical><full-title>Thromb Res</full-title></periodical><pages>289-94</pages><volume>95</volume><number>6</number><edition>1999/10/20</edition><keywords><keyword>Antigens, CD/blood/immunology</keyword><keyword>Antigens, Human Platelet/*immunology</keyword><keyword>Blood Platelets/*immunology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Shock, Septic/blood/*immunology</keyword><keyword>Thrombocytopenia/immunology</keyword></keywords><dates><year>1999</year><pub-dates><date>Sep 15</date></pub-dates></dates><isbn>0049-3848 (Print)&#xD;0049-3848 (Linking)</isbn><accession-num>10527406</accession-num><urls><related-urls><url>(99)00046-8</electronic-resource-num></record></Cite></EndNote>(283), pulmonary infection ADDIN EN.CITE <EndNote><Cite><Author>Schaub</Author><Year>1981</Year><RecNum>433</RecNum><DisplayText>(400)</DisplayText><record><rec-number>433</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1584310188">433</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schaub, R. G.</author><author>Rawlings, C. A.</author><author>Keith, J. C., Jr.</author></authors></contributors><titles><title>Platelet adhesion and myointimal proliferation in canine pulmonary arteries</title><secondary-title>Am J Pathol</secondary-title></titles><periodical><full-title>Am J Pathol</full-title></periodical><pages>13-22</pages><volume>104</volume><number>1</number><edition>1981/07/01</edition><keywords><keyword>Animals</keyword><keyword>Cell Adhesion</keyword><keyword>Dirofilariasis/pathology</keyword><keyword>Dogs</keyword><keyword>Elastic Tissue/*pathology</keyword><keyword>Endothelium/ultrastructure</keyword><keyword>Leukocytes/ultrastructure</keyword><keyword>Muscle, Smooth/*pathology</keyword><keyword>*Platelet Adhesiveness</keyword><keyword>Pulmonary Artery/*pathology</keyword></keywords><dates><year>1981</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0002-9440 (Print)&#xD;0002-9440 (Linking)</isbn><accession-num>7258294</accession-num><urls><related-urls><url>;(400) and AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bd2xhPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (292). In paper II it was showed that this notion is valid also in AP. When AP was induced, the number of NET-MP complexes, histone 3 and histone 4 formation in the pancreas as well as generation of DNA-histone complexes in plasma were markedly reduced in mice lacking IP6K1. Furthermore, the MPO activity and the numbers of neutrophils in the pancreatic tissue was much lower in the IP6K1-deficient group after induction of AP compared to normal mice. This is important, since the extravasation of neutrophils constitutes the most rate-limiting step and also a direct presumption for the occurrence of NETosis. One observation that could be connected with the lower number of recruited neutrophils and hence reduced tissue damage in IP6K1 depleted animals, is that in this group there was an evident decline in the extensive production of the chemokine CXCL 1, a strong attractant of neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Bacon</Author><Year>1998</Year><RecNum>147</RecNum><DisplayText>(186)</DisplayText><record><rec-number>147</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580214133">147</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bacon, K. B.</author><author>Oppenheim, J. J.</author></authors></contributors><auth-address>Neurocrine Biosciences and NCI-FCRDC, Frederick, MD 21702, USA.</auth-address><titles><title>Chemokines in disease models and pathogenesis</title><secondary-title>Cytokine Growth Factor Rev</secondary-title></titles><periodical><full-title>Cytokine Growth Factor Rev</full-title></periodical><pages>167-73</pages><volume>9</volume><number>2</number><edition>1998/10/01</edition><keywords><keyword>Animals</keyword><keyword>Chemokines/antagonists &amp; inhibitors/*physiology</keyword><keyword>Chemotaxis</keyword><keyword>Disease Models, Animal</keyword><keyword>Hematopoiesis</keyword><keyword>Humans</keyword><keyword>Hypersensitivity/immunology</keyword><keyword>Infections/immunology</keyword><keyword>Nervous System/immunology</keyword><keyword>Sepsis/immunology</keyword><keyword>Signal Transduction</keyword><keyword>T-Lymphocytes, Helper-Inducer/immunology</keyword></keywords><dates><year>1998</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1359-6101 (Print)&#xD;1359-6101 (Linking)</isbn><accession-num>9754710</accession-num><urls><related-urls><url>(98)00005-7</electronic-resource-num></record></Cite></EndNote>(186), that was otherwise noted when AP was induced.Not only was the local inflammatory response in the pancreas itself more modest, but also the otherwise blustery systemic reactions normally observed in AP were more restrained in the IP6K1 deficient mice. This was measured in terms of MPO activity in the lungs, plasma levels of Il-6 and MMP 9. This indicates that IP6K1is a key regulator of not only local, but also systemic inflammation in AP. These findings, namely reduced NETosis, ameliorated local and systemic inflammation, were corroborated in experiments were IP6K1 was block with the specific inhibitor TPN. The same observations were also done when AP was induced via an alternative method.Obviously IP6K1 is a key player in the pathogenesis of AP, and since it was demonstrated that it is the IP6K1 originated from the platelets, not from the neutrophils that affected the development of the disease, some mechanism executed by IP6K1 in the platelets seems to be essential. One such tasks performed by IP6K1 in the platelets is the regulation of PolyPs ADDIN EN.CITE <EndNote><Cite><Author>Ghosh</Author><Year>2013</Year><RecNum>369</RecNum><DisplayText>(291)</DisplayText><record><rec-number>369</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1582842251">369</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ghosh, S.</author><author>Shukla, D.</author><author>Suman, K.</author><author>Lakshmi, B. J.</author><author>Manorama, R.</author><author>Kumar, S.</author><author>Bhandari, R.</author></authors></contributors><auth-address>Laboratory of Cell Signalling, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.</auth-address><titles><title>Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels</title><secondary-title>Blood</secondary-title></titles><periodical><full-title>Blood</full-title></periodical><pages>1478-86</pages><volume>122</volume><number>8</number><edition>2013/06/21</edition><keywords><keyword>Animals</keyword><keyword>Bleeding Time</keyword><keyword>Blood Coagulation</keyword><keyword>Blood Platelets/*metabolism</keyword><keyword>Hemostasis</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>P-Selectin/metabolism</keyword><keyword>Phosphotransferases (Phosphate Group Acceptor)/*physiology</keyword><keyword>Phytic Acid/metabolism</keyword><keyword>Polyphosphates/*metabolism</keyword><keyword>Pulmonary Embolism/metabolism</keyword><keyword>Thrombin/metabolism</keyword><keyword>Thromboembolism/blood</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug 22</date></pub-dates></dates><isbn>1528-0020 (Electronic)&#xD;0006-4971 (Linking)</isbn><accession-num>23782934</accession-num><urls><related-urls><url>;(291), which by themself have a pro-inflammatory potential in that it could activate the kallikrein–kinin (26) and complement systems (40). In paper II it was however for the first time showed, that IP6K1 beside these other mechanisms, also, acts as a regulator of PolyPs from the platelets, directly promoted generation of NETs, and hence plays a major role in the development of AP. This is probably not limited to just AP but could be valid in a lot of other inflammatory conditions as well. It must be stated that since IP6K1 is pleiotropic in its effects on inflammation these findings do not exclude other mechanisms operating in parallel to just platelet mediated NETosis in AP. On such possible pathway could be the coagulation system in which IP6K1 is known to promote generation of bradykinin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWxsZXI8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (290), that is also by itself, a powerful activator of neutrophils. Since both inflammation and coagulation are at play in AP it could be very beneficial to concomitantly target both these systems. Here could IP6K1 be a key player.Taken together, Paper II showed that; NET-MP complexes are more potent than NETs alone when it comes to generate a more extensive inflammatory response in AP. Furthermore, the important role of platelets in generation of NETs and also in the process of NET-MP formation in AP was pointed out for the first time. It was also demonstrated that IP6K1 generated from the platelets exerts a major role in the regulation of NETosis and formation of NET-MP complexes in AP, possibly via its influence on the homeostasis of PolyPs. To summarize, targeting IP6K1 could be a useful strategy to attenuate both local and systemic inflammation in AP.Paper IIIThe purpose with paper III was to examine whether the protein eCIRP plays any role in NETosis in AP.Challenge with taurocholate increased the plasma levels of eCIRP to a 5-fold from the low baseline levels of eCIRP seen in healthy mice. Pretreatment with the eCIRP antagonist C23 decreased the levels of eCIRP in the plasma of animals with pancreatitis by 77%. Administration of C23 alone on the other hand had no effect on eCIRP levels in sham animals (Figure 1). Figure 1. Plasma levels of eCIRP, after injection of saline (sham) or Taurocholate. Mice were treated with PBS (vehicle) or C23 before induction of AP. A similar pattern was found in human patients that that were admitted to hospital with AP, were plasma levels of eCIRP was significantly increased in patients with both moderate or severe AP compared with healthy controls (Figure 2).Figure 2. Plasma levels of eCIRP in patients with AP. Plasma was drawn at 24–48 h after admission. Induction of pancreatitis with taurocholate increased plasma levels of DNA-histone complexes by 6-fold (Figure 3A). In the pancreatic tissue, levels of citrullinated histone 3 increased by more than 15-fold in mice exposed to taurocholate (Figures 3A-B), indicating that severe AP is associated with increased generation of NETs. When C23 was given prior to infusion of taurocholate, levels of citrullinated histone 3 were reduced in the pancreas by 82%. In the plasma the levels of DNA-histone complexes were lowered by 65%. This indicates that targeting eCIRP decreases NET generation in the inflamed pancreas (Figures 3A-B). This notion was further confirmed by electron microscope findings; where increased generation of extracellular fibrillar and web-like structures that co-localized with neutrophil-derived granule protein elastase as well as with citrullinated histone 3 (Figure 3B) was seen after infusion of taurocholate. These findings are all compatible with NETs formation, indicating that the AP was associated with increased generation of NETs. Notably, if the eCIRP antagonist C23 was given, the taurocholate-provoked formation of NETs was markedly reduced in the pancreas (Figure 3A). Injection of C23 alone on the other hand did not have any impact on the formation of NETs in the healthy pancreas Figure 3. (A) DNA-histone complexes (B) aggregate data showing H3cit protein normalized to total protein, after injection of saline (sham) or Taurocholate. Mice were treated with PBS (vehicle) or C23 before induction of AP. Retrograde infusion of taurocholate in the pancreatic duct increased blood levels of amylase by 8-fold compare with controls (Figure 4). Treatment with C23 generated a 58% reduction of blood amylase levels in taurocholate-induced animals, (Figure 4) whereas administration of C23 alone did not influence the blood levels of amylase in healthy mice at all (Figure 4).Figure 4. Quantitative measurements of blood amylase levels after injection of saline (sham) or Taurocholate. Mice were treated with PBS (vehicle) or C23 before induction of APHistological examination revealed that taurocholate infusion triggered destruction of the pancreatic tissue microarchitecture typified by acinar cell necrosis, hemorrhage, edema formation and leukocyte infiltration (Figures 5). When C23 was given prior induction of AP the taurocholate-provoked tissue injury (Figures 5) was substantially decreased. When the tissue damage in the inflamed pancreas was quantified, treatment with C23 decreased edema by 60%, acinar cell injury by 56%, hemorrhage by 64% and neutrophil infiltration by 67%, all and all a markedly ameliorated situation.Figure 5. (A) edema, (B) acinar cell necrosis, (C) hemorrhage, and (D) leukocyte infiltration, after injection of saline (sham) or Taurocholate. Mice were treated with PBS (vehicle) or C23 before induction of AP As an indicator of infiltration of neutrophils, MPO levels were measured, and it was noted that retrograde infusion of taurocholate increased the level of MPO in the pancreas by 14-fold (Figure 6A). Pre-treatment with C23 rendered a reduction by 70% of taurocholate-provoked activity of MPO in the pancreatic tissue (Fig. 6A). This is well in correspondence with the observed C23-performed reduction on the number of neutrophils in the inflamed pancreas by 67% (Figure 5D). Furthermore, increased pancreatic levels of both CXCL1 and CXCL2 respectively was seen when AP was induced. A3dministration of C23 however decreased the pancreatic levels of CXCL1 by 80% (fig 6B) and CXCL2 by 84% (Figure 6C). When C23 alone, without any induction of pancreatitis, was given, no impact on pancreatic levels of neither MPO, CXCL1 nor CXCL2 (Figures 5A-C) were observed in the healthy animals.Figures 6. Neutrophil recruitment and chemokines in the inflamed pancreas. Pancreatic levels of (A) MPO, (B) CXCL1, and (C) CXCL2Lung levels of MPO was measured to evaluate the pulmonary accumulation of neutrophils, and hence the degree of systemic inflammatory response in severe AP. It was observed that infusion of taurocholate enhanced lung levels of MPO by 11-fold, but if the animals were pre- treated with C23 MPO activity in the lung was reduced by 62% (Figure 7). Figure 7. Pulmonary levels of MPO after injection of saline (sham) or Taurocholate. Mice were treated with PBS (vehicle) or C23 before induction of APMoreover, taurocholate infusion generated a 5-fold increase in CXCL2, a 2.5-fold elevation of MMP-9 levels and 2.4-fold rise in IL-6 levels in the plasma. However, the plasma levels of CXCL2, MMP-9 and IL-6 decreased by 82%, 67% and 63%, respectively in pancreatitis animals treated with C23 (Figures 8 A-C). Figure 8. Plasma levels of (A) CXCL2, (B) MMP-9, (C) IL-6 after injection of saline (sham) or Taurocholate. Mice were treated with PBS (vehicle) or C23 before induction of APFurthermore, by use of scanning and transmission electron microscopy, formation of NETs containing significant levels of eCIRP was found when neutrophils were stimulated with PMA (Figure 9A). In line with the knowledge that eCIRP perform its actions by binding to the TLR4-MD2 complex, it was found that when the expressed TLR-4 of isolated acinar cells were stimulated with NETs, amylase secretion increased by 3.5-fold, and that co-incubation with C23 significantly reduced NET-induced secretion of amylase from acinar cells (Figures 9B-C).Figure 9. (A) Aggregate data on NET formation from PMA-stimulated bone marrow neutrophils in the presence or absence of an anti-CIRP antibody. (B) Flow cytometry showing the expression of TLR-4 in isolated acinar cells. (C) Amylase secretion by acinar cells- The cells were coincubation with NETs in the presence of vehicle or C23To conclude, paper III focused on the nuclear protein CIRP (cold-inducible RNA-binding protein) that is released from the nucleus as a response to stress, and, in the intracellular milieu promotes many stress coping strategies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaG9uZzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (378). However, if the stressful situation continues and the CIRP is released in a superfluous manner, the CIRP will be expressed extracellular as eCIRP and here act as a DAMP ADDIN EN.CITE <EndNote><Cite><Author>Aziz</Author><Year>2019</Year><RecNum>278</RecNum><DisplayText>(379)</DisplayText><record><rec-number>278</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581616476">278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aziz, M.</author><author>Brenner, M.</author><author>Wang, P.</author></authors></contributors><auth-address>Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA.&#xD;Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA.</auth-address><titles><title>Extracellular CIRP (eCIRP) and inflammation</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>133-146</pages><volume>106</volume><number>1</number><edition>2019/01/16</edition><keywords><keyword>Ali</keyword><keyword>Cirp</keyword><keyword>Damp</keyword><keyword>eCIRP</keyword><keyword>hemorrhage</keyword><keyword>inflammation</keyword><keyword>ischemia/reperfusion</keyword><keyword>macrophage</keyword><keyword>neutrophils</keyword><keyword>sepsis</keyword></keywords><dates><year>2019</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>30645013</accession-num><urls><related-urls><url>;(379). This have been noticed to be the case in AP, were it found that levels of CIRP to correlates to the grade of severity of AP ADDIN EN.CITE <EndNote><Cite><Author>Gong</Author><Year>2017</Year><RecNum>445</RecNum><DisplayText>(406)</DisplayText><record><rec-number>445</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1585651340">445</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gong, J. D.</author><author>Qi, X. F.</author><author>Zhang, Y.</author><author>Li, H. L.</author></authors></contributors><auth-address>Department of Gastroenterology, The Yinzhou People&apos;s Hospital, 251 Baizhang East Road, Ningbo 315040, China.&#xD;Department of Gastroenterology, The Yinzhou People&apos;s Hospital, 251 Baizhang East Road, Ningbo 315040, China. Electronic address: pengzhao2009@.</auth-address><titles><title>Increased admission serum cold-inducible RNA-binding protein concentration is associated with prognosis of severe acute pancreatitis</title><secondary-title>Clin Chim Acta</secondary-title></titles><periodical><full-title>Clin Chim Acta</full-title></periodical><pages>135-142</pages><volume>471</volume><edition>2017/06/08</edition><keywords><keyword>Acute Disease</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/blood/*diagnosis</keyword><keyword>Prospective Studies</keyword><keyword>RNA-Binding Proteins/*blood</keyword><keyword>Biomarker</keyword><keyword>Cold-inducible RNA-binding protein</keyword><keyword>Prognosis</keyword><keyword>Severe acute pancreatitis</keyword><keyword>Severity</keyword></keywords><dates><year>2017</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1873-3492 (Electronic)&#xD;0009-8981 (Linking)</isbn><accession-num>28587954</accession-num><urls><related-urls><url>;(406), the same pattern was noticed in our animal model when mice were challenged with taurocholate. The oligopeptide C23 that is derived from CIRP has the ability to preclude the function of eCIRP by blocking the TLR4/MD2complex PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5RaWFuZzwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (380), and since NETosis is a key event in the pathogenesis of AP, it was hypothesized that eCIRP would increase generation of NETs also in AP. Indeed, retrograde infusion of taurocholate generated a marked increase in two commonly used surrogate markers of NET formation, namely DNA-histone complex in the plasma and citrullinated histone 3 in the pancreas. These indicators of NETosis were both decreases when eCIRP was blocked by administration of C23. This notion was further underlined by use of electron microscopy where neutrophil extrusion of DNA structures containing neutrophil-derived granule protein elastase and citrullinated histone 3 were increased in AP but markedly decreased after C23 was given. This all together suggests that eCIRP is involved in controlling the generation of NETs in AP. When the effect eCIRP had on tissue damage in the pancreas was further studied, findings in parallel with the above mentioned was noted, with markedly attenuated plasma levels of amylase and a more preserved microarchitecture in the pancreas if C23 was given prior to induction of AP. This notion constitutes the first evidence in the literature indicating that eCIRP plays a role in the development of AP.Since eCIRP and NETs obviously are interconnected, in part by the fact that eCIRP controls NETosis, but also by the fact they are released by the same stressors, such as LPS, it was interested to note that they also physically interact. When NETs were induced by stimulation with PMA, it was noted that the NETs formed, was scattered with eCIRP, thus adding eCIRP to the list of NETs-associated proteins such as different histone types and HMBG1. This, further strengthened the link between eCIRP and NETs. In the same context it was noted that NETs depleted of eCIRP to a much lower extent induced secretion of amylase from activated isolated acinar cells compared to NETs not depleted of eCIRP. This suggests that NET-associated eCIRP is involved in the proteolytic activation of the inflamed pancreas.Since it is already known that MMP-9 derived from neutrophils holds the ability to activate trypsinogen into trypsin and hence contribute to the development of AP ADDIN EN.CITE <EndNote><Cite><Author>Awla</Author><Year>2012</Year><RecNum>109</RecNum><DisplayText>(111)</DisplayText><record><rec-number>109</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1579883910">109</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Awla, D.</author><author>Abdulla, A.</author><author>Syk, I.</author><author>Jeppsson, B.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Section for Surgery, Lund University, S-205 02 Malmo, Sweden.</auth-address><titles><title>Neutrophil-derived matrix metalloproteinase-9 is a potent activator of trypsinogen in acinar cells in acute pancreatitis</title><secondary-title>J Leukoc Biol</secondary-title></titles><periodical><full-title>J Leukoc Biol</full-title></periodical><pages>711-9</pages><volume>91</volume><number>5</number><edition>2011/11/22</edition><keywords><keyword>Acinar Cells/drug effects/*metabolism/*pathology</keyword><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Blotting, Western</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Flow Cytometry</keyword><keyword>Matrix Metalloproteinase 9/*physiology</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Knockout</keyword><keyword>Neutrophils/*enzymology</keyword><keyword>Pancreatitis/drug therapy/*metabolism/*pathology</keyword><keyword>Peroxidase/metabolism</keyword><keyword>Taurocholic Acid/pharmacology</keyword><keyword>Trypsinogen/*metabolism</keyword></keywords><dates><year>2012</year><pub-dates><date>May</date></pub-dates></dates><isbn>1938-3673 (Electronic)&#xD;0741-5400 (Linking)</isbn><accession-num>22100390</accession-num><urls><related-urls><url>;(111). It was interesting to note that markedly reduced levels of MMP-9 were seen when C23 was administrated before the introduction of AP, hence giving yet another possible explanation to why blocking eCIRP would lead to less tissue damage and a more ameliorated course of the disease.As have already been pointed repeatedly in this thesis extravascular recruitment of neutrophils into the pancreatic tissue constitutes the hallmark of inflammation and is considered to be the most rate limiting step ADDIN EN.CITE <EndNote><Cite><Author>Awla</Author><Year>2011</Year><RecNum>121</RecNum><DisplayText>(163)</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580116338">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Awla, D.</author><author>Abdulla, A.</author><author>Zhang, S.</author><author>Roller, J.</author><author>Menger, M. D.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Malmo, Section of Surgery, Skane University Hospital, Lund University, Malmo, Sweden.</auth-address><titles><title>Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis</title><secondary-title>Br J Pharmacol</secondary-title></titles><periodical><full-title>Br J Pharmacol</full-title></periodical><pages>413-23</pages><volume>163</volume><number>2</number><edition>2011/01/20</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Chemokines/metabolism</keyword><keyword>Lymphocyte Function-Associated Antigen-1/*physiology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Transgenic</keyword><keyword>*Neutrophil Infiltration</keyword><keyword>Pancreas/immunology/metabolism/pathology</keyword><keyword>Pancreatitis/chemically induced/*immunology/pathology</keyword><keyword>Taurocholic Acid</keyword></keywords><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1476-5381 (Electronic)&#xD;0007-1188 (Linking)</isbn><accession-num>21244370</accession-num><urls><related-urls><url>;(163). In the study it was noted that inhibition of eCIRP with C23 significantly reduced the otherwise, by taurocholate, elevated activity of MPO in the pancreas, indicating that eCIRP is a major regulator of neutrophil migration in the inflamed pancreas. Since this traffic to a large extent, as pointed out in paper I, is regulated by CXC chemokines such as CXCL 1 and CXCL 2, it was interesting to notice that challenge with taurocholate markedly increase the pancreatic levels of these chemokines, and that this elevation was significantly reduced if C23 was administrated. This finding suggests that eCIRP in some way are involved in the regulation of chemokine formation in the inflamed pancreas.The same pattern was also found in the context of systemic neutrophil infiltration, here defined as pulmonary MPO activity, were there was a clear-cut increase of MPO in the lungs after AP was induced, and that this increase was diminish by C23. This indicates that eCIRP also plays a role in the systemic inflammation seen in severe AP. In line with these findings were also the observation that C23 attenuated the plasma levels of one of the indicators of systemic inflammation, namely Il-6 after AP was induced. Since the amount of Il-6 directly correlates with mortality of severe AP patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (346), this further supports the notion that eCIRP is of importance in this development.There are, at least theoretically, a special feature of the mechanism by which C23 exert its function that could make it very interesting as a therapeutic strategy against AP. That is the fact that it seems to target a very specific eCIRP-binding site in the TLR4-MD2 receptor complex. This means that C23 will block eCIRP, but not other agonists of TLR4 such as bacterial components and thus C23 will not hamper desired and adequate anti-microbial responses. This is research that is still in its cradle, but it has been showed that C23 does not inhibit LPS- induced secretion of TNFα in macrophages, and also observations have been made that C23 binds to a special pocket of MD2 that is not a site for binding of LPS. If this turns out to be correct (these findings are not published yet), it means that C23 could block the eCIRP/TLR4-MD2 pathway, without interfering with host defense systems against infectious agents, thus constituting a very interesting way of targeting the development of AP. In conclusion, the results demonstrate that eCIRP regulates NETs formation, inflammation and tissue damage in AP. It also indicates that eCIRP promotes systemic inflammation in AP. Furthermore, it was found that eCIRP is a NETs-associated protein and that the eCIRP that is present on the NETs holds the ability to activate acinar cells. Finally, it was demonstrated that C23 is potent inhibitor of eCIRP and consequently of NETs-formation and inflammation in AP. Targeting eCIRP with inhibitors such as C23 might thus be an effective way to ameliorate both local and systemic inflammation in APPaper IVSince the importance of NETs in AP is evident and there are more and more data on interlinking between NETs and the complement cascade. The purpose with paper IV was to examine if C3, which long has been expected to be involved in the pathophysiology of AP, somehow affects the formation of NETs in APWhen taurocholate was infused into the pancreatic duct, it caused a 16-fold increase in the plasma levels of DNA-histone complexes. Resembling patterns were seen in the pancreas itself, were the DNA-histone complex however was reduced by 89% in the C3 knockout group (Figure 1).Figure 1. Plasma levels of DNA-histone complexes after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice.These notions were confirmed by experiments revealing that infusion of taurocholate increased generation of extracellular fibrillar, web-like structures co-localized with neutrophil-derived granule protein elastase and histone 3, in the inflamed pancreas, taken together the signs of NETs-presence. Notably, when the challenge with taurocholate was done on the C3 knock out mice, the formation of NETs in the pancreas was reduced by 84% (Figure 2). This indicates that C3 somehow plays a role in the generation of NETs in AP. Figure 2. Aggregate data on NET formation in the pancreas after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice. Retrograde infusion of taurocholate in the pancreatic duct increased blood levels of amylase by 12-fold. In the C3 -/- mice, the increase in taurocholate-induced blood amylase levels were significantly lower compared with the wild-type group, 454 ± 96 ?Kat/L compared to 188 ± 68 ?Kat/L, corresponding with a 65 % reduction. Injection of saline into the pancreatic duct did not cause any elevation in the levels of blood amylase in ether wild type or C3-/- mice (Figure 3). Figure 3. Levels of blood amylase after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice.Furthermore, taurocholate infusion caused destruction of the microarchitecture in the pancreas. This was typified in microscope by: acinar cell necrosis, hemorrhage, edema formation and leukocyte infiltration. When infusion of taurocholate was performed in the C3-/- mice, there was a substantial decrease in tissue injury (Figures 4A-D) compared with the wild type group. Quantification of tissue damage revealed that the C3-/-group had 51% less edema (Figure 4A), hemorrhage was reduced by 61% (Figure 4B), acinar cell injury by 52% (Figure 4C), and neutrophil infiltration was 58% lower (Figure 4D) in the inflamed pancreas compared to pancreatic tissue of wild type mice.Figure 4. Histological quantification of (A) edema, (B) hemorrhage, (C) acinar cell necrosis and (D) leukocyte infiltration, after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice.The MPO activity in the pancreas increased by 20-fold after infusion of taurocholate, in the C3 knock-out group however taurocholate-provoked activity of MPO in the pancreas was 74% lower (Figure 5). Figure 5. Quantitative measurements of pancreatic levels of MPO, after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice.This corresponds well with the observed reduction (by 70%) of neutrophils in the inflamed pancreas in the C3 knock-out mice. Additionally, challenge with taurocholate increased pancreatic levels of CXCL1 and CXCL2. The rise of the pancreatic levels of CXCL1 and CXCL2 in the C3 knock out mice were significantly lower 83% and 97%, respectively after induction of AP (Figures 6A-B). Figure 6. Quantitative measurements of pancreatic levels of (A) CXCL1 and (B) CXCL2, after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice.As can been seen in figure 5, 6A and 6B, administration of saline had no impact on levels of MPO, CXCL1 and CXCL2 in the healthy pancreas.Not only local pancreatic inflammation but also systemic inflammation was studied, and as a marker of a systemic inflammatory response in severe AP, accumulation of neutrophils in the lung was used. Here it was observed that infusion of taurocholate enhanced lung levels of MPO by 30-fold in wild type mice (Figure 7). When infusion of taurocholate was performed on the C3 knockout mice the lung levels of MPO was 77% lower compared with wild type (Figure 7). Figures 7. Levels of lung MPO, after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice.Moreover, taurocholate infusion increased CXCL2, MMP-9 and IL-6 levels in the plasma by 85-fold, 7-fold and 28-fold, respectively. Whereas lower elevations of the plasma levels of IL-6, MMP-9 and CXCL2 (92%, 83 % and 53%, respectively) were seen in the C3 -/-group compared with wild type, when pancreatitis were induced (Figures 8A-C). Figures 8. Plasma levels of (A) IL-6, (B) MMP-9 and (C) CXCL2, after infusion of sodium taurocholate or saline (sham) into the pancreatic duct in wild type and C3-deficient mice.So, in paper IV it was demonstrated, for the first time in the literature, something that has been suspected for long time, namely that C3 is directly involved in the pathophysiology of AP. We showed that C3 is contributing to neutrophil recruitment into the inflamed pancreas, and hence NETs formation and tissue damage, but also that it affects release of cytokines and chemokines and thus act as a promotor of systemic inflammation.The observation that complement components C3 and C4 are consumed in the plasma of patients with AP was made a long time ago ADDIN EN.CITE <EndNote><Cite><Author>Goldstein</Author><Year>1978</Year><RecNum>450</RecNum><DisplayText>(407)</DisplayText><record><rec-number>450</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599479065">450</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Goldstein, I. M.</author><author>Cala, D.</author><author>Radin, A.</author><author>Kaplan, H. B.</author><author>Horn, J.</author><author>Ranson, J.</author></authors></contributors><titles><title>Evidence of complement catabolism in acute pancreatitis</title><secondary-title>Am J Med Sci</secondary-title></titles><periodical><full-title>American Journal of the Medical Sciences</full-title><abbr-1>Am J Med Sci</abbr-1></periodical><pages>257-64</pages><volume>275</volume><number>3</number><edition>1978/05/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Amylases/blood</keyword><keyword>Complement System Proteins/*metabolism</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/blood/*immunology</keyword><keyword>alpha 1-Antitrypsin/blood</keyword><keyword>alpha-Macroglobulins/analysis</keyword></keywords><dates><year>1978</year><pub-dates><date>May-Jun</date></pub-dates></dates><isbn>0002-9629 (Print)&#xD;0002-9629 (Linking)</isbn><accession-num>80133</accession-num><urls><related-urls><url>;(407). In the same study it was also suggested that complements might play a role in some of the pathological systemic changes seen in AP. However, the general knowledge and laboratory techniques at the time did not allow further mapping of these mechanisms back then. In more recent times studies of patients with AP have showed that there are increased plasma levels of C3a and also that the severity of the disease were in correlation with this increase ADDIN EN.CITE <EndNote><Cite><Author>Gloor</Author><Year>2003</Year><RecNum>302</RecNum><DisplayText>(317)</DisplayText><record><rec-number>302</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581974219">302</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gloor, B.</author><author>Stahel, P. F.</author><author>Muller, C. A.</author><author>Schmidt, O. I.</author><author>Buchler, M. W.</author><author>Uhl, W.</author></authors></contributors><auth-address>Dept. of Visceral and Transplantation Surgery, University of Bern, Switzerland.</auth-address><titles><title>Predictive value of complement activation fragments C3a and sC5b-9 for development of severe disease in patients with acute pancreatitis</title><secondary-title>Scand J Gastroenterol</secondary-title></titles><periodical><full-title>Scand J Gastroenterol</full-title></periodical><pages>1078-82</pages><volume>38</volume><number>10</number><edition>2003/11/19</edition><keywords><keyword>Acute Disease</keyword><keyword>Complement C3a/*analysis</keyword><keyword>Complement Membrane Attack Complex/*analysis</keyword><keyword>Enzyme-Linked Immunosorbent Assay</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Pancreatitis/blood/*diagnosis/immunology</keyword><keyword>Predictive Value of Tests</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2003</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0036-5521 (Print)&#xD;0036-5521 (Linking)</isbn><accession-num>14621284</accession-num><urls><related-urls><url>;(317). This harmonize well with the old observations of complement consumption, since consumption of C3 will yield elevated levels of the fragments C3a (and C3b). Interestingly the same study also noted elevated plasma levels of the terminal complement complex (sC5b-9), connected with the same correlation with clinical severity of pancreatitis. This indicates that in AP the complement cascade is driven all the way to MAC-formation. The fact that trypsin could cleave complement C3 is also something that was demonstrated in the 70s ADDIN EN.CITE <EndNote><Cite><Author>Minta</Author><Year>1977</Year><RecNum>451</RecNum><DisplayText>(408)</DisplayText><record><rec-number>451</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599481644">451</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Minta, J. O.</author><author>Man, D.</author><author>Movat, H. Z.</author></authors></contributors><titles><title>Kinetic studies on the fragmentation of the third component of complement (C3) by trypsin</title><secondary-title>J Immunol</secondary-title></titles><periodical><full-title>J Immunol</full-title></periodical><pages>2192-8</pages><volume>118</volume><number>6</number><edition>1977/06/01</edition><keywords><keyword>Citrates/metabolism</keyword><keyword>Complement C3/analysis/*metabolism</keyword><keyword>Complement System Proteins/*metabolism</keyword><keyword>Electrophoresis, Polyacrylamide Gel</keyword><keyword>Humans</keyword><keyword>Immunoelectrophoresis</keyword><keyword>Kinetics</keyword><keyword>Time Factors</keyword><keyword>Trypsin/*pharmacology</keyword></keywords><dates><year>1977</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0022-1767 (Print)&#xD;0022-1767 (Linking)</isbn><accession-num>864257</accession-num><urls><related-urls><url>;(408), it is worth mentioning that in that study it was observed that C3 was much more susceptible to trypsin cleavage if pH was lowered. Taken together it is not farfetched to see a chain of events from preemptive trypsinogen activation into trypsin, that cleaves C3, thus yielding C3a (an anaphylatoxin) and C3b (an opsonin and part of C5 convertase), hence driving the cascade onwards cleaving C5 and thus generate C5a (an anaphylatoxin with strong chemoattractant properties to neutrophils), promoting neutrophil recruitment and thus NETs-formation, which will trigger further recruitment of neutrophils leading to inflammation both locally and systemically. These notions are in correlation with our findings that lack of C3 generated lower plasma levels of amylase and pancreatic MPO compare to wild type mice and also decrease in the plasma levels of the chemokines CXCL1 and CXCL2 which have been demonstrated to play a key role in neutrophil recruitment and hence the pathophysiology of AP PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (298, 342). Furthermore, the circulation plasma levels of Il-6, MMP-9 and CXCL2 was much lower in C3 deficient mice after induction of AP compared with wildtype. This indicate that C3 also are involved in regulating systemic inflammation in AP.The literature concerning complement C5 and AP is complex and somewhat contradictive. For instance, mice deficient of C5 developed less tissue edema in one study ADDIN EN.CITE <EndNote><Cite><Author>Merriam</Author><Year>1997</Year><RecNum>452</RecNum><DisplayText>(409)</DisplayText><record><rec-number>452</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599486648">452</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Merriam, L. T.</author><author>Webster, C.</author><author>Joehl, R. J.</author></authors></contributors><auth-address>Department of Surgery, Northwestern University Medical School, Chicago, Illinois, USA.</auth-address><titles><title>Complement component C5 deficiency reduces edema formation in murine ligation-induced acute pancreatitis</title><secondary-title>J Surg Res</secondary-title></titles><periodical><full-title>J Surg Res</full-title></periodical><pages>40-5</pages><volume>67</volume><number>1</number><edition>1997/01/01</edition><keywords><keyword>Amylases/blood</keyword><keyword>Animals</keyword><keyword>Complement C5/deficiency/*physiology</keyword><keyword>Disease Models, Animal</keyword><keyword>Edema/*etiology/pathology</keyword><keyword>Ligation</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Pancreatitis/*complications/etiology/pathology</keyword></keywords><dates><year>1997</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0022-4804 (Print)&#xD;0022-4804 (Linking)</isbn><accession-num>9070179</accession-num><urls><related-urls><url>;(409) whereas it generated more edema in another study PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaGF0aWE8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA (319). This might inhibit the damage mediated by neutrophils on the pancreas. In this way C5a will acts as a promotor of neutrophil-induced inflammation up to a certain point, after which C5a instead will hold anti-inflammatory abilities. This might explain the different findings.Whether complement fragments themselves could stimulate NETosis is a matter that is to a large extent still unknown. However, the fragment C5a has beyond its capacity as a powerful anaphylatoxin, been showed to directly stimulate NETs formation from neutrophils by itself, under condition that the neutrophils were primed with interferon -α or -γ ADDIN EN.CITE <EndNote><Cite><Author>Martinelli</Author><Year>2004</Year><RecNum>454</RecNum><DisplayText>(411)</DisplayText><record><rec-number>454</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599507056">454</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinelli, S.</author><author>Urosevic, M.</author><author>Daryadel, A.</author><author>Oberholzer, P. A.</author><author>Baumann, C.</author><author>Fey, M. F.</author><author>Dummer, R.</author><author>Simon, H. U.</author><author>Yousefi, S.</author></authors></contributors><auth-address>Department of Pharmacology, University of Bern, CH-3010, Switzerland.</auth-address><titles><title>Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation</title><secondary-title>J Biol Chem</secondary-title></titles><periodical><full-title>J Biol Chem</full-title></periodical><pages>44123-32</pages><volume>279</volume><number>42</number><edition>2004/08/11</edition><keywords><keyword>Base Sequence</keyword><keyword>Cell Differentiation/drug effects/*genetics</keyword><keyword>Cluster Analysis</keyword><keyword>DNA Primers</keyword><keyword>Extracellular Space/*physiology</keyword><keyword>Gene Expression Regulation/drug effects/immunology</keyword><keyword>Humans</keyword><keyword>Interferon-alpha/*pharmacology</keyword><keyword>Interferons/*physiology</keyword><keyword>Neutrophils/*cytology/drug effects</keyword></keywords><dates><year>2004</year><pub-dates><date>Oct 15</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>15302890</accession-num><urls><related-urls><url>;(411). Since TLRs could be triggered by endogenously produced ligands ADDIN EN.CITE <EndNote><Cite><Author>Rifkin</Author><Year>2005</Year><RecNum>469</RecNum><DisplayText>(412)</DisplayText><record><rec-number>469</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599741685">469</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rifkin, I. R.</author><author>Leadbetter, E. A.</author><author>Busconi, L.</author><author>Viglianti, G.</author><author>Marshak-Rothstein, A.</author></authors></contributors><auth-address>Department of Medicine, Renal Section, Boston University School of Medicine, Boston, MA 02118, USA.</auth-address><titles><title>Toll-like receptors, endogenous ligands, and systemic autoimmune disease</title><secondary-title>Immunol Rev</secondary-title></titles><periodical><full-title>Immunol Rev</full-title></periodical><pages>27-42</pages><volume>204</volume><edition>2005/03/26</edition><keywords><keyword>Animals</keyword><keyword>Autoimmune Diseases/genetics/*immunology/*metabolism</keyword><keyword>DNA/immunology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate/immunology</keyword><keyword>Ligands</keyword><keyword>Membrane Glycoproteins/*immunology/*metabolism</keyword><keyword>Receptors, Cell Surface/*immunology/*metabolism</keyword><keyword>Toll-Like Receptors</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0105-2896 (Print)&#xD;0105-2896 (Linking)</isbn><accession-num>15790348</accession-num><urls><related-urls><url>;(412), it is a possible mechanism that complement fragments also could activate TLRs to yield a innate response, such as NETosis ADDIN EN.CITE <EndNote><Cite><Author>Hajishengallis</Author><Year>2010</Year><RecNum>471</RecNum><DisplayText>(413)</DisplayText><record><rec-number>471</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599744589">471</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hajishengallis, G.</author><author>Lambris, J. D.</author></authors></contributors><auth-address>University of Louisville School of Dentistry, Division of Oral Health and Systemic Disease, Louisville, KY, USA. g0haji01@louisville.edu</auth-address><titles><title>Crosstalk pathways between Toll-like receptors and the complement system</title><secondary-title>Trends Immunol</secondary-title></titles><periodical><full-title>Trends Immunol</full-title></periodical><pages>154-63</pages><volume>31</volume><number>4</number><edition>2010/02/16</edition><keywords><keyword>Animals</keyword><keyword>Bacteria/immunology</keyword><keyword>Communicable Diseases/microbiology</keyword><keyword>Complement System Proteins/genetics/*metabolism</keyword><keyword>Host-Parasite Interactions</keyword><keyword>*Immunity, Innate</keyword><keyword>Receptors, Complement/metabolism</keyword><keyword>Signal Transduction</keyword><keyword>T-Lymphocytes/*immunology</keyword><keyword>Toll-Like Receptors/genetics/*metabolism</keyword><keyword>Viruses/immunology</keyword></keywords><dates><year>2010</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1471-4981 (Electronic)&#xD;1471-4906 (Linking)</isbn><accession-num>20153254</accession-num><urls><related-urls><url>;(413). Such a complement- TLR induction is possibly amplified by cytokines such as Il-6, which themselves are TLR induced that might enhance expression of receptors for C3a and C5a ADDIN EN.CITE <EndNote><Cite><Author>Rittirsch</Author><Year>2008</Year><RecNum>470</RecNum><DisplayText>(414)</DisplayText><record><rec-number>470</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599742388">470</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rittirsch, D.</author><author>Flierl, M. A.</author><author>Ward, P. A.</author></authors></contributors><auth-address>Department of Pathology, The University of Michigan Medical School, 1301 Catherine Road, Ann Arbor, Michigan 48109-0602, USA.</auth-address><titles><title>Harmful molecular mechanisms in sepsis</title><secondary-title>Nat Rev Immunol</secondary-title></titles><periodical><full-title>Nat Rev Immunol</full-title></periodical><pages>776-87</pages><volume>8</volume><number>10</number><edition>2008/09/20</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Autonomic Nervous System/immunology/metabolism</keyword><keyword>Blood Coagulation Factors/immunology/metabolism</keyword><keyword>Complement System Proteins/immunology/metabolism</keyword><keyword>Cytokines/immunology/*metabolism</keyword><keyword>Fibrinolysis</keyword><keyword>Humans</keyword><keyword>Inflammation/*immunology/metabolism</keyword><keyword>Inflammation Mediators/immunology/*metabolism</keyword><keyword>Multiple Organ Failure/*immunology/metabolism</keyword><keyword>Neutrophils/immunology</keyword><keyword>Sepsis/*immunology/metabolism</keyword><keyword>Toll-Like Receptors/immunology/metabolism</keyword></keywords><dates><year>2008</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1474-1741 (Electronic)&#xD;1474-1733 (Linking)</isbn><accession-num>18802444</accession-num><urls><related-urls><url>;(414). Our studies however did not indicate a similar capability of C3a, at least not I vitro. But it is possible that there are priming and activation of the neutrophils at play in vivo which pushes the neutrophils into NETosis when stimulated with C3a. In our study however C3a itself was not found to be a direct stimulator of NETs formation, but a promotor of neutrophil recruitment and as such very much involved in the process of NETosis. The opsonizing function of C3b is another matter that could be involved in the process of NETosis. It has been showed in some bacteria models that opsonization of the bacteria with C3b promotes NETosis ADDIN EN.CITE <EndNote><Cite><Author>Palmer</Author><Year>2016</Year><RecNum>288</RecNum><DisplayText>(306)</DisplayText><record><rec-number>288</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581719457">288</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palmer, L. J.</author><author>Damgaard, C.</author><author>Holmstrup, P.</author><author>Nielsen, C. H.</author></authors></contributors><auth-address>Section for Periodontology, Microbiology and Community Dentistry, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.&#xD;Department of Infectious Diseases and Rheumatology, Institute for Inflammation Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Influence of complement on neutrophil extracellular trap release induced by bacteria</title><secondary-title>J Periodontal Res</secondary-title></titles><periodical><full-title>J Periodontal Res</full-title></periodical><pages>70-6</pages><volume>51</volume><number>1</number><edition>2015/04/23</edition><keywords><keyword>Complement System Proteins</keyword><keyword>*Extracellular Traps</keyword><keyword>Macrophage-1 Antigen</keyword><keyword>Neutrophils</keyword><keyword>Receptors, Complement 3b</keyword><keyword>Staphylococcus aureus</keyword><keyword>biofilm</keyword><keyword>complement</keyword><keyword>inflammation</keyword><keyword>neutrophil extracellular traps</keyword><keyword>periodontal disease</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1600-0765 (Electronic)&#xD;0022-3484 (Linking)</isbn><accession-num>25900429</accession-num><urls><related-urls><url>;(306), but in sterile inflammation this has not yet been demonstrated. Furthermore, C3b is part of the C5 convertase of both the classical and alternative pathway and as such cleaves C5 and drives the cascade onwards ADDIN EN.CITE <EndNote><Cite><Author>Bettac</Author><Year>2017</Year><RecNum>283</RecNum><DisplayText>(307)</DisplayText><record><rec-number>283</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581672276">283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bettac, L.</author><author>Denk, S.</author><author>Seufferlein, T.</author><author>Huber-Lang, M.</author></authors></contributors><auth-address>Department of Internal Medicine I, University Hospital of Ulm , Ulm , Germany.&#xD;Department of Orthopedic Trauma, Hand, Plastic and Reconstructive Surgery, University Hospital of Ulm , Ulm , Germany.</auth-address><titles><title>Complement in Pancreatic Disease-Perpetrator or Savior?</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>15</pages><volume>8</volume><edition>2017/02/02</edition><keywords><keyword>acinar cells</keyword><keyword>complement</keyword><keyword>multiple organ failure</keyword><keyword>pancreas</keyword><keyword>pancreatic ductal adenocarcinomas</keyword><keyword>pancreatitis</keyword></keywords><dates><year>2017</year></dates><isbn>1664-3224 (Print)&#xD;1664-3224 (Linking)</isbn><accession-num>28144242</accession-num><urls><related-urls><url>;(307). Furthermore, C3b is part of the C3 convertase of the alternative pathway, and thus functioning as a self-amplifier.So, whether C3 and its cleaving products are directly involved in the process of NETosis thus remains a matter of discussion. It has been showed that blocking C3R-receptor significantly reduced production of NETs in lipopolysaccharide-stimulated neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Neeli</Author><Year>2009</Year><RecNum>456</RecNum><DisplayText>(415)</DisplayText><record><rec-number>456</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599584352">456</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Neeli, I.</author><author>Dwivedi, N.</author><author>Khan, S.</author><author>Radic, M.</author></authors></contributors><auth-address>Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tenn. 38163, USA.</auth-address><titles><title>Regulation of extracellular chromatin release from neutrophils</title><secondary-title>J Innate Immun</secondary-title></titles><periodical><full-title>J Innate Immun</full-title></periodical><pages>194-201</pages><volume>1</volume><number>3</number><edition>2009/01/01</edition><keywords><keyword>Actin Cytoskeleton/genetics/metabolism</keyword><keyword>Cell Degranulation</keyword><keyword>Cellular Structures/chemistry/*metabolism/*ultrastructure</keyword><keyword>Chromatin/*metabolism</keyword><keyword>Cytoskeleton/metabolism/ultrastructure</keyword><keyword>*Gene Expression Regulation/immunology</keyword><keyword>Histones/immunology/*metabolism</keyword><keyword>Humans</keyword><keyword>Imines/*metabolism</keyword><keyword>Inflammation/immunology</keyword><keyword>Macrophage-1 Antigen/genetics/immunology/metabolism</keyword><keyword>Microtubules/genetics/metabolism</keyword><keyword>*Neutrophils/immunology/metabolism/ultrastructure</keyword></keywords><dates><year>2009</year></dates><isbn>1662-8128 (Electronic)&#xD;1662-811X (Linking)</isbn><accession-num>20375577</accession-num><urls><related-urls><url>;(415). Furthermore, one study by Yipp et al. demonstrated that C3 deficient PMN totally lacked both the ability of phagocytosis and NETosis even though the numbers of PMN were adequate and also that their crawling during migration were seriously impaired compared to normal PMN PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZaXBwPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (228). The same study also saw that the ability of NETosis came back if serum, and thus complements (including C3) was added, underlining the importance of C3 in NETosis. It was also noted that not only C3 but also TLR 2 was needed for generating NETs, but that none of them by themselves was able to promote NETosis after activation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZaXBwPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (228). This indicates a multi-tiered regulation in which both TLR2 and C3 are inalienable, could explain why we saw no NETosis in vitro when incubating the neutrophils with recombinant C3a. In comparison it has also been noted that the C3a receptor is more important than the C5a receptor in the concept of NETosis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZaXBwPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (228). However, our findings are to some extent contradicting some of the findings in the quoted study, in that we found C3 deficient neutrophils capable of NETosis after stimulation with PMA. However, Yipp et al used a bacterial model in vivo whereas our neutrophils were stimulated with PMA in vitro making the two models hard to compareHowever, our findings suggest that C3 is of importance for NETs formation in AP. Since NETs play such a significant role in the pathophysiology of AP, the reduced damage seen both locally and systemically in C3 -/- mice is not surprising. Taken together, targeting C3 for instance with Compstatin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXN0ZWxsb3M8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFy

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ADDIN EN.CITE.DATA (416) a substance that binds to C3 and protects it from cleavage and at the same time prevent assembly of C3 convertase PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWNrbGluPC9BdXRob3I+PFllYXI+MjAxODwvWWVhcj48

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ADDIN EN.CITE.DATA (417), could thus be an effective way to attenuate both the local and systemic effects seen in AP.Considerations, concluding remarks, and future perspectivesThe studies of this thesis have mostly been performed on murine models. The use of mice is broadly accepted in biomedical research as a model for studying pathophysiological mechanism. However, some problems must be addressed. For the first, it is not obvious that the inflammatory response observed in mice could be directly transferred to humans. This has been showed in studies were correlation of gene expressions under inflammatory conditions between man and mice were poor PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZW9rPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (418). The study showed that within the human specie the inflammatory gene expression patterns had a high degree of similarity (between 88-97%). when trauma, burn and endotoxemia were compared. However, when the gene expressions of the corresponding murine models were compared to humans, the accordance were low (47-63%). This study also saw a noticeably weak correlation between gene expression in the different murine models used. This notion underlines that there could be of great value in repeating the experiments in different separate animal models, to confirm the new findings. This was done in papers I and II. Also, the use of patient samples from humans, to verify the mechanistic findings, constitutes a valuable link between experimental findings on mice, and man.The techniques to induce AP is also something that could be problematized. Two different well-established murine models have been used in this thesis. The primary technique has been the use of retrograde infusion of Taurocholate. This technique yields a severe form of AP that is rather easy to reproduce. However, it requires quite excessive surgery, including puncturing of the duodenum, all of which could give rise to both local and systemic inflammatory changes, that could disturb the reactions of interest. Perforation of the duodenum is also something that rises the amylase levels in the blood Furthermore, retrograde infusion of Taurocholate will undoubtfully give rise to injuries in the pancreas, however, these injuries could not solely be attributed to protease activation, which is the natural cause of most cases of pancreatitis. Even the small retrograde infusion of saline into the pancreas duct of the sham animals, gives rise to some irritation of the pancreas. emphasizing the sensitivity of the pancreas to external manipulation. To correlate this to the clinical setting it is transferable to the pathomechanism of ERCP-induced pancreatitis. This does not however constitute the major or most common cause of AP. The causative mechanism behind L-Arginine induced AP in murine does not have any counterpart in humans, raising the question once again if the findings is transferable to man. When concluding which mechanisms that best represents the condition of interest, one often faces that certain biological processes of interest in one model might have a contrary role in another ADDIN EN.CITE <EndNote><Cite><Author>Laukkarinen</Author><Year>2008</Year><RecNum>462</RecNum><DisplayText>(419)</DisplayText><record><rec-number>462</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599682709">462</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laukkarinen, J. M.</author><author>Weiss, E. R.</author><author>van Acker, G. J.</author><author>Steer, M. L.</author><author>Perides, G.</author></authors></contributors><auth-address>Department of Surgery, Tufts Medical Center, 750 Washington Street, Boston, MA 02111, USA.</auth-address><titles><title>Protease-activated receptor-2 exerts contrasting model-specific effects on acute experimental pancreatitis</title><secondary-title>J Biol Chem</secondary-title></titles><periodical><full-title>J Biol Chem</full-title></periodical><pages>20703-12</pages><volume>283</volume><number>30</number><edition>2008/05/31</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Bile Acids and Salts/pharmacology</keyword><keyword>Ceruletide/pharmacology</keyword><keyword>Enzyme Activation</keyword><keyword>Female</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Models, Biological</keyword><keyword>Pancreas/cytology</keyword><keyword>Pancreatitis/*enzymology/*metabolism</keyword><keyword>Peptides/chemistry</keyword><keyword>Protein Structure, Tertiary</keyword><keyword>Receptor, PAR-2/metabolism/*physiology</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul 25</date></pub-dates></dates><isbn>0021-9258 (Print)&#xD;0021-9258 (Linking)</isbn><accession-num>18511423</accession-num><urls><related-urls><url>;(419). There are also some aspects of the laboratory analysis that has to be addressed. First, to measure the amount of leukocyte infiltration into pancreas and lungs are an important assessing in AP, since it correlates to the progression of the disease ADDIN EN.CITE <EndNote><Cite><Author>Awla</Author><Year>2011</Year><RecNum>121</RecNum><DisplayText>(163)</DisplayText><record><rec-number>121</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580116338">121</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Awla, D.</author><author>Abdulla, A.</author><author>Zhang, S.</author><author>Roller, J.</author><author>Menger, M. D.</author><author>Regner, S.</author><author>Thorlacius, H.</author></authors></contributors><auth-address>Department of Clinical Sciences, Malmo, Section of Surgery, Skane University Hospital, Lund University, Malmo, Sweden.</auth-address><titles><title>Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis</title><secondary-title>Br J Pharmacol</secondary-title></titles><periodical><full-title>Br J Pharmacol</full-title></periodical><pages>413-23</pages><volume>163</volume><number>2</number><edition>2011/01/20</edition><keywords><keyword>Acute Disease</keyword><keyword>Animals</keyword><keyword>Chemokines/metabolism</keyword><keyword>Lymphocyte Function-Associated Antigen-1/*physiology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred C57BL</keyword><keyword>Mice, Transgenic</keyword><keyword>*Neutrophil Infiltration</keyword><keyword>Pancreas/immunology/metabolism/pathology</keyword><keyword>Pancreatitis/chemically induced/*immunology/pathology</keyword><keyword>Taurocholic Acid</keyword></keywords><dates><year>2011</year><pub-dates><date>May</date></pub-dates></dates><isbn>1476-5381 (Electronic)&#xD;0007-1188 (Linking)</isbn><accession-num>21244370</accession-num><urls><related-urls><url>;(163). 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ADDIN EN.CITE.DATA (172). This is relevant since MPO is an enzyme stored in neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Schultz</Author><Year>1962</Year><RecNum>463</RecNum><DisplayText>(420)</DisplayText><record><rec-number>463</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599691228">463</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schultz, J.</author><author>Kaminker, K.</author></authors></contributors><titles><title>Myeloperoxidase of the leucocyte of normal human blood. I. Content and localization</title><secondary-title>Arch Biochem Biophys</secondary-title></titles><periodical><full-title>Arch Biochem Biophys</full-title></periodical><pages>465-7</pages><volume>96</volume><edition>1962/03/01</edition><keywords><keyword>*Coloring Agents</keyword><keyword>Leukocytes/*metabolism</keyword><keyword>Oxidoreductases/*blood</keyword><keyword>*Peroxidase</keyword><keyword>*LEUKOCYTES/metabolism</keyword><keyword>*OXIDASES/blood</keyword></keywords><dates><year>1962</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0003-9861 (Print)&#xD;0003-9861 (Linking)</isbn><accession-num>13909511</accession-num><urls><related-urls><url>(62)90321-1</electronic-resource-num></record></Cite></EndNote>(420) and release during the neutrophil oxidative burst thus generating microbicidal reactive oxidants ADDIN EN.CITE <EndNote><Cite><Author>Albrich</Author><Year>1981</Year><RecNum>464</RecNum><DisplayText>(421)</DisplayText><record><rec-number>464</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599691483">464</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Albrich, J. M.</author><author>McCarthy, C. A.</author><author>Hurst, J. K.</author></authors></contributors><titles><title>Biological reactivity of hypochlorous acid: implications for microbicidal mechanisms of leukocyte myeloperoxidase</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci U S A</full-title></periodical><pages>210-4</pages><volume>78</volume><number>1</number><edition>1981/01/01</edition><keywords><keyword>Amines/metabolism</keyword><keyword>Amino Acids/metabolism</keyword><keyword>Amino Sugars/metabolism</keyword><keyword>Bacteria/drug effects</keyword><keyword>Carotenoids/metabolism</keyword><keyword>Cytochromes/metabolism</keyword><keyword>Enzyme Inhibitors/metabolism</keyword><keyword>Ferredoxins/metabolism</keyword><keyword>Hypochlorous Acid/*metabolism/pharmacology</keyword><keyword>Nucleotides/metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Peroxidase/*metabolism</keyword><keyword>Peroxidases/*metabolism</keyword><keyword>Porphyrins/metabolism</keyword><keyword>Sulfhydryl Compounds/antagonists &amp; inhibitors</keyword></keywords><dates><year>1981</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0027-8424 (Print)&#xD;0027-8424 (Linking)</isbn><accession-num>6264434</accession-num><urls><related-urls><url>;(421). However, the measurement of MPO in pancreas and lungs might very well be affected by other biochemical compounds. Firstly, since there is no assay specific for Neutrophil MPO, assessment of total peroxidase activity in a tissue will probably include both eosinophilic and monocyte derived MPO ADDIN EN.CITE <EndNote><Cite><Author>Grisham</Author><Year>1990</Year><RecNum>465</RecNum><DisplayText>(422)</DisplayText><record><rec-number>465</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599692462">465</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Grisham, M. B.</author><author>Benoit, J. N.</author><author>Granger, D. N.</author></authors></contributors><titles><title>Assessment of leukocyte involvement during ischemia and reperfusion of intestine</title><secondary-title>Methods Enzymol</secondary-title></titles><periodical><full-title>Methods Enzymol</full-title></periodical><pages>729-42</pages><volume>186</volume><edition>1990/01/01</edition><keywords><keyword>Animals</keyword><keyword>Antioxidants/pharmacology</keyword><keyword>Capillary Permeability/drug effects</keyword><keyword>Cats</keyword><keyword>Cell Adhesion</keyword><keyword>Intestinal Mucosa/*blood supply/enzymology</keyword><keyword>Intestine, Small/*blood supply</keyword><keyword>Ischemia/*physiopathology</keyword><keyword>Kinetics</keyword><keyword>Leukocytes/*physiology</keyword><keyword>Muscle, Smooth/blood supply</keyword><keyword>Peroxidase/*metabolism</keyword><keyword>*Reperfusion</keyword><keyword>Xanthine Oxidase/antagonists &amp; inhibitors</keyword></keywords><dates><year>1990</year></dates><isbn>0076-6879 (Print)&#xD;0076-6879 (Linking)</isbn><accession-num>2172726</accession-num><urls><related-urls><url>(90)86172-r</electronic-resource-num></record></Cite></EndNote>(422). This will however probably be in a rather small amounts since it is neutrophils and not monocytes or eosinophils that are the predominating cell type infiltrating tissues in an acute inflammatory response. However, since MPO assay is based on H2O2-oxidation of an artificial electron donor, several compound, for instance Fe2+ might disturb this reaction. Other potential interfering substances are: ascorbic acid, catalase and ceruloplasmin ADDIN EN.CITE <EndNote><Cite><Author>Dawra</Author><Year>2008</Year><RecNum>418</RecNum><DisplayText>(423)</DisplayText><record><rec-number>418</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583763591">418</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dawra, R.</author><author>Ku, Y. S.</author><author>Sharif, R.</author><author>Dhaulakhandi, D.</author><author>Phillips, P.</author><author>Dudeja, V.</author><author>Saluja, A. K.</author></authors></contributors><auth-address>Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.</auth-address><titles><title>An improved method for extracting myeloperoxidase and determining its activity in the pancreas and lungs during pancreatitis</title><secondary-title>Pancreas</secondary-title></titles><periodical><full-title>Pancreas</full-title></periodical><pages>62-8</pages><volume>37</volume><number>1</number><edition>2008/06/27</edition><keywords><keyword>Animals</keyword><keyword>Ceruletide</keyword><keyword>Disease Models, Animal</keyword><keyword>Lung/*enzymology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Neutrophils/*enzymology</keyword><keyword>Pancreas/*enzymology</keyword><keyword>Pancreatitis/chemically induced/*enzymology</keyword><keyword>Peroxidase/antagonists &amp; inhibitors/*isolation &amp; purification/*metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Reproducibility of Results</keyword><keyword>Spectrophotometry/*methods</keyword><keyword>Time Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1536-4828 (Electronic)&#xD;0885-3177 (Linking)</isbn><accession-num>18580446</accession-num><urls><related-urls><url>;(423). In order to minimize the effect of these pitfalls, protocols for the entire procedure of MPO assessments, that for instance emphasizes the importance of flushing the lungs during tissue procurement, have been develop which has greatly reduce the sources of error ADDIN EN.CITE <EndNote><Cite><Author>Dawra</Author><Year>2008</Year><RecNum>418</RecNum><DisplayText>(423)</DisplayText><record><rec-number>418</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1583763591">418</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dawra, R.</author><author>Ku, Y. S.</author><author>Sharif, R.</author><author>Dhaulakhandi, D.</author><author>Phillips, P.</author><author>Dudeja, V.</author><author>Saluja, A. K.</author></authors></contributors><auth-address>Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.</auth-address><titles><title>An improved method for extracting myeloperoxidase and determining its activity in the pancreas and lungs during pancreatitis</title><secondary-title>Pancreas</secondary-title></titles><periodical><full-title>Pancreas</full-title></periodical><pages>62-8</pages><volume>37</volume><number>1</number><edition>2008/06/27</edition><keywords><keyword>Animals</keyword><keyword>Ceruletide</keyword><keyword>Disease Models, Animal</keyword><keyword>Lung/*enzymology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Neutrophils/*enzymology</keyword><keyword>Pancreas/*enzymology</keyword><keyword>Pancreatitis/chemically induced/*enzymology</keyword><keyword>Peroxidase/antagonists &amp; inhibitors/*isolation &amp; purification/*metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Reproducibility of Results</keyword><keyword>Spectrophotometry/*methods</keyword><keyword>Time Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1536-4828 (Electronic)&#xD;0885-3177 (Linking)</isbn><accession-num>18580446</accession-num><urls><related-urls><url>;(423). 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ADDIN EN.CITE.DATA (320).Some words must also be said on the topic of pseudo coloring which could be done in order to clarify an electron microscopy image. Because the substances of interest are of such small size, something must often be done in order to illustrate their presence. Since the techniques for doing so to some extent could be interpreted as making changes in the image, this could interfere with the roles of journals that prohibits manipulation of pictures. Here more robust routines as where the line between, adding markers etc. in order to present a picture in an understandable manner, and what is consider to be manipulation and dishonesty, is actually drawn.The methods for evaluation of NETs itself both in vivo and in vitro is also an issue that holds it specific challenges ADDIN EN.CITE <EndNote><Cite><Author>Masuda</Author><Year>2016</Year><RecNum>466</RecNum><DisplayText>(424)</DisplayText><record><rec-number>466</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599734945">466</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Masuda, S.</author><author>Nakazawa, D.</author><author>Shida, H.</author><author>Miyoshi, A.</author><author>Kusunoki, Y.</author><author>Tomaru, U.</author><author>Ishizu, A.</author></authors></contributors><auth-address>Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.&#xD;Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.&#xD;Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.&#xD;Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address: aishizu@med.hokudai.ac.jp.</auth-address><titles><title>NETosis markers: Quest for specific, objective, and quantitative markers</title><secondary-title>Clin Chim Acta</secondary-title></titles><periodical><full-title>Clin Chim Acta</full-title></periodical><pages>89-93</pages><volume>459</volume><edition>2016/06/05</edition><keywords><keyword>Biomarkers/*analysis</keyword><keyword>Extracellular Traps/*chemistry/immunology</keyword><keyword>Flow Cytometry</keyword><keyword>Humans</keyword><keyword>Neutrophils/*chemistry/immunology</keyword><keyword>Citrullinated histone</keyword><keyword>MPO-DNA complex</keyword><keyword>Neutrophil extracellular trap</keyword><keyword>Peptidylarginine deiminase 4</keyword></keywords><dates><year>2016</year><pub-dates><date>Aug 1</date></pub-dates></dates><isbn>1873-3492 (Electronic)&#xD;0009-8981 (Linking)</isbn><accession-num>27259468</accession-num><urls><related-urls><url>;(424). The golden standard for examining NETs is still not concluded, but the use of scanning electron microscopy (SEM) seems to be considered as reliable. This is however not very easy to conduct and also it has the methodological weakness that it lacks objectivity since the it is the examiner self that has to interpret the picture, even though computer programs for image analysis could diminish this source of error. Furthermore, it could not be excluded that the fixation process could yield morphological changes that could be interpreted as NETs. Another difficulty is that it could be hard to distinguish NETs from fibrin using SEM ADDIN EN.CITE <EndNote><Cite><Author>Krautgartner</Author><Year>2010</Year><RecNum>467</RecNum><DisplayText>(425)</DisplayText><record><rec-number>467</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599735634">467</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Krautgartner, W. D.</author><author>Klappacher, M.</author><author>Hannig, M.</author><author>Obermayer, A.</author><author>Hartl, D.</author><author>Marcos, V.</author><author>Vitkov, L.</author></authors></contributors><auth-address>Department of Light &amp; Electron Microscopy, Organismic Biology, University of Salzburg, Salzburg, Austria.</auth-address><titles><title>Fibrin mimics neutrophil extracellular traps in SEM</title><secondary-title>Ultrastruct Pathol</secondary-title></titles><periodical><full-title>Ultrastruct Pathol</full-title></periodical><pages>226-31</pages><volume>34</volume><number>4</number><edition>2010/07/03</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Cytological Techniques</keyword><keyword>Female</keyword><keyword>Fibrin/*metabolism/ultrastructure</keyword><keyword>Gingival Crevicular Fluid/cytology/immunology/microbiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Microscopy, Electron, Scanning</keyword><keyword>Middle Aged</keyword><keyword>Neutrophil Activation/immunology</keyword><keyword>Neutrophils/immunology/microbiology/*pathology</keyword><keyword>Periodontitis/immunology/microbiology/pathology</keyword></keywords><dates><year>2010</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1521-0758 (Electronic)&#xD;0191-3123 (Linking)</isbn><accession-num>20594043</accession-num><urls><related-urls><url>;(425). Citrullinated histone 3 is generally accepted as a specific NETs marker ADDIN EN.CITE <EndNote><Cite><Author>Leshner</Author><Year>2012</Year><RecNum>468</RecNum><DisplayText>(426)</DisplayText><record><rec-number>468</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599736204">468</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Leshner, M.</author><author>Wang, S.</author><author>Lewis, C.</author><author>Zheng, H.</author><author>Chen, X. A.</author><author>Santy, L.</author><author>Wang, Y.</author></authors></contributors><auth-address>Department of Biochemistry and Molecular Biology, Center for Eukaryotic Gene Regulation, Pennsylvania State University, University Park PA, USA.</auth-address><titles><title>PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>307</pages><volume>3</volume><edition>2012/10/13</edition><keywords><keyword>chromatin decondensation</keyword><keyword>heterochromatin protein 1</keyword><keyword>histone modifications</keyword><keyword>hypercitrullination</keyword><keyword>neutrophil extracellular traps</keyword><keyword>pad4</keyword></keywords><dates><year>2012</year></dates><isbn>1664-3224 (Electronic)&#xD;1664-3224 (Linking)</isbn><accession-num>23060885</accession-num><urls><related-urls><url>;(426), however some cancer cells could also express citrullinated H3. Other suggested markers such as cfDNA, MPO and neutrophil derived elastase are often elevated in the presence of NETs but could not be considered NETs specific, since they could be elevated even in the absence of NETs. Flow cytometric techniques for detection and quantification for NETs is currently developing and could turn out to have great potential, however the procedures are still immature and more research is needed ADDIN EN.CITE <EndNote><Cite><Author>Masuda</Author><Year>2016</Year><RecNum>466</RecNum><DisplayText>(424)</DisplayText><record><rec-number>466</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599734945">466</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Masuda, S.</author><author>Nakazawa, D.</author><author>Shida, H.</author><author>Miyoshi, A.</author><author>Kusunoki, Y.</author><author>Tomaru, U.</author><author>Ishizu, A.</author></authors></contributors><auth-address>Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.&#xD;Division of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.&#xD;Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.&#xD;Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. Electronic address: aishizu@med.hokudai.ac.jp.</auth-address><titles><title>NETosis markers: Quest for specific, objective, and quantitative markers</title><secondary-title>Clin Chim Acta</secondary-title></titles><periodical><full-title>Clin Chim Acta</full-title></periodical><pages>89-93</pages><volume>459</volume><edition>2016/06/05</edition><keywords><keyword>Biomarkers/*analysis</keyword><keyword>Extracellular Traps/*chemistry/immunology</keyword><keyword>Flow Cytometry</keyword><keyword>Humans</keyword><keyword>Neutrophils/*chemistry/immunology</keyword><keyword>Citrullinated histone</keyword><keyword>MPO-DNA complex</keyword><keyword>Neutrophil extracellular trap</keyword><keyword>Peptidylarginine deiminase 4</keyword></keywords><dates><year>2016</year><pub-dates><date>Aug 1</date></pub-dates></dates><isbn>1873-3492 (Electronic)&#xD;0009-8981 (Linking)</isbn><accession-num>27259468</accession-num><urls><related-urls><url>;(424). 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ADDIN EN.CITE.DATA (79, 121). This happening involves several systems that are all highly intermingled and a lot of them have, each by them self, been identified as playing a part in the development of AP. However, an Alexandrian cut that solves the entire issue is yet to be identified, and it is highly unlikely that any such mechanism will be found. Instead targeting the recruitment process and the development of inflammation at the many different points of the course of AP seems like a more credible ambition. In this thesis several different systems: platelets and hence the coagulation, neutrophil activation and NETosis, the interaction between neutrophils and platelets, expulsion of MPs, expression of nuclear products such as CIRP, and the complement system, are studied and found in some way to be involved and interconnected in the pathogenesis of AP.Serine proteases are in the very centre of the pathophysiology of AP, since pre-emptive activation of trypsin is considered to be the starting point of the disease. Furthermore trypsin is by some even considered to be the main driving force behind development of MODS in AP ADDIN EN.CITE <EndNote><Cite><Author>Sha</Author><Year>2009</Year><RecNum>295</RecNum><DisplayText>(427)</DisplayText><record><rec-number>295</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581784539">295</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sha, H.</author><author>Ma, Q.</author><author>Jha, R. K.</author></authors></contributors><auth-address>Department of Surgery, First Affiliated Hospital of Xi&apos;an Jiaotong University, Xi&apos;an 710061, China.</auth-address><titles><title>Trypsin is the culprit of multiple organ injury with severe acute pancreatitis</title><secondary-title>Med Hypotheses</secondary-title></titles><periodical><full-title>Med Hypotheses</full-title></periodical><pages>180-2</pages><volume>72</volume><number>2</number><edition>2008/10/22</edition><keywords><keyword>Humans</keyword><keyword>Liver/drug effects/pathology</keyword><keyword>Multiple Organ Failure/*etiology/pathology</keyword><keyword>Necrosis/chemically induced</keyword><keyword>Pancreatitis, Acute Necrotizing/*complications/pathology</keyword><keyword>Trypsin/*toxicity</keyword></keywords><dates><year>2009</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0306-9877 (Print)&#xD;0306-9877 (Linking)</isbn><accession-num>18938042</accession-num><urls><related-urls><url>;(427). Other serine proteases (some of which are trypsin-like), are also known to play a direct crucial role in driving both the complement and the coagulation cascade PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb2xleTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (428). It is thus not farfetched to see that the different systems could be somewhat interconnected in one global protease system which would be very much affected by AP. Since NETs are of the outmost importance in the development of AP, inter alia by means of trypsin activation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJ6YTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZXJ6YTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (183). The role of NETs and NETosis is therefore evident also in this context.That the coagulation, the complement system and NETosis are somehow interlinked is getting more and more and obvious. NETs and the coagulation interplay in several manners. Neutrophils are the first cell type to arrive at sites of endothelia damage, and here they assist in initiating the coagulation. Neutrophils and NETs are also found in a great number in thrombi of both man and mice PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmlsbDwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (429, 430). In different inflammatory conditions neutrophils are known to form complexes, presumably with involvement of P-selectin. This is a notion that is further underlined in paper II. These platelet-neutrophil aggregates enhanced NETs formation, possibly via expelled HMGB1 from the platelets. The precise trail is still elusive, but it could be that the close attachment between platelets and neutrophils in these complexes will bring the HMGB1 from platelets close enough to activate neutrophils via their TLR2 TLR4 or RAGE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdGFyazwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (431). Furthermore, as stated in paper I the platelets expel chemokines and thus also indirectly promotes NETs-formation in means of neutrophil recruitment. It seems that not only has the coagulation-cascade the capability of promoting NETosis, but the NETs expelled from the neutrophils has the ability to promote coagulation itself. The precise mechanisms are unknown, but several possible substances and ways of action, have been identified. First it is a possibillity that NETs function as a scaffold on which fibrin formation could occur ADDIN EN.CITE <EndNote><Cite><Author>Fuchs</Author><Year>2010</Year><RecNum>204</RecNum><DisplayText>(218)</DisplayText><record><rec-number>204</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1580849688">204</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fuchs, T. A.</author><author>Brill, A.</author><author>Duerschmied, D.</author><author>Schatzberg, D.</author><author>Monestier, M.</author><author>Myers, D. D., Jr.</author><author>Wrobleski, S. K.</author><author>Wakefield, T. W.</author><author>Hartwig, J. H.</author><author>Wagner, D. D.</author></authors></contributors><auth-address>Immune Disease Institute, Boston, MA 02115, USA.</auth-address><titles><title>Extracellular DNA traps promote thrombosis</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci U S A</full-title></periodical><pages>15880-5</pages><volume>107</volume><number>36</number><edition>2010/08/28</edition><keywords><keyword>Animals</keyword><keyword>DNA/*isolation &amp; purification</keyword><keyword>Humans</keyword><keyword>Thrombosis/*etiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep 7</date></pub-dates></dates><isbn>1091-6490 (Electronic)&#xD;0027-8424 (Linking)</isbn><accession-num>20798043</accession-num><urls><related-urls><url>;(218). Furthermore, it is possible that since the NETs are negatively charge, they could activate FXII and thus the intrinsic pathway PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52b24gQnJ1aGw8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy

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ADDIN EN.CITE.DATA (434), is another mechanism that points to how closely associated the coagulation and NETs are.The interconnection of the complement system and NETs has already been stated repeatedly in this thesis. The complements promotes NETosis through opsonization, here the fragment C3b seems to be of the outmost importance ADDIN EN.CITE <EndNote><Cite><Author>Palmer</Author><Year>2016</Year><RecNum>288</RecNum><DisplayText>(306)</DisplayText><record><rec-number>288</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1581719457">288</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Palmer, L. J.</author><author>Damgaard, C.</author><author>Holmstrup, P.</author><author>Nielsen, C. H.</author></authors></contributors><auth-address>Section for Periodontology, Microbiology and Community Dentistry, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.&#xD;Department of Infectious Diseases and Rheumatology, Institute for Inflammation Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.</auth-address><titles><title>Influence of complement on neutrophil extracellular trap release induced by bacteria</title><secondary-title>J Periodontal Res</secondary-title></titles><periodical><full-title>J Periodontal Res</full-title></periodical><pages>70-6</pages><volume>51</volume><number>1</number><edition>2015/04/23</edition><keywords><keyword>Complement System Proteins</keyword><keyword>*Extracellular Traps</keyword><keyword>Macrophage-1 Antigen</keyword><keyword>Neutrophils</keyword><keyword>Receptors, Complement 3b</keyword><keyword>Staphylococcus aureus</keyword><keyword>biofilm</keyword><keyword>complement</keyword><keyword>inflammation</keyword><keyword>neutrophil extracellular traps</keyword><keyword>periodontal disease</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1600-0765 (Electronic)&#xD;0022-3484 (Linking)</isbn><accession-num>25900429</accession-num><urls><related-urls><url>;(306), but also through the effect of the anaphylatoxins C3a and C5a, which promotes neutrophil recruitment¨. The anaphylatoxins also induces upregulation of complement receptors and other immune receptors like TLRs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (321). On the other hand, NET itself could activate the complement cascade. Properdin, Factor B and C3 have all been showed to be deposited on the NETs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA (320, 321). Since these three are the substances needed for formation of the C3 convertase of the alternative pathway, it is possible that NETs again constitute a scaffold on which the assembly of convertase and hence activation of the complement cascade could occur. Strengthening this notion is the fact that it has been showed that complement activation decreases when DNase, which disrupt the NETs, is given PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWZmbGVyPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48

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ADDIN EN.CITE.DATA (320, 322). The biological relevance for why NETs holds the ability to activate the complement cascade could ultimately be the generation of the anaphylatoxins C3a and C5a in order to alert the immune system and promote neutrophil recruitment.The interplay between the complement cascade and the coagulation is beyond the scope of this thesis. However that a close intermingling exists is something that has been known for many years ADDIN EN.CITE <EndNote><Cite><Author>Conway</Author><Year>2018</Year><RecNum>479</RecNum><DisplayText>(435)</DisplayText><record><rec-number>479</rec-number><foreign-keys><key app="EN" db-id="v2vaxdfd1xtr0hepx5fp5ftu5x5eed2sex0a" timestamp="1599816359">479</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Conway, E. M.</author></authors></contributors><auth-address>Centre for Blood Research, Division of Hematology-Oncology, Department of Medicine, University of British Columbia, Vancouver, Canada.</auth-address><titles><title>Complement-coagulation connections</title><secondary-title>Blood Coagul Fibrinolysis</secondary-title></titles><periodical><full-title>Blood Coagul Fibrinolysis</full-title></periodical><pages>243-251</pages><volume>29</volume><number>3</number><edition>2018/03/09</edition><keywords><keyword>Animals</keyword><keyword>*Blood Coagulation</keyword><keyword>*Complement System Proteins</keyword><keyword>Humans</keyword><keyword>Therapeutics</keyword></keywords><dates><year>2018</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1473-5733 (Electronic)&#xD;0957-5235 (Linking)</isbn><accession-num>29517503</accession-num><urls><related-urls><url>;(435) and the general opinion moves more and more towards regarding them not as two separate entities but as one. Some of the substances that have been showed to be involved in this cooperation are among others, thrombin, fibrin and TF PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbWFyYTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA (432, 437) and, as pointed out in papers I and II, since platelets play an important role in neutrophil recruitment, a direct link between complements, platelets, neutrophil recruitment and hence NETosis also exists.All and all, there seem to be a triangular relationship between Neutrophils and NETs, the platelets (and hence coagulation) and the complement cascade. All the details of the interplay, regulation and finetuning of this big conglomerate of systems are still to a large extend elusive, and much more research is indicated and needed. The role of neutrophil recruitment and NETs in this context must however again be underlined and, as this thesis has pointed out, some of the signalling pathways and regulation mechanisms that are at play in the development of acute pancreatitis. Even though they exert their actions in different places of the system they all in one way or the other affects the generation of NETs and hence the course of the disease. Each of these mechanisms holds the capacity to aggravate the clinical course of AP but, on the other hand targeting each of them offer opportunities to affect the disease, even though much more research is necessary before therapies and drugs based on this are available for clinical use. To find a targeted treatment against AP has proven to be very hard. The role of NETs and NETosis and its importance for the development of AP seems to be central and hence targeting the NETosis might prove to be an effective angel of approach. Since the role of NETs are gaining more and more attention in pathophysiological mechanisms for many other diseases such as cancer and autoimmunity, it is possible that treatments originally develop for treating NETosis in these conditions will prove effective also on pancreatitis. The increasing use of DNase, both in laboratory settings and in the clinic might give new insights in this matter. Other possible future concepts of treatment include many different approaches to immune modulation such as targeting the immune response (i.e. cytokines and chemokines), impair the activation of platelets, ameliorate tissue necrosis in the pancreas (by targeting or promoting interleukins), strengthening the endothelial barrier thus complicating migration of neutrophils by blocking adhesion molecules, strengthening the intestinal barrier hindering bacterial translocation and blocking steps in the complement cascade, just to mention some PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba2lub3NvZ2xvdTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1ll

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ADDIN EN.CITE.DATA (438). All the mechanisms studied in this thesis each holds the potential to be possible approaches for therapy in order to ameliorate AP. However much more research is needed.The pancreas is a very powerful organ which hold the potential to destroy itself and the body around it. Therefore, it needs to be very delicately monitored. I chose here to conclude this thesis with the words of General Sun Tzu from “the Art of war “, since my impression is that this is what the pancreas are saying to the rest of the body:“Can you imagine what I would do if I could do all I can?”?ConclusionsCXCL4 play an important role in the neutrophil recruitment in acute pancreatitis, and thus in the inflammation and tissue damage. The CXCL4 is secreted from the platelets and exert its action probably via CXCL2.Platelets are key regulators of the NETs formation in acute pancreatitis. The expelled NETs forms complexes with microparticles (MP) in a process that is also platelet dependent. NETs-MP-complexes generates more tissue damage and inflammation than NETs or MP would do each by the selves.Platelets and neutrophils form aggregates, in AP. These complexes induce a more pronounced NETs formation and inflammation than neutrophils alone.Platelet derived enzyme IP6K1 is an important promotor of NETs production and hence inflammation and tissue damage in acute pancreatitis, possibly via regulation of PolyP secretion from the plateletsThe nuclear protein eCIRP is elevated in acute pancreatitis. C23 is a specific inhibitor of eCIRP, and treatment with C23 reduced NETs formation in acute pancreatitis. Complement component 3 (C3) plays a central role in the NET formation, inflammation and tissue damage in acute pancreatitis.Targeting CXCL4, IP6K1, eCIRP and/or C3 are all possible strategies for treatment of acute pancreatitisAcknowledgment – TackMy first thanks go to my Alma Mater, det Kongl. G?tiska karolinska Universitetet i Lund, a.k.a. Lund University, who always showed the outmost patience, parental harshness and loving care, spite my shortcomings and lack of discipline. Not only has You given me this remarkable opportunity, but has for many hundred years made it possible for my ancestors to fulfill their dreams, desires and destinies.My most profound thanks go to my main supervisor Prof H Thorlacius without whom there would not have been anything at all. You took care of the cuckoo nestling I was, and feed and nourished me with all your scientific brilliance. I cannot express my gratitude and how impressed I am with your great knowledge, your brilliant intellect and your creative spirit. I am also grateful for the more unofficial friendship we have developed. You are the best general a soldier in the field of science could ask for, and I am looking forward to future projects.Every general need competent captains and colonels to put his intention into practice, and Dr M Rahman, has proven to hold the highest of quality in these ranks. The day you became my co-supervisor marks, without question, the turning point of my career as a PhD-student. Your diligence, accuracy and your disinclination to bargain on quality has impressed me and been an unquestionable success factor both for me as for the entire group. Thank you!To Ass Prof S Regnér thanks for all your help in navigating the rather hard maneuvered waters of the university world. I also owe you the deepest gratitude for invaluable feedback and help with my writing.My warmest thanks to the freshly appointed Dr R Madhi, who thought me the all the basics in the lab and also most generously shared thoughts and results. Your exactitude, tireless and indefatigable work in the lab constitute the very definition of excellence.Thanks also to Dr E Wetterholm, Dr M Merza, Dr D Taha, Dr M M?rgelinand Dr Y Wang for their invaluable contributions and munificently sharing of results Thanks to Prof A Blom and Dr B King for great help, support and interesting discussions concerning complements.Thanks to Prof P Wang and Ass Prof M Brenner, for providing C23 and fruitful inputs on the matter of CIRP.To Anne-Marie Rorstock and Pernilla Simming I owe the deepest of thanks for all help with, what in military slang is referred to as “food and potatoes”, i.e. upholding the infrastructure and all measures needed for survival. People like you are an absolute necessity for coming through a project like this.Thanks also to Ass Prof C Sj?berg for help with the Latin.Thanks to the extremely helpful personnel at Media-Tryck, specially J Palm and G Albertén Thank you also my former colleagues at the surgical department in Helsingborg where I took my first tentative steps as a surgeon. First and foremost, I would thank the persons I regard as my mentors, who provided the best thinkable conditions for a young surgeon to learn, grow and develop, namely: my de facto supervisor the late Ass prof J Th?rne, furthermore, Ass Prof P-A Larsson, Ass prof P Qvarfordt and Dr M Bl?ckberg. To this bunch can also be added, Ass Prof G Plate, Dr M Cornelius, Ass Prof P Herlin, Ass prof S Wallgren, Dr S Smedberg and Dr C Lindstedt. Furthermore, the friends and ST colleagues from Underl?karsalen, who constituted the greatest of companions and competitors during the rather hard years of residency. Ever since my days as a med student Dr C Montán has, during both hard working and hard playing been my brother in arms. I am convinced that we both have spurred each other onwards. For this my friend I would like to declare my deepest gratitude, but more so, I would like to send my most joyous thanks to you and your lovely family for all the fun!To former colleagues at the transplant unit in Malm? and present colleagues at the department of surgery in Lund, I send my thanks and gratitude for providing collegial spirit, fun and interesting task assignments. Also, thanks for your forbearance with regard to me being absent from the clinic from time to timeThanks to friends and colleagues in the area of military medicine, and especially my most respectful gratitude to my eternal wing man Lt Col, Dr K Chevalley, without whom my military engagement probably would not have been as profound as it is. I am most impressed by your unfailing combating against stupidity and counterproductive ideas, waged with perseverance and excellence as your mark of nobility.To all sm?rrebr?der, resp.tekn, k?rl.ridd., k?rl.m?nd. of Det Kongl. K?rlighedshusholdningssellskabet Sm?rrebr?derna, I send my humble respect and a Vivat Ministern for your important work and everlasting efforts to beautify our lugubrious world. The incessant cheering you have provided has propelled me onwards during these years. Vi holder en plads hvis Han skul tillfriskne….Thanks to Joh. Henr. Thomanders studenthem, for being a beacon in the night for everyone who in their heart forever is a student of Lund University.Thanks also to all of my friends and drinking companions no one mentioned and no one forgotten. Since life is mostly made up of weekdays, I would like to address my thanks to the neighbors at Tegv?gen, specially families Bertilsson and Axelsson-Olsson for gilding these weekdays, making them not only bearable, but pleasant. A special thanks goes here to my sister in law Anna Axelsson for help with the cover and general computer stuff. That we were going to have such intermingled lives was nothing I expected during our time in Lundaspexarna.My deepest thanks are forwarded to my parents in law Bitte and Kjell-?ke Axelsson, for all love, help and support.Thanks also to the rest of my family members and kinsmen of the families Linders, Lindstr?m, Axelsson (Vinsl?v branch), Axelsson (Link?ping branch), Axelsson-Uggla and Axelsson-S?derlund, where ever they are. Family is the foundation and you know that you are all important to meA cordial thanks go to my inimitable brother Filip Linders, one of the most witty and creative persons I know. Thank you for a tremendously funny childhood and (using one of Mum’s child psychologist-terms) adolescence. Luckily your contribution to my life still continuous. Even though our opinions on different things often are in the opposite ends of the spectrum, you are at the same time one of the persons I feel the deepest kindship with. Thanks also to your lovely family for all joy and support!The deepest and most loving thanks are presented to my parents, Anita and Lars Linders who have always stood by, giving unconditional love, encouragement and endorsement, and on the same time in a relaxed, discrete but still obvious way imprinted the necessity of ambition, striving and making use of the abilities one has been blessed with. Thanks also for all the fun, and showing me a lot of the good life has to offer. I ow a lot of what I am to you, once again thanks!My proudest and deepest thanks go to my three children, who I love more than I can express. Being your father is the finest title I will ever be awarded. Thank you my lovely daughter Hildur, you are the most gentle and wise little girl and listening to your sounding laughter is truly one of the joys in life. Thank you, my wonderful daughter Ingeborg you are a condensed bundle of emotions and positive energy, and your warm hugs always give me renewed spirit and happiness. Thank you, my fantastic son and “?ttel?gg” Frithiof, witty, kind, clever and funny. You are the best stable boy and tin soldier there is! I wish the three of you all the best in life and you should know that your father is very proud of you, all the time.Also, thanks to my beloved friend Caballero Legionario Melker who faithfully has been sleeping on my feet and for providing a framework of routine to my many lonely days of writing.And finally, the absolute greatest and most profound thanks to my wife and fellow travel companion on the journey of life, Mia. I use the words from Operation Garbo by Harry Winter, “tack f?r du stod ut och stod bi”. Without your endless love and support I would have been a wreck a long time ago, thanks for just being there. You are literally, as said in the old song text, “five feet of heaven in a ponytail”. I love you! Popul?rvetenskaplig sammanfattning p? svenskaBakgrundBukspottsk?rteln eller pankreas ?r kroppens n?st st?rsta k?rtel och ?r bel?gen mycket centralt i buken. Den har flera funktioner; en endokrin som producerar hormon vilka fris?tts direkt till blodbanan. Vidare har den en exokrin funktion, vilket inneb?r att pankreas uts?ndrar sekret via kanaler till kroppens externa milj?. Hit r?knas ?ven mag-tarmkanalen. Pankreas exokrina funktion spelar en viktig roll i matspj?lkningen, d? den uts?ndrar potenta enzymer, d?ribland trypsin som har till uppgift att bryta ner protein. Eftersom pankreas till stor del best?r av protein har k?rteln s?ledes f?rm?gan att bryta ner sig sj?lv. F?r att f?rebygga att s? sker, uts?ndras trypsin som ett inaktivt f?rstadium, kallat trypsinogen. Detta aktiveras till aktivt trypsin f?rst utanf?r sj?lva k?rteln. Om denna aktivering av n?gon anledning ist?llet sker f?r tidigt, dvs inne i sj?lva pankreas, kan detta leda till en inflammation i Bukspottk?rteln kallad akut pankreatit (AP). Denna sjukdom ?r relativt vanlig och sp?nner ifr?n en mycket mild sjukdom, som g?r ?ver av sig sj?lv inom n?gon dag, till ett mycket allvarligt, livshotande tillst?nd. Det senare kan kr?va m?nader av intensivv?rd och ?r f?renlig med en betydande d?dlighet. D? det inte finns n?gon riktad behandling mot pankreatit ?r man, som kliniker h?nvisad till endast lindrande och st?ttande terapi. Varf?r sjukdomen utvecklas s? olika vet man ?nnu inte. Till stor del beroende p? att alla mekanismerna bakom sjukdomen ?nnu ej ?r kartlagda. Detta ?r ocks? orsaken till att n?gon specifikt riktad terapi ?nnu ej finns. Man vet emellertid att sjukdomsutvecklingen av pankreatit kan delas upp i tv? faser. Fas ett utg?rs av den f?r tidiga aktiveringen av trypsinogen till trypsin inne i pankreas. Fas tv? definieras som n?r den typ av vita blodkroppar som kallas neutrofiler, l?mnar blodbanan f?r att ist?llet invadera sj?lva bukspottk?rtelv?vnaden. Det ?r allm?nt vedertaget att fas tv? utg?r det begr?nsande steget i sjukdomsutvecklingen och ?r den fas som det ?r mest relevant att f?rs?ka p?verka med riktad behandling mot pankreatit.Neutrofiler ?r allts? en typ av vita blodkroppar, och som s?dana spelar de en viktig roll i kroppens f?rsvar. De brukar j?mf?ras vid kroppens skyttesoldater, vilka patrullerar blodomloppet f?r att vid tecken p? inflammation l?mna cirkulationen och ta sig till det ber?rda omr?det f?r att d?r utk?mpa sin strid. I normalfallet ?r neutrofiler s?ledes till godo f?r kroppen eftersom de skyddar mot angrepp av sjukdomsalstrande organismer s?som bakterier. De har ocks? till uppgift att st?da bort d?d och gammal v?vnad. Emellertid sl?r de ganska brett och kan d?rf?r under vissa omst?ndigheter, s? som vid exempelvis pankreatit, i st?llet orsaka skada. De vapen som neutrofilerna har i sin arsenal har historiskt ansetts vara fagocytos och degranulering. Fagocytos inneb?r att neutrofilen helt omsluter och ”?ter upp” den invaderade organismen. Degranulering inneb?r att neutrofilen sl?pper ut det aggressiva bakteried?dande inneh?llet fr?n sina granules, sm? bubblor som finns inne i cellen. P? senare tid har ?ven ett tredje ”vapensystem” identifierats, n?mligen att neutrofilerna fr?n sin cellk?rna uts?ndrar DNA bekl?tt med olika proteiner, vilket sammantaget utg?r en n?tlik struktur som kallat NETs (f?rkortning f?r Neutrophil Extracellular Traps). Dessa n?t av NETs f?ngar in det sjukdomsalstrande organismerna och bryter ner dem. ?ven NETs har dock visat sig vara ett tveeggat sv?rd, som vid bl.a. pankreatit ?ven bidrar till sjukdomsutvecklingen. I vissa fall har man funnit att NETs ?ven bekl?s med mikropartiklar, dvs sm? fragment fr?n andra cellers yta. Detta tror man ?r av betydelse b?de f?r NETs effektivitet, men tros ocks? ha betydelse f?r de fall d? NETs-bildning driver p? sjukdomsutveckling.Rekryteringen av neutrofiler ut till platsen f?r inflammation orkestreras till stor del av ?mnen som kallas cytokiner och chemokiner, vilka uts?ndras fr?n flera olika celltyper. En celltyp som har p?visats vara mycket betydelsefull h?rvidlag ?r blodpl?ttarna eller trombocyterna. De ?r mest k?nda f?r sin helt centrala roll i blodets levringsf?rm?ga, men deras betydelse inom inflammationsomr?det b?rjar dock bli allt mer oomtvistlig. Neutrofiler och blodpl?ttar samverkar intimt s? till den grad att de till och med bildar sammankopplade cellkomplex vid flera inflammatoriska tillst?nd. Detta ?r en delikat process d?r en m?ngd olika substanser, enzymer och ?ven NETs tros spela in. Sjukdomsutvecklingen vid pankreatit ?r som redan antytts en mycket komplex historia, vilken till stora delar ?r ok?nd. Ut?ver rekrytering av neutrofiler vilket involverar flera olika signalsubstanser, samspel mellan blodpl?ttar och neutrofiler, uts?ndring av NETs samt mikropartiklar spelar h?r ?ven andra faktorer in. H?r kan n?mnas fris?ttningen av proteiner fr?n cellk?rnorna i bukspottk?rtelcellerna, s?som exempelvis proteinet eCIRP, samt aktivering av det s? kallade komplementsystemet vilket utg?r en del av det medf?dda immunf?rsvaret. M?let med denna avhandling har varit att f?rs?ka kartl?gga ett antal specifika substansers roll i de nyss n?mnda mekanismerna, deras eventuella betydelse vid akut pankreatit, samt hur de samspelar i denna sjukdomsutveckling.MetodI tv? v?letablerade djurmodeller p? mus inducerades bukspottk?rtelinflammation. Djuren delades in i olika grupper och innan djuren fick pankreatit erh?ll m?ssen i n?gra grupper olika substanser eller antikroppar f?r att ta bort specifika faktorer. En del m?ss var framavlade med en speciell gen utslagen och saknade s?ledes en s?rskild egenskap. Blod och v?vnad fr?n m?ssen analyserades sedan avseende bl.a. hur stor lokal respektive systemisk (dvs i hela kroppen) inflammation som hade genererats i de olika grupperna. Detta gjordes dels genom att i mikroskop analysera de v?vnadsskador som uppkommit med hj?lp av ett p? f?rhand definierat scoring-system. Vidare analyserade, m?ttes och kvantifierades de olika substanser vilka man vet ?r involverade i de inflammatoriska processerna. Med hj?lp av elektronmikroskop kunde man identifiera huruvida NETs hade bildats och om n?gon skillnad f?rel?g mellan de olika grupperna. Vissa analyser av blodprover fr?n m?nniskor vilka utvecklat akut pankreatit. gjordes f?r j?mf?relse.ResultatStudie 1.Den f?rsta studien fokuserad p? en specifikt chemokin, CXCL4. V?ra analyser visade f?rh?jda niv?er av CXCL4 vid akut pankreatit. Detta s?g man b?de i djurf?rs?k och vid analys av blodprov fr?n patienter med AP. Det visade sig vidare att CXCL4 vid bukspottk?rtelinflammation kommer ifr?n blodpl?ttarna. Om dessa avl?gsnades med en antikropp minskade inte bara niv?n av CXCL4 utan ?ven de skador som annars upptr?der s?v?l lokalt som systemiskt. Samma m?nster kunde man se om CXCL4 specifikt avl?gsnades med en antikropp. Vidare noterades att om CXCL4 f?rsvann sj?nk ?ven halterna av ett annat chemokin, n?mligen CXCL2. Det ?r k?nt att CXCL2 spelar stor roll n?r det kommer till rekrytering av neutrofiler. Detta ?r som redan har n?mnts av stor betydelse f?r sjukdomsutvecklingen av AP. Tillsammans med andra observationer blir den sammantagna bilden att CXCL4 via CXCL2 ?r delaktig i sjukdomsutvecklingen vid akut bokspottk?rtelsinflammation genom rekrytering av neutrofiler.Studie 2I studie nummer tv? noterades initialt att om man med en specifik antikropp avl?gsnade blodpl?ttarna, s? minskade b?de m?ngden NETs och m?ngden mikropartiklar, samt att man fick en mildare inflammation s?v?l lokalt som systemiskt. Vi s?kte d? f?rdjupa oss i samspelet mellan neutrofiler och trombocyter och utr?na om de vid akut pankreatit bildar t?tt sammankopplade cellkomplex, s? som de har demonstrerats g?ra vid andra inflammatoriska tillst?nd. Det visade sig att s? var fallet och att substansen P-selectin f?rmodligen ?r inblandad i denna process. eftersom bildandet av trombocyt-neutrofilkomplex, kallade PNA, minskade om P-selectin avl?gsnades eller blockerades. Vid minskad m?ngd PNA s?gs ocks? en p?tagligt minskad m?ngd NETs och f?ljaktligen en mildare inflammation i djurmodellen. N?sta sak att unders?ka var ifall det vid pankreatit ?r, s? som man noterat vid andra inflammatoriska tillst?nd, n?mligen att det NETs som fris?tts bildar komplex med mikropartiklar. Om det skulle visa sig vara fallet, p?verkar det i s? fall sjukdomsbilden? V?ra f?rs?k avsl?jade att dylika komplex bildades och vidare, att NETs tillsammans med mikropartiklar gav en mer h?ftig pankreatit med st?rre v?vnadsskada ?n vad NETs utan mikropartiklar ensamt gav upphov till. I blodpl?ttarna finns ett enzym som heter IP6K1 vilket har till uppgift att reglera balansen av ?mnet polyfosfat. Detta enzym har vid andra tillst?nd visat sig var engagerat i bildandet av PNA. F?r att unders?ka om s? var fallet ?ven vid akut pankreatit anv?ndes m?ss som saknade genen f?r IP6K1 och s?ledes inte hade detta enzym. Ytterligare andra m?ss med normal genupps?ttning erh?ll TNP, en specifik inhibitor (dvs ett ?mne som blockerar ett annat ?mne) riktat mot IP6K1. Det visade sig att vid fr?nvaro eller blockering av IP6K1 bildades avsev?rt mindre NETs vid pankreatit, och d? ocks? en mer m?ttlig inflammation s?v?l lokalt som systemiskt. Eftersom IP6K1 reglerar balansen av polyfosfat, ett ?mne som i sig sj?lv besitter inflammationsbefr?mjande f?rm?ga, antog vi att polyfosfat p? n?got s?tt kunde vara inbladat i processen. Det visade sig att vid avsaknad av IP6K1 och s?ledes l?gre polyfosfat, genererades mindre NETs, men att NETs-bildningen kunde kompenseras upp om extra polyfosfat tillf?rdes. Man kan s?ledes anta att ut?ver att vara inblandat i bildandet av PNA, ?r det via polyfostaregleringen som IP6K1 p?verkar produktionen av NETs Studie 3I den tredje studien unders?ktes vilken betydelse proteinet eCIRP har vid pankreatit. Det har i andra modeller f?r andra inflammatoriska tillst?nd noterats att eCIRP ?r f?rh?jt och spelar en roll. F?r att svara upp mot yttre p?frestningar bildar celler protein vilka inuti cellerna ska bist? med viktiga funktioner och skyddsmekanismer mot det hot som cellerna uts?tts f?r. Om belastningen ?r stor och eller p?g?r l?nge kommer dessa proteiner att bildas i s?dan m?ngd att de kommer l?mna cellens insida och ist?llet finnas p? utsidan. H?r kommer de inte l?ngre g?ra nytta, utan kan ist?llet bidra till utveckling av olika sjukdomstillst?nd. Detta g?ller t.ex. proteinet CIRP som d? det upptr?der utanf?r cellen kallas eCIRP. I v?r studie visade det sig att eCIRP var f?rh?jt vid akut pankreatit, b?de i djurmodellen och hos patienter. Vidare noterades att om substansen C23, vilket ?r ett ?mne som blockerar effekten av eCIRP, gavs innan pankreatit inducerades minskade inte bara m?ngden eCIRP utan ocks? m?ngden NETs. Detta gav upphov till en mildare pankreatit med mindre v?vnadsskada, men ocks? mindre systemiska effekter och komplikationer.Studie 4Komplementsystemet ?r en del av det medf?dda immunf?rsvaret och utg?r som s?dant en avg?rande akt?r i kroppens skydd mot olika sjukdomsalstrande organismer. Systemet aktiveras av olika stimuli via ett antal f?rdefinierade v?gar s? kallade ”pathways”, d?r en komplementkomponent klyver en annan komponent s? att den blir aktiverad och sedan klyver n?sta komponent etc. Dessa pathways g?r samtliga ?ver komplementkomponent C3 varefter de f?ljer en gemensam kaskad vilket slutligen leder fram till att det utf?r sin verkan mot det fientliga m?let. I studie fyra var fokus att studera om komplementkomponent C3 spelar n?gon roll i sjukdomsutveckling vid akut pankreatit och fr?mst d? med avseende p? eventuell NETs formation Det ?r k?nt sedan tidigare att komplementsystemet kan aktivera NETS formation och ?ven vise versa att NETs kan aktiver komplementsystemet. Vidare ?r det ett k?nt faktum att trypsin, vilket spelar en nyckelroll vid pankreatit, kan klyva C3 och p? s? sett initiera kaskaden av komplementaktivering.I studien anv?ndes m?ss vilka hade f?tt genen f?r C3 utslagen och s?ledes saknades komplementkomponent C3. Det noterades att hos dessa m?ss bildades avsev?rt mindre NETs och f?ljaktligen blev det en mer mild sjukdom s?v?l lokalt som systemiskt.KonklusionerCXCL4 fr?n blodpl?ttarna ?r involverad i rekryteringen av neutrofilerna in i bukspottk?rtelv?vnaden, och spelar s?ledes en viktig roll i sjukdomsutvecklingen av akut pankreatit CXCL4 utf?r f?rmodligen denna rekrytering via reglering av CXCL2Blodpl?ttarna ?r delaktiga i regleringen av NETs-bildandet och s?ledes sjukdomsutvecklingen vid akut pankreatitBlodpl?ttar och neutrofiler bildar cellkomplex med varandra vilket p?verkar uts?ndringen av NETs vid akut bukspottk?rtelinflammation. I denna process spelar substansen P-selektin en avg?rande roll.Vid akut pankreatit bildar NETs och mikropartiklar komplex och f?rekomst av s?dana komplex ?r direkt kopplat till graden av inflammation.Enzymet IP6K1 fr?n blodpl?ttarna ?r en betydelsefull regulator f?r bildandet av NETs vid akut pankreatit, h?gst troligt via reglering av ?mnet polyfosfat.Proteinet eCIRP var f?rh?jt i akut pankreatit och direkt involverat i inflammation, NETs-bildning och v?vnadsskadaC23 blockerar eCIRP och leder till minskad NETs-produktion.Komplementkomponent C3 p?verkar graden av NETs-bildning och s?ledes graden av inflammation vid akut pankreatit.Riktade insatser mot CXCL4, IP6K1, eCIRP (med tex C23) och C3 ?r alla potentiellt m?jliga s?tt att p?verka sjukdomsutvecklingen vid akut pankreatit och ?r s?ledes t?nkbara behandlingsstrategier.References ADDIN EN.REFLIST 1.Tsuchiya R, and Fujisawa N. On the etymology of "pancreas". Int J Pancreatol. 1997;21(3):269-72.2.Tsuchiya R, Kuroki T, and Eguchi S. 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