Healing and Repair/2014-2015



TISSUE REPAIR Tissue repair = restoration of tissue architecture and function after an injuryOccurs in two ways:Regeneration : proliferation of cells to replace lost structures Replacement by connective tissue (scarring) Usually, tissue repair involves both processesInvolves cell proliferation, and interaction between cells and extracellular matrixCELLULAR PROLIFERATIONLots of cells proliferate during tissue repair:injured tissue remnantsvascular endothelial cellsfibroblastsControl of Normal Cell Proliferation and Tissue GrowthIn adult tissues the size of cell populations is determined by the rates of cell proliferation, differentiation, and death by apoptosis Stem cellsThey are source of mature cellsThere is a homeostatic equilibrium between replication and differentiation of stem cells and the death of the mature, fully differentiated cells. Examples are skin and GI tract. Stem cells with the capacity to generate multiple cell lineages (pluripotent stem cells) can be isolated from embryos and are called embryonic stem (ES) cells. Bone marrow stem cells are able to generate fat, cartilage, bone, endothelium, and muscle. Stem cells have 2 characteristic properties:Self-renewal capacityAsymmetric replicationSome differentiate to a specific cell typeSome remain undifferentiated: These maintain their self-renewal capacity.Tissues of the body are divided into three groups according to their proliferative capacity:1. Continuously dividing (labile) tissues cells are continuously proliferatingcan easily regenerate after injurycontain a pool of stem cellsexamples: bone marrow, skin, GI epithelium2. Stable tissuescells have limited ability to proliferate limited ability to regenerate (except liver!)normally in G0, but can proliferate if injuredexamples: liver, kidney, pancreas3. Permanent tissuescells can’t proliferatecan’t regenerate (so injury always leads to scar)examples: neurons, cardiac muscleGROWTH FACTORSCell proliferation can be triggered by: Growth factors, hormones, cytokines.Growth factors are polypeptides produced by leukocytes, parenchymal cells, and connective tissue ,affect cell proliferation by:1)Expanding cell population Stimulating cell division (mitosis)Increase cell size (growth)Protection from apoptotic death (survival)2)Other functionsStimulate migration, differentiation, angiogenesis, contractility, and fibrogenesis Involved in growth control – can stimulate or inhibitMay act on multiple cell typesHuge list! Usually have “GF” in name:EGF: Epidermal Growth FactorTGF: Transforming Growth Factor PDGF :Platelet Derived Growth FactorVEGF: Vascular Endothelial Growth FactorSignaling Mechanisms of Growth Factor:3 types:Autocrine Substance acts on cell that secretes it:Lymphocyte proliferation, liver regenerationParacrine Substance affects cell in the vicinity:Recruiting inflammatory cells, wound healingEndocrineActs on target cells at a distance:HormonesGF either :Affect receptors on cell surface membraneAffect receptors inside the cell – intracellular:must be hydrophobic to enterVitamin D, steroid and thyroid hormonesTHE EXTRACELLULAR MATRIX (ECM)ECM is the network that surrounds cellsTwo forms: interstitial matrix and basement membraneDoes lots of things!Sequesters water and mineralsGives cells a scaffold(Mechanical support) to adhere toStores growth factorsECM regulates proliferation, movement, and differentiation of the cells living in it.If ECM is damaged, tissue can’t regenerate! It will form a scar instead.REGENERATION Occurs all the time in labile tissues Cells are constantly being lost and replacedIf demand increases, supply increases easilyOccurs in limited form in stable tissuesRemove one kidney: the other one undergoes hypertrophy and hyperplasiaRemove half of the liver: it will grow backOnly occurs if residual tissue is intact!SCARRING If injury is severe, regeneration can’t happenSo, fibrosis (a scar) replaces the injured tissueFour components to this process:new vessel formation (angiogenesis)fibroblast proliferationsynthesis of collagen (scar formation)remodeling of scarBy 24 hours:Endothelial cells start proliferatingFibroblasts emigrateBy 3-5 days:Granulation tissue is formed which has pink, soft, granular gross appearance and histologically characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis), in a loose ECM .Weeks later:dense fibrosis (scar)scar is remodeled over timeSKIN WOUND HEALING Healing by First Intention:This is referred to as primary union or healing by first intention.Occurs in small wounds that close easilyEpithelial regeneration predominates over fibrosisHealing is fast, with minimal scarring/infectionExamples: Paper cuts Clean ,uninfected surgical incision approximated by surgical sutures Timeline:By 24 hours clot forms neutrophils come in epithelium begins to regenerate By 3-7 days macrophages come in granulation tissue is formed new blood vessels fibroblasts collagen begins to bridge incision epithelium increases in thicknessWeeks later granulation tissue gone collagen is remodeledepidermis full, mature (but without dermal appendages!) eventually, scar formsHealing by Second Intention:Also known as healing by secondary union When cell or tissue loss is more extensive, such as in large wounds, that have gaps between wound margins abscess formation, large burns , ulcers, and infarction in parenchymal organs. The repair process is more complex. Fibrosis predominates over epithelial regenerationHealing is slower, with more inflammation and granulation tissue formation, and the wound contraction by the action of myofibroblasts which are modified fibroblasts exhibiting many of the ultrastructural and functional features of contractile smooth muscle cells.This is followed by formation of a large scar. Within 6 weeks, large skin defects may be reduced to 5% to 10% of their original size, by contraction. Secondary healing differs from primary healing in several respects: A larger clot or scab rich in fibrin and fibronectin .Inflammation is more intense because large tissue defects have a greater volume of necrotic debris, exudate, and fibrin that must be removed.Much larger amounts of granulation tissue are formed. Larger defects require a greater volume of granulation tissue to fill in the gaps.Wound contraction: a greater volume of granulation tissue results in a greater mass of scar. Wound StrengthAt suture removal: 10%Rapid increase over next 4 weeksAt third month: 70-80%LOCAL AND SYSTEMIC FACTORS THAT INFLUENCE WOUND HEALING Systemic factors:Nutrition: vitamin C deficiency inhibits collagen synthesis and retards healing. Inadequate blood supply: due either to arteriosclerosis and diabetes or to obstructed venous drainage (e.g. in varicose veins), also impairs healing. Diabetes mellitus: hyperglycemia, reduced immunity, impairment of the leukocyte movement. Steroids: have well-documented anti-inflammatory effects and their administration may result in poor wound strength due to diminished fibrosis. Local factors:Infection is the single most important cause of delay in healing; it prolongs inflammation and increases the local tissue injury. Foreign bodies: such as fragments of steel, glass, or even bone impede healing. Mechanical factors: early motion, increased local pressure or torsion may cause wounds to pull apart, or dehisce. Size, location, and type of wound: larger wounds are slower in healing; wounds in the face are healed faster than in the lower limb because of rich blood supply, healing by first intension is faster than second intension. Complications in wound healingDehiscence (rupture )of a wound Most common after abdominal surgery due to increased abdominal pressureulcerationinadequate vascularization areas devoid of sensationkeloid The accumulation of excessive amounts of collagen, giving rise to prominent, raised scars. Develops after thermal or traumatic injury. There is a heritable predisposition to keloid formation, and the condition is more common in blacks. Proud fleshExcessive formation of granulation tissueContracturecommonly seen after serious burns can impair the movement of jointsNotesNot all injuries result in permanent damage; some are resolved almost completelyMore often, there is some degree of scarringScar is usually good (provides a resilient patch) but occasionally bad (can cause permanent dysfunction). ................
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