Inflammation Outcomes:Healing, SepsisSummary of acute inflammation Stimulated by physical injury, infection, foreign body Resident macrophages and/or damaged endothelium, mast cellsIL-1, !", endothelin, histamine Vascular response:#asodilation, endothelial contraction, e$udation of plasma Neutrophils:marginate %selectin-glycoprotein&, adhere %integrin-'()&, e$tra#asate %'*+1&, migrate %IL-,, chemotactic stimuli& Phagocytosis-recognition, engulfment, .illing/hagocytosis receptors bind mannose, o$idi0ed lipids, lipopolysaccharides, lipoteichoic acids, opsonins1illing is 23-dependent %respiratory burst, !(*/4 o$idase generated 43235 myelopero$idase generated 42'l5 i!2S generated !2& or independent %lyso0yme, lactoferrin, defensins& Responding leu.ocytes cause pain and loss-of-function #ia prostaglandins, en0ymes 'omplete resolution5 fibrosis, organi0ation or scarring5 abcess formation5 progression to chronic inflammationOutcomes of Acute Inflammation Resolution of tissue structure and function 6ith elimination of stimulus issue destruction and persistent inflammation (bscess pus-filled ca#ity %neutrophils, monocytes and li7uefied cellular debris& 6alled off by fibrous tissue and inaccessible to circulation tissue destruction caused by lysosomal and other degradati#e en0ymes 8lcer loss of epithelial surface acute inflammation in epithelial surfaces "istula abnormal communication bet6een organs or an organ and a surface Scar 'auses distortion of structure and sometimes altered function 'hronic inflammation )ar.ed by replacement of neutrophils and monocytes 6ith lymphocytes, plasma cells and macrophages (ccompanied by proliferation of fibroblasts and ne6 #essels 6ith scarringCauses of chronic inflammation/ersistent infections2rganisms usually of lo6 to$icity that in#o.e delayed hypersensiti#ity reactionM. tuberculosis and T. pallidum causes granulomatous reaction /rolonged e$posure to potentially to$ic agents9$ogenous agents include silica 6hich causes silicosis9ndogenous causes include atherosclerosis caused by to$ic plasma lipid components (utoimmunity(uto-antigens pro#o.e self-perpetuating immune responses that cause chronic inflammatory diseases li.e R(, )SResponses against common en#ironmental substances cause chronic allergic diseases, such as bronchial asthmaGranulomatous inflammation"ocus of chronic inflammation encountered in a limited number of conditions'ellular attempt to contain a foreign body or an offending agent that is difficult to eradicate %i:e: b&)icroscopic aggregation of macrophages that are transformed into epithelioid cells, surrounded by a collar of lymphocytes and occasionally plasma cells9pithelioid cells ha#e a pale pin. granular cytoplasm 6ith indistinct cell boundaries, often merging as giant cells"oreign body epitheloids ha#e dispersed nucleiInfectious body epitheloids ha#e marginal or horse-shoe nuclei9nlarged granuloma 6ith central necrosis is an abcess9nlarged granuloma on a surface is an ulcerPatterns of Inflammation Serous Inflammation )ar.ed by outpouring of thin fluid "rom blood serum, e:g: burn blisters 9ffusion from mesothelial cells lining the pleural, peritoneal and pericardial ca#ity Firinous Inflammation ( feature of pericardial and peritoneal inflammation ;ascular permeability allo6s larger molecules li.e fibrin to pass or procoagulant stimulus e$ists in the interstitium %e:g: cancer cells& Suppurati!e Inflammation 'haracteri0ed by production of large amount of pus composed of neutrophils, necrotic cells and edema fluidIn#ol#es pyogenic bacteria e:g: Streptococci and Staphylococcus aureus(bscesses are focal locali0ed collections of purulent inflammatory tissue caused by suppuration: "lcers Local defect or e$ca#ation of the surface of an organ or tissue by sloughing of inflammatory necrotic tissue (cute stage - intense polymorphonuclear infiltration and #ascular dilation in margin 'hronic stage - margin and base de#elop fibroblastic proliferation, scarring and accumulation of lymphocytes, plasma cells and macrophagesSystemic inflammatory response(cute /hase Response "e#er(cute-phase protein secretion from li#erLeu.ocytosisachycardia, increased blood pressureShi#ering, chills(nore$ia, somnolence, malaiseSeptic shoc.Acute Phase ProteinsSecretion of (cute /hase proteins by the li#er '-reacti#e /rotein %'R/& Serum (myloid ( %S((& Serum (myloid / %S(/& 'omplement "ibrinogen /rothrombin "erritin 'eruloplasmin BC beats/min5 @+3 mm 4g respiratory rate >3C breaths/min, /a'23 or need for mechanical #entilation D=' count >13,CCC/uL or @E,CCC/uL or >1CF immature forms %bands&Sepsis is defined as SIRS associated 6ith suspected or confirmed infection--positi#e blood cultures are not necessarySe#ere sepsis is sepsis complicated by a predefined organ dysfunctionSeptic shoc. is cardio#ascular collapse %hypotension& related to se#ere sepsis despite ade7uate fluid resuscitation Septic stimuliGram-negati#e bacteriaL/S, endoto$in=inds to L/S binding protein %L=/&=inds to '*1E opsonin receptorLR-E binds L/S and L/S-L=/Stimulates release of !", IL-1, IL-AGram-positi#e bacteria9$oto$ins, superantigens=ind ;b regions of 'Rs and/or to )4'-IILR-3 binds cell 6all componentsStimulates release of I"!-g, !", IL-1, IL-AProgression of sepsis'yto.ine release and amplification;asular response and neutrophil migration'oagulation cascadeShort arm, e$trinsic path6ay, acti#ated by e$pression of issue "actor ;IIa Ha thrombin fibrinhigh plasma le#els of plasminogen-acti#ator inhibitor type-1 %/(I-1& suppress plasmin and fibrinolysisdisseminated intra#ascular coagulation in +C-ICF cases'ounter-inflammatory response(poptosis of h and =-cellsSystemic acute phase responseincreased cortisol production and release of catecholaminesupregulation of adhesion moleculesrelease of prostanoids and platelet-acti#ating factor %/("&2rgan failure&ultiple organ failure!eutrophils damage tissue directly by releasing lysosomal en0ymes and supero$ide-deri#ed free radicals!"-< induces nitric o$ide synthasenitric o$ide causes further #ascular instability contributes to direct myocardial depressionDidespread #asodilation*ecreased production of #asopressin %(*4& and glucocorticoids'irculatory collapse and tissue hypo$iaFin#ings of shoc' at autopsy 'ongestion of lung may also ha#e fibrinous casts lining al#eolar spaces /etechial or ecchymotic hemorrhages on serosal and endothelial surfaces !ecrosis pro$imal tubular epithelium in .idneys entrilobular hepatocytes %estoration of Structure an# Function2ccurs if connecti#e tissue structure relati#ely intact Sur#i#ing parenchymal cells must ha#e the capacity to regenerate Labile 'ells (cti#ely di#ide throughout life cells of the epidermis and gastrointestinal mucosa cells lining surface of the genitourinary tract hematopoietic cells of the bone marro6 Stable 'ells 8ndergo fe6 di#isions normally, but can be acti#ated from GC cells 6hen needed hepatocytes renal tubular cells parenchymal cells of glands mesenchymal cells %smooth muscle, cartilage, connecti#e tissue, endothelium, osteoblasts& %egeneration/roliferation of cells and tissues to replace lost structuresDhole organs and comple$ tissues rarely regenerate after injury'ompensatory gro6th rather than true regenerationLi#er hypoplasia and .idney hypertrophy'ontinuously rene6ing tissues regenerate after injury if tissue stem cells are not destroyedStem Cells'haracteri0ed by self-rene6al properties and capacity to generate differentiated cell lineagesobligatory asymmetric replication one daughter cell retains its self-rene6ing capacity the other enters a differentiation path6aystochastic differentiation stem cell di#isions generate either t6o self-rene6ing stem cells or t6o cells that differentiate Stimulation for either outcome is conjectureseemingly randomembryonic stem cells %9S cells& are pluripotentadult %somatic& stem cells are restricted by niche s.in, gut lining, cornea, hematopoietic tissue(S cells an# )O*transgenic mice12 mice ha#e specific gene deletion or inacti#ationransform cultured 9S cellsransformants injected into blastocysts=lastocyst transplanted to surrogate dam)ouse de#elops in uteroransgenic mice ha#e specific human gene insertion or replacementransformed 9S cells injected into blastocysts'ontinued de#elopment in surrogate damSomatic cell cloningReproducti#eransfer of adult nucleus into enucleated oocyte restores pluripotencyransfer of resulting embryo to surrogate dam/roduction of cloned indi#idualherapeuticransfer of adult nucleus into enucleated oocyte restores pluripotencyInduced to differentiate into #arious cell types in #itroInjected into damaged organIn#uce# Pluripotent Stem Cells)ouse 9S cell pluripotency depends on the e$pression of 2ct+/E, So$3, c-myc, 1lfE, !anog4uman fibroblasts from adults and ne6borns ha#e been reprogrammed2ct+/E, So$3, c-myc and 1flE2ct+/E, So$3, !anog, and Lin3,Generated cells from endodermal, mesodermal, and ectodermal originc-myc and 1flE are oncogenesStem Cells in Homeostasis an# Healing=one marro64ematopoietic Stem 'ells generate all of the blood cell lineages)arro6 Stromal 'ells generate precursors of tissue to 6hich migratedLi#er2#al cells are bipotential progenitors of hepatocytes and biliary cells=rain!eural precursor cells generate neurons, astrocytes, and oligodendrocytes in the sub#entricular 0one and the dentate gyrus of the hippocampusS.in4air follicle bulge, interfollicular areas of the surface epidermis, and sebaceous glandsIntestinal epitheliumcrypts are monoclonal structures deri#ed from single stem cells#illus contains cells from multiple cryptsS.eletal and cardiac musclesatellite cells beneath the myocyte basal lamina generate differentiated myocytes after injury'ornealimbal stem cells maintain corneal transparencyProliferati!e capacity of tissuesLabile tissues'ontinuously di#iding tissues containing stem cellsStable tissues/arenchymal cells of solid organs in GC9ndothelial cells, fibroblasts, smooth muscleLimited regeneration after 6ounding/ermanent tissues(bsolutely nonproliferati#e'ardiac muscle, neuronsGro+th factors/olypeptides that promote sur#i#al and proliferation by signal transductionIncrease in cell si0etrue gro6th factorsIncrease in cell numbermitogens/rotection from apoptosissur#i#al factorsSignaling mechanismsReceptors 6ith intrinsic tyrosine .inase acti#ity*imeric transmembrane moleculesLigand binding induces stable dimeri0ation and phosphorylationJtm G/'RsSe#en transmembrane proteinsLigand binding induces association 6ith G/-binding protein, 6hich s6aps G*/ for G/Gi or Gs protein inacti#ates or stimulates another effector Gs acti#ates membrane adenylyl cyclase5 G/G*/ c()/ acti#ates /1(, etc:Receptors 6ithout intrinsic en0ymatic acti#ity)onomeric transmembrane moleculesLigand binding stimulates interaction 6ith K(1sGro+th Factor,me#iate# Proliferation /latelet *eri#ed Gro6th "actor %/*G"& promotes the chemotactic migration of fibroblasts and smooth muscles chemotactic for monocytes competence factor that promotes the proliferati#e response of fibroblasts and smooth muscles upon concurrent stimulation 6ith progression factors 9pidermal Gro6th "actor %9G"& promotes gro6th for fibroblasts, endothelial and epithelial cells is a progession factor - promotes cell-cycle progression: "ibroblast Gro6th "actor %"G"& promote synthesis of fibronectin and other e$tracellular matri$ proteins chemotactic for fibroblast and endothelial cells promotes angiogenesis lin.s e$tracellular matri$ components %collagen, proteoglycans& and macromulocules %fibrin, heparin& to cell-surface integrins: ransforming Gro6th "actors %G"s& G"-< - similar to 9G" G"-L - mitosis inhibitor that aids in modulating the repair process: )ay be responsible for hypertrophy by pre#enting cell di#ision: 'hemotactic for macropahges and fibroblasts )acrophage-deri#ed cyto.ines %IL-1 and !"& promote proliferation of fibroblasts, smooth muscle and endothelial cells %epair ProcessRemo#al of *ebris begins early and initiated by li7uefaction and remo#al of dead cells and other debris "ormation of Granulation issues connecti#e tissue consisting of capillaries and fibroblasts that fills the tissue defect created by remo#al of debris Scarring fibroblasts produce collagen until granulation tissue becomes less #ascular and less cellular progessi#e contraction of the 6ound occurs, resulting in deformity of original structure Factors that Impe#e %epairRetention of debris or foreign body Impaired circulation /ersistent infection )etabolic disordersdiabetes*ietary deficiencyascorbic acid proteinHealing an# granulation "ibroplasia is a response to*amaged connecti#e tissue/arenchymal damage e$ceeds regenerati#e capacity4yperplasia of connecti#e tissue !eo#asculari0ationGranulationcoordinated proliferation of fibroblasts 6ith a rich bed of capillaries intensely hyperemic 6ith a roughened or granular, glistening surface healthy granulation tissue resists secondary infections Healing y First Intention'lean, surgical incision or other clean narro6 cut"ocal disruption of epithelial basement membrane 6ith little cell damageRegeneration dominates fibrosisScabbing 6ith fibrin-clotted blood!eutrophils migrate to edges9pidermis becomes mitotic and deposits 9'))acrophages replace neutrophils;asculari0ation and collagen deposition fills gap'ontraction of collagen minimi0es epidermal regenerationHealingy Secon# IntentionLarger area of tissue injury such as abcess, ulcer, infarction that destroys 9')Large clot or scab 6ith fibrin and fibronectin fills gapLarger #olume of necrotic debris must be remo#ed by more neutrophils and macrophages2pportunity for collateral damage by phagocytesScar tissue formed from #ascular cells, fibroblasts, and myofibroblasts'ontraction of myofibroblasts distorts tissue)ore prone to infection)eloi#-e.cessi!e cutaneous firosisGranulation at tracheotomy