1o Inflammation is a protective response intended to eliminate the initial cause of cell injury- Dilute- Destroy- Isolate- Initiate Repairo Acute and Chronic formsINFLAMMATION Acute InflammationExudation of fluid & plasma proteins (edema) and the emigration of LEUKOCYTES Chronic Inflammationroliferation of !lood vessels" fi!rosis & tissue destruction#refer to ta!le $%& page '(CARDINAL SIGN OF INFLAMMATION Calor ) *eat" resulting from vasodilation of !lood vessels Rubor ) Redness" resulting from vasodilation of !lood vessels Tumor ) +,elling" resulting from edema Dolor ) ain" resulting from local release of prostaglandin and -inins Functio laesa ) .oss (or impairment) of functionACUTE INFLAMMATION%Immediate & early response to tissue injury (physical" chemical" micro!iological" etc/)o 0ascular Changes- 0asodilation- Increase vascular permea!ilityo Cellular Events- Cellular recruitment (12)STIMULI FOR ACUTE INFLAMMATION Infections (3acterial" viral" fungal" parasitic) and micro!ial toxins 4rauma 4issue necrosis 5oreign !odies Immune reactionsRECOGNITION OF MICROES! NECROTIC CELLS " FOREIGNSUSTANCES#$attern reco%nition rece&tors'o 4oll% .i-e Receptors (4.Rs)- 1icro!ial sensors (!acteria" viruses" other pathogens)- 1ediators of inflammation" antiviral cyto-ines (interferons)" and proteino Inflammasome- 1ulti%protein cytoplasmic complex that recogni6es products of dead cells" such as uric acid & extracellular A4" as ,ell as crystals from micro!ial product- Activate caspase ( Activate cyto-ine Interleu-in I7 (I.%(7)(ASCULAR C)ANGESo Changes in vascular cali!er & flo, - 0asodilation- +tasis- 1argination- Increased 0ascular ermea!ility- Responses of lymphatic vesselsLEUKOCYTE CELLULAR E(ENTS%.eu-ocyte leaves the vasalature routinely through the follo,ing se8uence of events9o 1argination and Rollingo Adhesion & 4ransmigrationo Chemotaxis & Activation%4hey are then free to participate in9 hagocytosis & degranulation .eu-ocyte%induced tissue injury1AR:I2A4I;2 A2D R;..I2:- 1argination% leu-ocyte accumulation at the periphery of vesselsE2D;4*E.IA. CE..+ AC4I0A4ED 3< C3C attachR;..I2: CE..+ 3I2D & DE4AC* - and thus !egin to tum!le on the endothelial surfaceMARGINATION AND ROLLING- Early rolling adhesion mediated !y selectin familyo E% selectin (Endothelium)o % selectin (latelets" endothelium)o .% selectin (.eu-ocytes)AD)ESION- 5irm adhesion to endothelial surfaces of >3C- 1ediated !y integrins on >3C .5A%(" 1ac%(" 0.A%?- Interact ,ith endothelial ligands ICA1%(" 0CA1%( (ICA1%( !inds .5A%(@1ac%(" 0CA1 !inds 0.A%?)TRANSMIGRATION *DIA$EDESIS+- .eu-ocytes migrate through the vessel ,all primarily !y s8uee6ing !et,een cells at intercellular junction via ECA1%( (CD$()- 1ust then cross !asement mem!raneC)EMOTA,IS - .eu-ocytes follo, chemical gradient to site of injury (chemotaxis)- +olu!le !acterial products- Complement components (CAa)- Cyto-ines (Chemo-ine family e/g I.%B)- .43? (AA meta!olite)C)EMOTA,IS AND ACTI(ATION .eu-ocytes- External pseudopods ,ith overlying surface adhesion molecules (integrins) that !ind EC1 during chemotaxis Cndergo Activation- hagocytosis of particles- Intracellular destruction of phagocytose micro!es & dead cells- .i!eration of su!stances that destroy extracellular micro!es and dead tissues- roduction of mediatorsLEUKOCYTE INDUCES TISSUE IN-URYDestruction id caused !y free radicals (R;+) generated in activated leu-ocytes and lysosomal en6ymes Cases9 Infections that hard to eliminate rolonged inflammation resulting to ischemia Inflammatory response is inappropriately directed against host tissuesDefects of .eu-ocyte 5unction- Inherited defects in leu-ocyte adhesionChapter III (GenPath- Midterms)Outcomes- Resolution- Chronic infammationFibrosisGenetic or acquired deects in leu!oc"te unctions #i$e rise to recurrent inectionsPha#oc"tosis% !illin# and de#radation o the o&endin# a#ent ollo'(eu!oc"te Cellular )$ents- Mar#ination * Rollin#- +dhesion-,ransmi#ration- Chemota-isIncrease .ascular Permeabilit"- )-udates / protein rich e-tracellular fuid- ,issue edema.ascular Chan#es- Increase 0lood fo'- 1ilation - )r"thema * 'armth2- Inherited defects in phagolysosome function- Inherited defects in micro!icidal activity- Ac8uired deficiencies1orphologic atterns of Acute Inflammation- +erous inflammation- 5i!rinous inflammation- +uppuratic (purulent) inflammation and a!scess- ClcerMEDIATORS OF INFLAMMATIONC.emical Me/iatorso lasma derived- Complement" -inins" coagulation factors- 1any in Dpro%formE re8uiring activation (En6ymatic cleavage)o Cell derived9- reformed" se8uestered & release (mast cell histamine)- +ynthesi6ed as needed (rostaglandin)C.ronic In0lammation- Is the persistence of inflammation ,ith attempts of repair resulting from persistence of the injurious agent- .ymphocyte" macrophage" plasma cell (mononuclear cell) infiltration- 4issue destruction !y inflammatory cells- Attempts at repair ,ith fi!rosis and angiogenesis (ne, vessel formation)- >hen acute phase cannot !e reduced ersistent injury or infection (Clcer" 43) rolonged toxic agent exposure (+ilica) Autoimmune disease states (RA" +.E)Causes o0 C.ronic In0lammation- ersisting infection or prolonged exposure to irritants (intracellular surviving of agents" 43)- Repeated Acute inflammation (;titis" rhinitis)- rimary chronic inflammation ) lo, virulence sterile inflammations (silicosis)- Autoimmune reactions (Rheumatoid arthritis" +.E)Mor&.olo%ic Features- Infiltration ,ith mononuclear cells" ,hich include macrophages" lymphocytes & plasma cells- 4issue destruction" induced !y the persistent offending agent or !y the inflammatory cells- Attempts at healing !y connective tissue replacement of damaged tissue accomplished !y proliferation of small !lood vessels (angiogenesis) & in particular fi!rosisT.e $la1ers *Mononuclear $.a%oc1te S1stem+o Macro&.a%es- +cattered all over ( microglia" -upffer cells" histiocytes" alveolar macrophages" etc/)- Ciculate as monocyte and reach site of injury ,ithin &?%?B hrs & transform- 3ecome activated !y 4%cell derived cyto-ines" endotoxins & other products of inflammationOt.er Cells in C.ronic In0lammationo T "L1m&.oc1tes- Antigen activated ( via macrophages & dendritic cells)- Release macrophage%activating cyto-ines (in turn" macrophages release lymphocyte% activating cyto-ines until inflammatory stimulus is removed)o $lasma cells- 4erminally differential 3 cells- roduce Anti!odieso Eosino&.ils- 5ound especially at sites of parasitic infection" or at allergic (IgE%mediated) sitesGranulomatous In0lammationo Clusters of 4%cell activated macrophages" ,hich engulf and surround indigesti!le foreign !odies (1yco!acteria" */ capsulatum" silica" suture arterial)o Resem!le s8uamous cells" therefore called DepithelioidE granulomas$atterns o0 Acute " C.ronic In0lammationo +erous- >atery" protein%poor effusion (e/g !lister)o 5i!rinous- 5i!rin accumulationChapter III (GenPath- Midterms)SEQUENCE OF EVENTS INACUTE INFLAMMATION3- Either entirely removed or !ecomes fi!rotico Su&&urati2e - resence of pus (pyogenic +taph spp/)- ;ften ,alled off if persistento Ulceration- 2ecrotic & eroded epithelial surface- Cnderlying acute & chronic inflammation- 4rauma" toxins" vascular insufficiencySYSTEMIC EFFECTSo Fe2er- ;ne of the easily recogni6ed cyto-ine%mediated (esp/ I.%(" I.%F" 425) acute phase including reactions- Anorexia- +-eletal muscle protein degradation- *ypotensiono Leu3oc1tosis- Elevate ,hite !lood cell count- 3acterial infection (neutrophilia)- arasitic infection (eosinophilia)- 0iral infection (lymphocytosis)o Acute $.ase Res&onse- Increased heart rate and 3lood ressure (3)- Decreased s,eating- Rigors (shivering)- Chills (erception of !eing cold)o Se&sis ) +evere !acterial infections in !lood- roduction of cyto-ines causing DIC- Acidosis- *ypotensive shoc-o Ele2ate/ &lasma le2els o0 acute &.ase &roteins- C reactive protein (CR) fi!rinogen & +erum Amyloid A (+AA) proteinChapter III (GenPath- Midterms)