Inflammationaprotectiveresponseinvolvinghostcells,bloodvessels,andproteinsandothermediatorsthatisintendedtoeliminatetheinitialcauseofcellinjury,aswellasthenecroticcellsandtissuesresultingfromtheoriginalinsult,andtoinitiatetheprocessofrepair.

WhatisInflammation?Thosewhokillthemicrobesmayalsoinjurethenormaltissues.Whenthereactionsaretoostrong,prolongedorinappropriate,damagemaybecomedominant.Relatedwithchronicdiseaseandcancer.Whydoweuseanti-inflammatorydrugssometimes?StimuliforInflammationInfectionTraumaandvariousphysicalandchemicalagentsTissuenecrosisForeignbodiesImmunereactionsAnythingthathurtcellsRecognitionofMicrobes,NecroticCells,andForeignSubstancesPhagocytes,dendriticcellsandepithelialcells…expressreceptorsthatsensethepresenceofinfectiouspathogensandsubstancesreleasedfromdeadcells.Toll-likereceptors(TLRs)InflammasomeuricacidandextracellularATPcholesterolcrystalsandfreefattyacidsWhatisgoingon?InflammationisastereotypedresponseDilutetoxinsDestroycausativeagentsRemovedebrisIsolatethedamagedareaInitiaterepairingExudatesThecomponentsofacuteandchronicinflammatoryresponsesandtheirprincipalfunctions5cardinalsignsAeromonashydrophilainfectionfollowingpuncturewithfishinghookCellulitisChronicglomerulonephritisTypesofinflammationAcuteinflammationShortdurationNeutrophils(PMNs)accumulationFluidandplasmaproteinexudationChronicinflammationLongerdurationAccumulationofM

andlymphocytesProliferationoffibroblastsandbloodvesselsFeaturesofAcuteandChronicInflammationFeatureAcuteChronicOnsetFast:minutesorhoursSlow:daysCellularinfiltrateMainlyneutrophilsMonocytes/macrophagesandlymphocytesTissueinjury,fibrosisUsuallymildandself-limitedOftensevereandprogressiveLocalandsystemicsignsProminentLessprominent;maybesubtle

AcutePneumonia

ChronicPneumonia

AcuteinflammationAcuteinflammationVascularchanges

vasodilation(hyperemia)increasedvascularpermeability(leakage)increasedadhesionofleukocytes

Cellularevents

cellularrecruitment

eliminationtheoffendingagent(activation)Howhyperemiaoccurs?inflammatorymediatorsDilationofarteriolesOpeningupofcapillariesTransientArteriolerConstrictionFluidandproteinleakageIncreasedinterendothelialspacestransudateExudatemostlythevenules20-60micronsStasisandMarginationWhatincreasesthepermeability?Endothelialcellcontractionleadingtointercellulargapsinpostcapillaryvenules

Endothelialinjury(necrosisordetachment)ImmediateDelayed

IncreasedtranscytosisofproteinsLeakagefromnewbloodvesselsImmediatetransientleakage

Beginsimmediately;last15to60minCausedbyhistamineandleukotrienes,etcBasementmembraneEndothelialcellIntactcelljunctionGapsbetweencellsNormalvessel

VesselduringinflammationHyperemiaandleakageresultin…Protein-richfluidmovesout(exudatesandexudation)Fluidaccumulationinextravascularspacesproducesedema/effusionStasisandLeuko-cytesmarginationTransudatesCrossesintactmembraneMostclear(acellular)CausedbyhydrostaticimbalanceorosmoticgradientsExudatesCrossesthroughgapsincapillaryMostcloudy(cellular)CausedbyinflammationEdemacanbecausedbyexudatesortransudatesPericardialEffusion:ExudateVersusTransudate

ExudateTransudateEtiologyMalignancy

Infectious

Postpericardiotomysyndrome

CollagenvasculardiseasesRadiation

Uremia

Hypothyroidism

TraumaSpecificgravity(g/mL)>1.015<1.015Totalprotein(g/dL)>3.0<3.0Fluid/serumproteinratio>0.5<0.5Fluid/serumLDHratio>0.6<0.6Fluid/serumglucoseratio<1.0>1.0LDH=lactatedehydrogenaseExudatesortransudates?Exudatesortransudates?Exudatesortransudates?AscitesApatientwithlivercirrhosisResponsesofLymphaticVesselsHelpsdrainedemafluid,leukocytes,andcelldebrisMaytransporttheoffendingagent(especiallymicrobes)lymphangitislymphadenitislymphangitisduetoTrypanosomiasistsetseflylymphadenitisduetotularemiaGroinArmpitNeckUnderthejawandchinBehindtheearsOnthebackofthehead

Commonareaswherethelymphnodescanbefeltinclude:

LeukocyteRecruitmentandActivationLeukocytesarerecruitedandactivatedonlywhenandwheretheyareneeded.Leukocytesareinformedandendowedwithabilities:tostopinthebloodflowtodiapedesisandtraveltowardthetargettokillLeukocyterecruitmentmarginationandrollingalongthevesselwallfirmadhesiontotheendotheliumtransmigrationbetweenendothelialcells(diapedesis)migrationininterstitialtissuestowardachemotacticstimulus(chemotaxis)EndothelialMoleculeLeukocyteMoleculeMajorRoleP-selectinSialyl-LewisX-modifiedproteinsRolling(neutrophils,monocytes,lymphocytes)E-selectinSialyl-LewisX-modifiedproteinsRollingandadhesion(neutrophils,monocytes,Tlymphocytes)GlyCam-1,CD34L-selectinRolling(neutrophils,monocytes)*ICAM-1(immunoglobulinfamily)CD11/CD18integrins(LFA-1,Mac-1)Adhesion,arrest,transmigration(neutrophils,monocytes,lymphocytes)VCAM-1(immunoglobulinfamily)VLA-4integrinAdhesion(eosinophils,monocytes,lymphocytes)CD31CD31Transmigration(allleukocytes)chemoattractantsChemotaxisChemoattractantsSolublebacterialproductsComplementcomponentsC5aChemokines(IL-8,MCP-1)LTB4(AAmetabolite)TransmigrationAmoeboidmovementWhattypeofleukocytesarerecruitedindifferentsettingsofinflammation?VarieswiththeageoftheinflammatoryresponsethetypeofstimulusViralinfection---lymphocytesHypersensitivityreactions---eosinophilsPMNsMonocytes/macrophges6hr24hr48hr72hrViralencephalitisAsthmaLeukocytesactivationPhagocytosis

recognitionandattachmentoftheparticletotheingestingleukocyteengulfmentkillinganddegradationoftheingestedmaterial.ProductionofmediatorsLiberationofsubstancesthatdestroyextracellularmicrobesanddeadtissuesPhagocytosisOxygendependent(oxidativeburst)reactiveoxygenspecies(ROS)Oxygen-independentlysosomalenzymes…DestructivemechanismsoftheleukocytessuperoxideionhydrogenperoxidehypochlorousradicalOxygen-independentkillingBactericidalpermeabilityincreasingprotein(BPIP)DegradesmembranephospholipidDefensinsPunchesholesinbacterialmembraneLysozymeCleavesugarchainsinbacterialcellwallsAlsofoundintears,mucus,urineOxygen-independentkillingMajorbasicproteinCytotoxicforparasitesIneosinophilgranule

LactoferrinBindsironforbacteriagrowthAcidicpH(around4-6)DegradativeenzymesDigestbacterialcomponentsLiquefydebrisphagocyteAlongfibreLeakedenzymes

FrustratedphagocytosisNeutrophilextracellulartraps(NETs)Leukocyte-InducedTissueInjury"bystander"tissuesIschemiareperfusionAutoimmunediseasesAcquiredDefectsinLeukocyteFunctionRadiationinjuryCancertherapyGlucocorticoidadministrationDiabetesAlcoholismInheritedDefectsinLeukocyteFunctionDefectsinleukocyteadhesionLAD-1LAD-2Defectsinmicrobicidalactivity

ChronicgranulomatousdiseaseDefectsinphagolysosomeformation

Chédiak-HigashisyndromeCGDOutcomesofacuteinflammation

SARSSARS

suvivingpatientDifusseinterstitialpulmonaryfibrosisSummary:Acuteinflammationrapidlydelivers…and…tositesofinjurythemainvascularreactionsare…and…theresultingfluidaccumulationiscalled…aftertheendothelialcellsgetthesignalfrom…,theyandleukocytesupregulatetheexpressionof…tofacilitatethemovementsofleukocytesthatinclude………and……predominateintheearlyinflammatoryinfiltrateandarelaterreplacedby….themainjobsofleukocytesatsiteare…and…themostpowerfulweaponstokilliscalled…ownedby…acuteinflammationoftencauseunwanteddamagebecause…theoutcomesmaybe…,…or…Summary:AcuteinflammationMorphologicPatternsofAcuteInflammationSerousinflammationFibrinousinflammationSuppurative(purulent)inflammationandabscessformationUlcerSerousinflammation

AskinblisterHerpessimplexvirusinfection

Skinblister

Skinblisters

pleuraleffusionFibrinouspericarditisFibrinousPericarditis

FibrinousPericarditis

Earlyorganizationofthefibrinousexudateadhesivepericarditis

constrictivePericarditis

PseudomembraneAPSEUDOMEMBRANEresultswhentheupperportionofamucosalsurfaceundergoesnecrosis,freeingfibrinogenfromvesselsthatthenclotsalongthesurfaceDiphtheriaCorynebacteriumdiphtheriaeDiphtheriatheintenseintrabronchialexudatethatmakesupthepseudomembraneIrregularyellowplaquesofpseudomembrane(blackarrow)withinterveningedematousbowelmucosa(whitearrow)inan87-year-oldwoman.ProctoscopePseudomambranouscolitisHistoryofthepatient10daysearlier,shehadbeentreatedforrightlowerlobepneumoniaatanotherinstitution.Shewasdischargedonmoxifloxacin(Avelox)anddoxycycline(Vibramycin).Shereturnedhome,whereshewasrecovering,butthenshebecameweak,shortofbreath,andconstipated.Shealsopassedseveralloosestools.Pseudomambranouscolitis

47yearoldpatientwhorecentlyfinishedacourseofantibiotics,nowhaswaterydiarrheaandabdominalpain.

ClostridiumdifficileinfectionRecenthistoryofantibioticuseSuddenleukocytosisAgeandfrailconditionHowtodiagnose?Howtotreat?

acutelobarpneumoniaNormallung

acutelobarpneumoniaPulmonaryfibrosis(complication)Suppurative(purulent)inflammationAnexudateconsistingofneutrophils,necroticcells,andedemafluidisPUSThepreferredadjectivetodescribethingswithlotsofpusisPURULENT.ToproducepusistoSUPPURATEPusthatliterallyfillsanimportantbodycavityiscalledanEMPYEMAPurulentmeningitisGyrusSulusPurulentmeningitisPurulentmeningitisSuppurativeexudatesonappendixserosaAcuteappendicitisNormalappendixAcuteappendicitisAcuteappendicitisAcuteappendicitis…thelumenPusinthelumenoftheappendixAcuteappendicitisNormalappendix…musclesDiscussion

Whentreatedpromptly,mostpatientsrecoverwithoutdifficulty.Iftreatmentisdelayed,theappendixcanburst,causingperitonealinfectionandevendeath.

Why?AbscessPusinaconfinedspaceotherthananaturalbodycavityCausedbyseedingofpyogenicorganismsintoatissuesecondaryinfectionsofnecroticfociAsthepusbuildsuppressure,abscessesmayfindtheirwaytoasurfaceandrupture.renalabscessLiverabscessLungabscessFuruncle(boil)Furuncle(boil)Furuncle(boil)carbuncleToothabscessFistulaformedfromanorectalabscessCavityduetopulmonaryabscessacutepyelonephritisUlceranulcerformswhennecrosishasinvolvedabodysurfaceandaportionofitissloughed.theremustbenecrosisofboththeepitheliumandatleastsomeoftheunderlyingconnectivetissue.PepticulcerduodenalulcersstomachulcersUpperendoscopyX-ray(barium)PepticulcerChemicalmediatorsResponsibleforthevascularandcellulareventsReleased(histamine),produced(PG)oractivatedatthesiteofinflammationDerivedfromcellsorplasmaMostactbybindingtospecificreceptorsondifferenttargetcells,othershavedirectenzymaticand/ortoxicactivities(ROS).Theactionsofmostmediatorsaretightlyregulatedandshort-lived.ChemicalmediatorsCell-derivedmediatorsHistamin(vasoactiveamines)releasedfrommastcellcausesarteriolardilationandrapidlyincreasesvascularpermeabilityby…ArachidonicAcidMetabolites(Eicosanoids):Prostaglandins,Leukotrienes,andLipoxinsArachidonicAcidMetabolitesAAisacomponentofcellmembranephospholipids

(GlucocorticoidsinhibittheactivityofphospholipaseA2andthusthereleaseofAA)

Leukocytes,mastcells,endothelialcells,andplateletsarethemajorsourcescanmediatevirtuallyeverystepofinflammationArachidonicAcidMetabolitesProstaglandins(PG..)vasodilationandpotentiatesedemaformationcontributetothepainandfever

Nonsteroidalanti-inflammatorydrugs(NSAIDs)inhibitcyclooxygenaseactivitythusblockingeicosanoidsynthesis

ArachidonicAcidMetabolitesLTB4isproducedbyneutrophilsandsomemacrophagesandisapotentchemotacticagentforneutrophils.

LipoxinsinhibitneutrophilchemotaxisandadhesionMadebycellsthathaveescapedthebloodPlateletsproducelipoxinsbyatranscellularbiosyntheticpathway

PrincipalInflammatoryActionsofAAMetabolitesActionEicosanoidVasodilationProstaglandinsPGI2(prostacyclin),PGE1,PGE2,PGD2VasoconstrictionThromboxaneA2,leukotrienesC4,D4,E4IncreasedvascularpermeabilityLeukotrienesC4,D4,E4Chemotaxis,leukocyteadhesionLeukotrieneB4,HETEOthercell-derivedmediatorsPlatelet-ActivatingFactorCytokines(TNF,IL-1,IL-6,chemokines)

ROSNitricOxideLysosomalEnzymesofLeukocytesNeuropeptidessuchassubstancePThecomplement-derivedfactorsPositivevasculareffects(C3aandC5a)Leukocyteactivation,adhesion,andchemotaxis(C5a)Phagocytosis(C3basaopsinin)membraneattackcomplex(MAC)killsCoagulationandKininSystemsbradykinincausesincreasedvascularpermeability,arteriolardilationandpainCoagulationproteins:ActivatedfactorXIItriggerstheclotting,kinin,andcomplementcascadesandactivatesthefibrinolyticsystem.

Chronicinflammationofprolongedduration(weekstoyears)PersistentinfectionsImmune-mediatedinflammatorydiseasesProlongedexposuretopotentiallytoxicagentsConditionsassociatedwithchronicdiseasesuchasAlzheimerdisease,atherosclerosis,type2diabetes,andsomeformsofcancer

continuinginflammation,tissueinjury,andhealing,proceedsimultaneously

ChronicinflammationInfiltrationwithmononuclearcells,

includingmacrophages,lymphocytes,andplasmacellsTissuedestruction,

largely