Mediators of the Acute Inflammatory Reaction.docx

Mediators of the Acute Inflammatory Reaction.docx

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MediatorsoftheAcuteInflammatoryReaction

10MediatorsoftheAcuteInflammatoryReaction

Theclosesimilarityoftheacuteinflammatoryreactiontodiversetypesofinjury,thehighlyorderedsuccessionofeventsextendingovermanyhourswhichfollowaninjurylastingonlyabreifperiod,andthespreadoftheinflammatoryreactiontoadjacentuninjuredtissuesallsuggestthatchemicalsubstances,liberatedwithininjuredtissues（endogenouschemicalmediators）,playaroleinthegenesisoftheacuteinflammatoryreaction.

Endogenousmediatorsappeartoberesponsibleforbothvasodilatationandleucocyticcausethoseformsofincreasedvascularpermeabilitywhicharenotaresultofdirectinjurytoofendogenoussubstanceswhichcanreproduceoneormorefeaturesofacuteinflammationhavebeenidentifiedininjuredtissuesandininflammatoryexudates,butlittleisknownforcertainaboutwhichofthesepotentialmediatorsareofimportanceinparticulartypesofinflammation.

Proofoftheparticipationofaspecifiemediatorrequiresthedetectionofitspresenceinactiveformandeffectiveconcentrationduringtherelevantperiod,andinhibitionoftheresponsebyprioradministrationofspecificantagonisticdrugs.Thesecreteriahavenotbeensatisfiedforanymediatorexcepthistaminewhichhasbeenshowntoberesponsibleforthebrief,andrelativelyunimportant,initialphaseofleakageaftermanytypesofinjury.Itisthereforenotappropriatetogiveadetailedaccountofthepossiblechemicalmediatorsofiflammation,andthenoteswhichfollowontheirproductionandactionsareintentionallybrief.

Possibleendogenousmediators

Thesemaybedividedintothoseformedinplasmaandthosearisingfromtissuecells.

Plasmafactors

Theseincludeproductsofactivationandinteractionoffourmajorcascadesystems–thekinin,complement,coagulationandfibrinolyticsystems.

1.Thekininsystem.Onamolarbasisthemostpotentknownvascularpermeabilityfactorisbradykinin,anonapeptideformedbydigestionofaplasmaglycoprotein,kininogen,byaproteolyticenzyme,kallikrein,foundinnormalplasmaasitsinactiveprecursor,prekallikrein.ContactofplasmawithdamagedtissuesorwithaforeignsurfaceactivatesHagemanfactor（factorXIIofthecoagulationcascade）whichconvertsprekallikreintokallikrein.Enzymeswithkallikreinactivityarepresentinmanytissues,inurineandinglandularsecretions.Severalpeptidescloselyrelatedtobradykinincanbereleasedbysimilarenzymesystemsandarealsopowerfulpermeabilityfactors（i.e.increasevascularpermeability）.Kininsaredestroyedrapidlybykininasesinplasmaandintissues,bothofwhichalsocontairkallikreinantagonists.

Beforethekininsystemwascharacterised,apartofitwasdescribedbyMilesandWilhelmunderthenameofPF/dil,whichisprobablyacombinationofseveralelementsofthekininsystemandnotaspecificsubstance.

2.Thecomplementsystem.Itsactivationbythe‘classicalpathway’isacascadereactioninwhichninemajorcomponents,someofwhicharepro-enzymes,reactsequentially,resultinginacytolyticcomplexwhichdisruptstheintegrityofcellmembranes.Asecondsequenceofativation,thealternativepathway,involvesadditionalcomponentsandby-passesthefirstthreestagesoftheclassicalcomplementcascade.

Atvariousstagesalongthecomplementcascade,biologicallyactiveby-productsarereleasedbyenzymiccleavageofcomplementcomponents.Somearepermeabilityfactorsandothershavechemotacticorchemokineticeffectsonbloodleucocytes.Theseactiveby-productscanbegeneratedalsobythedirectactionofvariousproteolyticenzymes,presentindamagedtissues,oncomplementcomponents,especiallyC3andC5.

Complementby-productsincludethefollowing.

（1）C5a,acleavageproductofthefifthcomponentofcomplement（C5）,whichhasbothchemotacticandpermeability-increasingproperties.Thelatereffectispartlyadirectoneonvenularendotheliumandpartlymediatedbytriggeringreleaseofhistaminefrommastcells.C3a,aproductofC3,hassimilarbutweakerproperties,andC3aandC5aarewidelybutinappropriatelyknownasanaphylatoxins.

（2）AhighmolecularweightcomplexofC5,6and7,whichhasbeenclaimedtohavechemotacticactivity.

Formationofakinin-likesubstancebycleavageofC2haslongbeensuspectedbutitnowseemslikelythatthisisreallyakinin,productionofthichisinhibitedbyC-INHwhichalsoinhibitsactivationofcomplement.

Inthecomplexenvironmentofacuteinflammation,thecomplementsystemcanbeactivatedinvariousways,notablyasfollows.

（i）Ininfections,unionofantibodieswithmicro-organismsortheirantigenicproductscanactivatecomplement.TheendotoxinsofGramvebacteriacanactivatecomplementattheC3stageandenzymessecretedbysomebacteriaarecapableofactivatingC3andC5.

（ii）Intissueinjury,e.g.ischaemicnecrosisofheartmuscle,enzymescapableofactivatingC3andC5arereleasedfromthedyingcells.

（iii）Activatioproductsofthekinin,clottingandfibrinolyticsystems（seebelow）,arecapableofactivatingcomplement.

3.Thecoagulationandfibrinolyticsystems.Thecoagulationorclottingsystembringsabouttheconversiongofsolublefibrinogentoinsolublefibrin.Biologicallyactivepeptidesarereleasedduringthisconversionandinthesubsequentlysisoffibrinbyplasmin,anenzymepresentininactiveform,plasminogen,innormalplasma.Thesepeptidescanaffectbothvascularpermeabilityandthemovementofleucocytes.

Thedifferentcascadesystemsoutlinedabovearerelatedinavarietyofways,andeachcanenhacetheactivityoftheothers.Hagemanfactorplaysakeyrole.Itisactivatedbycontactwithextravasculartissueelementsincludingbasementmembrane,bybacterialenzymesandbycertainproteolyticenzymes.Onceinflammationhasbegun,Hagemanfactorleakingthroughgapsintheendotheliumofsmallbloodvesselscanactivateallthreemediatorsystems.Elementsineachsystemcan,inturn,activatemoreHagemanfactor.

Despitethesecomplexinteractions,itseemslikelythatthemajorinflammatoryendproductsofthethreeplasmacascadesarebradykininandcomplementactivationproductsC3aandC5a.

Factorsreleasedfromtissuecells

Histamineispresentininactiveforminmastcells,eosinophilandbasophilleucocytesandplatelets.Itcanbereleasedfromthesedepotsbyinflammatorystimuli,bycomplementactivationproductsC3aandC5aandbyalysosomalproteinsecretedbypolymorphs.Histaminecanalsobesynthesisedbytheenzymehistidinedecarboxylasepresentinothertypesofcell.

Histaminecausesactivehyperaemiaandincreasedvascularpermeabilitylasting10-15minutes.Itisresponsiblefortheimmediatetransientphaseofincreasedpermeabilityseenaftermanytypesofmildinjury.

Serotonin（5-hydroxytryptamine）isfoundinlargeamountsinmastcellsandinplateletsandinlesseramountsinmanyothertypesofcell.Inratsandmice,serotoninincreasesvascularpermeabilityinasimilarwaytohistamine.Inmanitisapotentvasoconstrictorbutdoesnotincreasevascularpermeability.

Aswellashistamineandserotonin,stimulatedmastcellscanreleaseotheractiveproductsincludingSRS-Aandaneosinophilchemotacticfactorofanaphylaxis,ECF-A,whichisstronglychemotacticforeosinophils.

Prostaglandins（PG）andleukotrienes.Prostaglandinsarelong-chainhydroxy-fattyacidswhichcanbesynthesisedandreleasedbymosttypesofcells,butarenotstoredwithincells.Individualprostaglandinsdifferintheireffects.Some,includingE,andE2,arepowerfulvasodilatorsandpotentiategreatlytheincreasedpermeabilityinducedbyotheragents.Despiteearlierclaimstheydonotthemselvesincreasevascularpermeability.Otherprostaglandinscaninhibitcertainoftheprocessesofinflammation.ProstaglandinI2（prostacyclin）,secretedbyvascularendothelium,hasapowerfulinhibitorydffectonplateletaggregationandappearstoinhibitalsotheadherenceofleucocytestovascularendothelium.ThromboxaneA2,liberatedfromboodplatelets,hastheoppositeeffect,beingamostpowerfulplateletaggregatingagent.Firmevidenceoftheroleofprostaglandinsininflammationisscanty,buttheanti-inflammatoryeffectofaspirinandrelateddrugshasbeenshowntobeduetoinhibitionofprostaglandinsynthetase（cyclo-oxygenase）,anenzymeconcernedinthesynthesisofprostaglandins.

Leukotrienes.Morerecently,compoundstermedleukotrienes（LTs）havebeenproposedeasmediatorsofacuteinflammation.Theyareproducedbytheactionoflipoxygenaseonarachidonicacid.LTB4issecretedbyneutrophilpolymorphsininflammatorylesions:

itischemotaciticforneutrophilandeosinophilpolymorpinsandmonocytes.Onceafewneutrophilpolymorphshavemigratedintoinflamedtissues,releaseofLTB4presumablypromotestheaccumulationofmorepolymorphs.LTC4andLTD4aresecretedbyactivatedmastcells:

theyarecapableofinducingvasculardilatationandincreasedvenularpermeability.SRS-A（slow-reactingsubstanceofanaphylaxis）isamixtureofLTC4andLTD4,andhasbeenshowntobeinvolvedinthebronchospasmofasthma.

Lysosomalcomponents.Potentialmediatorsmaybereleasedfromlysosomes,especiallyfromneutrophilpolymorphs,butalsofromothercellsincludingmacrophagesandplatelets.Themostimportantlysosomalproductsininflammationappeartobecationicproteinsandneutralproteases.Cationicproteinscanincreasepermeability,eitherdirectlyorviamastcells,andarechemotactictomonocytes.Theneutralproteasesareinvolvedintissuedamageaftermanytypesofinjury,andcangeneratechemotacticfactorsbycleavingC5andprobablyalsoC3.

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