動脈粥樣硬化血栓疾病的炎癥和發(fā)病機制課件

InflammationandthePathogenesisofAtherothromboticDisease

PeterLibby,M.D.Atheromaarenotmerelyfilledwithlipid,butcontaincellswhosefunctionscriticallyinfluenceatherogenesis:IntrinsicVascularWallCells:EndotheliumSmoothMuscleCellsInflammatoryCells:MacrophagesTLymphocytesMastCellsCellTypesintheHumanAtheromaMonocyte/

MacrophageT-lymphocytesTunica

MediaIntimaSmoothmuscle

cellsEndotheliumNo

symptoms+SymptomsSchematicTimeCourseofHumanAtherogenesisTime(y)SymptomsLesioninitiationIschemicHeart

DiseaseCerebrovascular

DiseasePeripheralVascular

DiseaseMacrophageFunctionsinAtherogenesisAttachmentLeukocyte–EndothelialAdhesionMoleculesMonoTBPMNVascularCellAdhesionMolecule1

(VCAM-1)Bindsmonocytesandlymphocytes

-CellsfoundinatheromaExpressedbyendotheliumovernascentfattystreaksExpressedbymicrovesselsofthematureatheromaAnatherogenicdietrapidlyinducesVCAM-1,acytokine-regulatablemononuclearleukocyteadhesionmolecule,inrabbitaorticendotheliumLiHetal.ArteriosclerThromb

1993;13:197-204.VCAM-1ExpressioninRabbitAortaLiHetal.ArteriosclerThromb

1993;13:197-204.3weeksonatherogenicdietPenetrationMacrophageFunctionsinAtherogenesisMonocyte

ChemoattractantProtein1

(MCP-1)ApotentmononuclearcellchemoattractantProducedbyendothelialandsmoothmusclecellsLocalizesinhumanandexperimentalatheromaAbsenceofmonocyte

chemoattractantprotein-1reducesatherosclerosisinlow-densitylipoproteinreceptor–deficientmiceGuLetal.MolCell1998;2:275-281.ReducedLipidDepositioninMCP-1–DeficientAtheroscleroticMiceGuLetal.MolCell1998;2:275-281.LDL-R–/–

MCP-1+/+LDL-R–/–

MCP-1–/–GuLetal.MolCell1998;2:275-281.ReducedLipidDepositioninMCP-1–DeficientAtheroscleroticMiceOilRedStaining%AorticSurfaceStainedTimeonDiet:12–14weeks+/+-/-***+/+-/-20–25weeks*P=0.001comparedto+/+

**p=0.005comparedto+/+MacrophageFunctionsinAtherogenesisActivationMacrophageFunctionsinAtherogenesisDivisionMacrophageColony-StimulatingFactor

(M-CSF)Apotentmonocyteactivatorandco-mitogenProducedbyendothelialandsmoothmusclecellsLocalizesinhumanandexperimentalatheromaAugmentedM-CSFgeneexpressioninhumanandexperimentalatherogenesisRosenfeldMEetal.AmJPathol

1992;140:291-300.ClintonSKetal.AmJPathol

1992;140:301-316.M-CSFExpressioninAtheroma

Intimal

M-CSF

in

AtheromaM-CSFPromotesAtherogenesisSmithJDetal.Decreasedatherosclerosisinmicedeficientinbothmacrophagecolony-stimulatingfactor(op)andapolipoproteinE.ProcNatlAcadSciUSA1995;92:8264-8268.QiaoJHetal.Roleofmacrophagecolony-stimulatingfactorinatherosclerosis:studiesofosteopetroticmice.AmJPathol

1997;150:1687-1699.RajavashisthTetal.Heterozygousosteopetrotic(op)mutationreducesatherosclerosisinLDLreceptor–deficientmice.JClinInvest1998;101:2702-2710.M-CSFDeficiency(opmutation)ReducesAtheromainLDLReceptor–KnockoutMiceRajavashisthTetal.JClinInvest1998;101:2702-2710.+/+op/+op/opM-CSFGeneDosageRelatestoAtheromaSizeinLDLR–/–MiceRajavashisthTetal.JClinInvest1998;101:2702-2710.107FattyLesionsinAorticRoot

(m2/section)106105104103(10)*(4)*(12)Genotypeop/++/+op/opMolecularMediatorsofAtherogenesisM-CSFMCP-1VCAM-1AnatomyoftheAtheroscleroticPlaqueLumenLipidCoreFibrouscapShoulderIntimaMediaElasticlamin?InternalExternalSchematicTimeCourseofHumanAtherogenesisTransitionfromchronictoacuteatheromaIschemicHeart

DiseaseCerebrovascular

DiseasePeripheralVascular

DiseaseThrombosisofaDisruptedAtheroma,theCauseofMostAcuteCoronarySyndromes,Resultsfrom:Weakeningof

thefibrouscapThrombogenicityofthelipidcoreIllustrationcourtesyofMichaelJ.Davies,M.D.MatrixMetabolismandIntegrityofthePlaque’sFibrousCapLibbyP.Circulation1995;91:2844-2850.++++++–SynthesisBreakdownLipidcoreIL-1

TNF-

MCP-1

M-CSFFibrous

capIFN-CD-40LCollagen-degradingProteinasesTissueFactorProcoagulantIncreasedExpressionofInterstitialCollagenase(CL)bySmoothMuscleCells(SMC)andMacrophages(M)inHumanAtheromaGalisZSetal.JClinInvest1994;94:2493-2503.PlaqueRupturewithThrombosisThrombusFibrouscap1mmLipidcoreIllustrationcourtesyofFrederickJ.Schoen,M.D.,Ph.D.ThrombosisofaDisruptedAtheroma,theCauseofMostAcuteCoronarySyndromes,Resultsfrom:Weakeningof

thefibrouscapThrombogenicityofthelipidcoreIllustrationcourtesyofMichaelJ.Davies,M.D.CD40andTissueFactorinAtheromaCD40MachFetal.Circulation1997;96:396-399.TissueFactorCD40LigationInducesTissueFactorExpressioninHumanMonocyte-DerivedMacrophagesLogFluorescenceCellNumbers1601208040016012080400100101102103100101102103rCD40L/-CD40LrCD40LTcell/membranes/

-CD40LTcell/

membranesMachFetal.Circulation1997;96:396-399.CD40ligandonactivatedplateletstriggersaninflammatoryreactionofendothelialcellsHennVetal.Nature1998;391:591-594.Inf