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InflammationandthePathogenesisofAtherothromboticDisease
PeterLibby,M.D.InflammationandthePathogeneAtheromaarenotmerelyfilledwithlipid,butcontaincellswhosefunctionscriticallyinfluenceatherogenesis:IntrinsicVascularWallCells:EndotheliumSmoothMuscleCellsInflammatoryCells:MacrophagesTLymphocytesMastCellsAtheromaarenotmerelyfilledCellTypesintheHumanAtheromaMonocyte/
MacrophageT-lymphocytesTunica
MediaIntimaSmoothmuscle
cellsEndotheliumCellTypesintheHumanAtheroNo
symptoms+SymptomsSchematicTimeCourseofHumanAtherogenesisTime(y)SymptomsLesioninitiationIschemicHeart
DiseaseCerebrovascular
DiseasePeripheralVascular
DiseaseNo
symptoms+SymptomsSchematiMacrophageFunctionsinAtherogenesisAttachmentMacrophageFunctionsinAtheroLeukocyte–EndothelialAdhesionMoleculesMonoTBPMNLeukocyte–EndothelialAdhesionVascularCellAdhesionMolecule1
(VCAM-1)Bindsmonocytesandlymphocytes
-CellsfoundinatheromaExpressedbyendotheliumovernascentfattystreaksExpressedbymicrovesselsofthematureatheromaVascularCellAdhesionMoleculAnatherogenicdietrapidlyinducesVCAM-1,acytokine-regulatablemononuclearleukocyteadhesionmolecule,inrabbitaorticendotheliumLiHetal.ArteriosclerThromb1993;13:197-204.AnatherogenicdietrapidlyinVCAM-1ExpressioninRabbitAortaLiHetal.ArteriosclerThromb1993;13:197-204.3weeksonatherogenicdietVCAM-1ExpressioninRabbitAoPenetrationMacrophageFunctionsinAtherogenesisPenetrationMacrophageFunctionMonocyteChemoattractantProtein1
(MCP-1)ApotentmononuclearcellchemoattractantProducedbyendothelialandsmoothmusclecellsLocalizesinhumanandexperimentalatheromaMonocyteChemoattractantProteAbsenceofmonocytechemoattractantprotein-1reducesatherosclerosisinlow-densitylipoproteinreceptor–deficientmiceGuLetal.MolCell1998;2:275-281.AbsenceofmonocytechemoattraReducedLipidDepositioninMCP-1–DeficientAtheroscleroticMiceGuLetal.MolCell1998;2:275-281.LDL-R–/–
MCP-1+/+LDL-R–/–
MCP-1–/–ReducedLipidDepositioninMCGuLetal.MolCell1998;2:275-281.ReducedLipidDepositioninMCP-1–DeficientAtheroscleroticMiceOilRedStaining%AorticSurfaceStainedTimeonDiet:12–14weeks+/+-/-***+/+-/-20–25weeks*P=0.001comparedto+/+
**p=0.005comparedto+/+GuLetal.MolCell1998;2:27MacrophageFunctionsinAtherogenesisActivationMacrophageFunctionsinAtheroMacrophageFunctionsinAtherogenesisDivisionMacrophageFunctionsinAtheroMacrophageColony-StimulatingFactor
(M-CSF)Apotentmonocyteactivatorandco-mitogenProducedbyendothelialandsmoothmusclecellsLocalizesinhumanandexperimentalatheromaMacrophageColony-StimulatingAugmentedM-CSFgeneexpressioninhumanandexperimentalatherogenesisRosenfeldMEetal.AmJPathol1992;140:291-300.ClintonSKetal.AmJPathol1992;140:301-316.AugmentedM-CSFgeneexpressioM-CSFExpressioninAtheroma
Intimal
M-CSF
in
AtheromaM-CSFExpressioninAtheroma
IM-CSFPromotesAtherogenesisSmithJDetal.Decreasedatherosclerosisinmicedeficientinbothmacrophagecolony-stimulatingfactor(op)andapolipoproteinE.ProcNatlAcadSciUSA1995;92:8264-8268.QiaoJHetal.Roleofmacrophagecolony-stimulatingfactorinatherosclerosis:studiesofosteopetroticmice.AmJPathol1997;150:1687-1699.RajavashisthTetal.Heterozygousosteopetrotic(op)mutationreducesatherosclerosisinLDLreceptor–deficientmice.JClinInvest1998;101:2702-2710.M-CSFPromotesAtherogenesisSmM-CSFDeficiency(opmutation)ReducesAtheromainLDLReceptor–KnockoutMiceRajavashisthTetal.JClinInvest1998;101:2702-2710.+/+op/+op/opM-CSFDeficiency(opmutation)M-CSFGeneDosageRelatestoAtheromaSizeinLDLR–/–MiceRajavashisthTetal.JClinInvest1998;101:2702-2710.107FattyLesionsinAorticRoot
(m2/section)106105104103(10)*(4)*(12)Genotypeop/++/+op/opM-CSFGeneDosageRelatestoAMolecularMediatorsofAtherogenesisM-CSFMCP-1VCAM-1MolecularMediatorsofAtherogAnatomyoftheAtheroscleroticPlaqueLumenLipidCoreFibrouscapShoulderIntimaMediaElasticlamin?InternalExternalAnatomyoftheAtheroscleroticSchematicTimeCourseofHumanAtherogenesisTransitionfromchronictoacuteatheromaIschemicHeart
DiseaseCerebrovascular
DiseasePeripheralVascular
DiseaseSchematicTimeCourseofHumanThrombosisofaDisruptedAtheroma,theCauseofMostAcuteCoronarySyndromes,Resultsfrom:Weakeningof
thefibrouscapThrombogenicityofthelipidcoreIllustrationcourtesyofMichaelJ.Davies,M.D.ThrombosisofaDisruptedAtheMatrixMetabolismandIntegrityofthePlaque’sFibrousCapLibbyP.Circulation1995;91:2844-2850.++++++–SynthesisBreakdownLipidcoreIL-1
TNF-
MCP-1
M-CSFFibrous
capIFN-CD-40LCollagen-degradingProteinasesTissueFactorProcoagulantMatrixMetabolismandIntegritIncreasedExpressionofInterstitialCollagenase(CL)bySmoothMuscleCells(SMC)andMacrophages(M)inHumanAtheromaGalisZSetal.JClinInvest1994;94:2493-2503.IncreasedExpressionofIntersPlaqueRupturewithThrombosisThrombusFibrouscap1mmLipidcoreIllustrationcourtesyofFrederickJ.Schoen,M.D.,Ph.D.PlaqueRupturewithThrombosisThrombosisofaDisruptedAtheroma,theCauseofMostAcuteCoronarySyndromes,Resultsfrom:Weakeningof
thefibrouscapThrombogenicityofthelipidcoreIllustrationcourtesyofMichaelJ.Davies,M.D.ThrombosisofaDisruptedAtheCD40andTissueFactorinAtheromaCD40MachFetal.Circulation1997;96:396-399.TissueFactorCD40andTissueFactorinAtheCD40LigationInducesTissueFactorExpressioninHumanMonocyte-DerivedMacrophagesLogFluorescenceCellNumbers1601208040016012080400100101102103100101102103rCD40L/-CD40LrCD40LTcell/membranes/
-CD40LTcell/
membranesMachFetal.Circulation1997;96:396-399.CD40LigationInducesTissueFCD40ligandonactivatedplateletstriggersaninflammatoryreactionofendothelialcellsHennVetal.Nature1998;391:591-594.CD40ligandonactivatedplateInflammationCanPromoteThrombosisPlateletTissue
FactorFibrinogenViagpllb/lllaFibrinCD40LPlatelet-
Fibrin
ThrombusFibrinopeptidesPlateletInflammationCanPromoteThromInflammationParticipatesinAllPhasesofAtherothromboticDiseaseLesioninitiationLesionprogressionThromboticcomplicationsInflammationParticipatesinA動(dòng)脈粥樣硬化血栓疾病的炎癥和發(fā)病機(jī)制課件InflammationandthePathogenesisofAtherothromboticDisease
PeterLibby,M.D.InflammationandthePathogeneAtheromaarenotmerelyfilledwithlipid,butcontaincellswhosefunctionscriticallyinfluenceatherogenesis:IntrinsicVascularWallCells:EndotheliumSmoothMuscleCellsInflammatoryCells:MacrophagesTLymphocytesMastCellsAtheromaarenotmerelyfilledCellTypesintheHumanAtheromaMonocyte/
MacrophageT-lymphocytesTunica
MediaIntimaSmoothmuscle
cellsEndotheliumCellTypesintheHumanAtheroNo
symptoms+SymptomsSchematicTimeCourseofHumanAtherogenesisTime(y)SymptomsLesioninitiationIschemicHeart
DiseaseCerebrovascular
DiseasePeripheralVascular
DiseaseNo
symptoms+SymptomsSchematiMacrophageFunctionsinAtherogenesisAttachmentMacrophageFunctionsinAtheroLeukocyte–EndothelialAdhesionMoleculesMonoTBPMNLeukocyte–EndothelialAdhesionVascularCellAdhesionMolecule1
(VCAM-1)Bindsmonocytesandlymphocytes
-CellsfoundinatheromaExpressedbyendotheliumovernascentfattystreaksExpressedbymicrovesselsofthematureatheromaVascularCellAdhesionMoleculAnatherogenicdietrapidlyinducesVCAM-1,acytokine-regulatablemononuclearleukocyteadhesionmolecule,inrabbitaorticendotheliumLiHetal.ArteriosclerThromb1993;13:197-204.AnatherogenicdietrapidlyinVCAM-1ExpressioninRabbitAortaLiHetal.ArteriosclerThromb1993;13:197-204.3weeksonatherogenicdietVCAM-1ExpressioninRabbitAoPenetrationMacrophageFunctionsinAtherogenesisPenetrationMacrophageFunctionMonocyteChemoattractantProtein1
(MCP-1)ApotentmononuclearcellchemoattractantProducedbyendothelialandsmoothmusclecellsLocalizesinhumanandexperimentalatheromaMonocyteChemoattractantProteAbsenceofmonocytechemoattractantprotein-1reducesatherosclerosisinlow-densitylipoproteinreceptor–deficientmiceGuLetal.MolCell1998;2:275-281.AbsenceofmonocytechemoattraReducedLipidDepositioninMCP-1–DeficientAtheroscleroticMiceGuLetal.MolCell1998;2:275-281.LDL-R–/–
MCP-1+/+LDL-R–/–
MCP-1–/–ReducedLipidDepositioninMCGuLetal.MolCell1998;2:275-281.ReducedLipidDepositioninMCP-1–DeficientAtheroscleroticMiceOilRedStaining%AorticSurfaceStainedTimeonDiet:12–14weeks+/+-/-***+/+-/-20–25weeks*P=0.001comparedto+/+
**p=0.005comparedto+/+GuLetal.MolCell1998;2:27MacrophageFunctionsinAtherogenesisActivationMacrophageFunctionsinAtheroMacrophageFunctionsinAtherogenesisDivisionMacrophageFunctionsinAtheroMacrophageColony-StimulatingFactor
(M-CSF)Apotentmonocyteactivatorandco-mitogenProducedbyendothelialandsmoothmusclecellsLocalizesinhumanandexperimentalatheromaMacrophageColony-StimulatingAugmentedM-CSFgeneexpressioninhumanandexperimentalatherogenesisRosenfeldMEetal.AmJPathol1992;140:291-300.ClintonSKetal.AmJPathol1992;140:301-316.AugmentedM-CSFgeneexpressioM-CSFExpressioninAtheroma
Intimal
M-CSF
in
AtheromaM-CSFExpressioninAtheroma
IM-CSFPromotesAtherogenesisSmithJDetal.Decreasedatherosclerosisinmicedeficientinbothmacrophagecolony-stimulatingfactor(op)andapolipoproteinE.ProcNatlAcadSciUSA1995;92:8264-8268.QiaoJHetal.Roleofmacrophagecolony-stimulatingfactorinatherosclerosis:studiesofosteopetroticmice.AmJPathol1997;150:1687-1699.RajavashisthTetal.Heterozygousosteopetrotic(op)mutationreducesatherosclerosisinLDLreceptor–deficientmice.JClinInvest1998;101:2702-2710.M-CSFPromotesAtherogenesisSmM-CSFDeficiency(opmutation)ReducesAtheromainLDLReceptor–KnockoutMiceRajavashisthTetal.JClinInvest1998;101:2702-2710.+/+op/+op/opM-CSFDeficiency(opmutation)M-CSFGeneDosageRelatestoAtheromaSizeinLDLR–/–MiceRajavashisthTetal.JClinInvest1998;101:2702-2710.107FattyLesionsinAorticRoot
(m2/section)106105104103(10)*(4)*(12)Genotypeop/++/+op/opM-CSFGeneDosageRelatestoAMolecularMediatorsofAtherogenesisM-CSFMCP-1VCAM-1MolecularMediatorsofAtherogAnatomyoftheAtheroscleroticPlaqueLumenLipidCoreFibrouscapShoulderIntimaMediaElasticlamin?InternalExternalAnatomyoftheAtheroscleroticSchematicTimeCourseofHumanAtherogenesisTransitionfromchronictoacuteatheromaIschemicHeart
DiseaseCerebrovascular
DiseasePeripheralVascular
DiseaseSchematicTimeCourseofHumanThrombosisofaDisruptedAtheroma,theCauseofMostAcuteCoronarySyndromes,Resultsfrom:Weakeningof
thefibrouscapThrombogenicityofthelipidcoreIllustrationcourtesyofMichaelJ.Davies,M.D.ThrombosisofaDisruptedAtheMatrixMetabolismandIntegrityofthePlaque’sFibrousCapLibbyP.Circulation1995;91:2844-2850.++++++–SynthesisBreakdownLipidcoreIL-1
TNF-
MCP-1
M-CSFFibrous
capIFN-CD-40LCollagen-degradingProteinasesTissueFactorProcoagulantMatrixMetabolismandIntegritIncreasedExpressionofInterstitialCollagenase(CL)bySmoothMuscleCells(SMC)andMacrophages(M)inHumanAtheromaGalisZSetal.JClinInvest1994;94:2493-2503.IncreasedExpressionofIntersPlaqueRupturewithThrombosisThrombusFibrouscap
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