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1、Inflammation and the Pathogenesis of Atherothrombotic DiseasePeter Libby,M.D.Atheroma are not merely filled with lipid,but contain cells whose functions critically influence atherogenesis:Intrinsic Vascular Wall Cells:nEndotheliumnSmooth Muscle CellsInflammatory Cells:nMacrophagesnT LymphocytesnMast
2、 CellsCell Types in the Human AtheromaMonocyteMonocyte/MacrophageMacrophageT-lymphocytesT-lymphocytesTunicaMediaIntimaSmooth musclecellsEndotheliumEndotheliumNo No symptomssymptoms+Symptoms SymptomsSchematic Time Course of Human AtherogenesisTime(y)Time(y)SymptomsSymptomsLesion initiationLesion init
3、iationIschemic Ischemic HeartHeartDiseaseDiseaseCerebrovascularCerebrovascularDiseaseDiseasePeripheral VascularPeripheral VascularDiseaseDiseaseMacrophage Functions in AtherogenesisAttachmentAttachmentLeukocyteEndothelial Adhesion MoleculesMonoMonoT TBBPMNPMNVascular Cell Adhesion Molecule 1(VCAM-1)
4、nBinds monocytes and lymphocytes-Cells found in atheromanExpressed by endothelium over nascent fatty streaksnExpressed by microvessels of the mature atheromaAn atherogenic diet rapidly induces VCAM-1,a cytokine-regulatable mononuclear leukocyte adhesion molecule,in rabbit aortic endotheliumLi H et a
5、l.Arterioscler Thromb 1993;13:197-204.VCAM-1 Expression in Rabbit AortaLi H et al.Arterioscler Thromb 1993;13:197-204.3 weeks on atherogenic dietPenetrationPenetrationMacrophage Functions in AtherogenesisMonocyte Chemoattractant Protein 1(MCP-1)nA potent mononuclear cell chemoattractantnProduced by
6、endothelial and smooth muscle cellsnLocalizes in human and experimental atheromaAbsence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptordeficient miceGu L et al.Mol Cell 1998;2:275-281.Reduced Lipid Deposition in MCP-1Deficient Atherosclerotic MiceGu
7、L et al.Mol Cell 1998;2:275-281.LDL-R/LDL-R/MCP-1+/+MCP-1+/+LDL-R/LDL-R/MCP-1/MCP-1/Gu L et al.Mol Cell 1998;2:275-281.Reduced Lipid Deposition in MCP-1Deficient Atherosclerotic MiceOil Red Staining%Aortic Surface StainedTime on Diet:12 14 weeks+/+-/-*+/+-/-20 25 weeks *P=0.001 compared to+/+*p=0.00
8、5 compared to+/+Macrophage Functions in AtherogenesisActivationMacrophage Functions in AtherogenesisDivisionMacrophage Colony-Stimulating Factor(M-CSF)nA potent monocyte activator and co-mitogennProduced by endothelial and smooth muscle cellsnLocalizes in human and experimental atheromaAugmented M-C
9、SF gene expression in human and experimental atherogenesisRosenfeld ME et al.Am J Pathol 1992;140:291-300.Clinton SK et al.Am J Pathol 1992;140:301-316.M-CSF Expression in M-CSF Expression in AtheromaAtheromaIntimalM-CSFinAtheromaM-CSF Promotes AtherogenesisSmith JD et al.Decreased atherosclerosis i
10、n mice deficient in both macrophage colony-stimulating factor(op)and apolipoprotein E.Proc Natl Acad Sci U S A 1995;92:8264-8268.Qiao JH et al.Role of macrophage colony-stimulating factor in atherosclerosis:studies of osteopetrotic mice.Am J Pathol 1997;150:1687-1699.Rajavashisth T et al.Heterozygou
11、s osteopetrotic(op)mutation reduces atherosclerosis in LDL receptordeficient mice.J Clin Invest 1998;101:2702-2710.M-CSF Deficiency(op mutation)Reduces Atheroma in LDL ReceptorKnockout MiceRajavashisth T et al.J Clin Invest 1998;101:2702-2710.+/+/+op/+op/+op/opop/opM-CSF Gene Dosage Relates to Ather
12、oma Size in LDLR/MiceRajavashisth T et al.J Clin Invest 1998;101:2702-2710.107Fatty Lesions in Aortic Root(m2/section)106105104103(10)*(4)*(12)Genotypeop/+/+op/opMolecular Mediators of AtherogenesisM-CSFMCP-1VCAM-1Anatomy of the Atherosclerotic PlaqueLumenLipidCoreFibrous capShoulderIntimaMediaElast
13、iclaminInternalExternalSchematic Time Course of Human AtherogenesisTransition from chronic to acuteTransition from chronic to acute atheroma atheromaIschemic Ischemic HeartHeartDiseaseDiseaseCerebrovascularCerebrovascularDiseaseDiseasePeripheral VascularPeripheral VascularDiseaseDiseaseThrombosis of
14、 a Disrupted Atheroma,the Cause of Most Acute Coronary Syndromes,Results from:n nWeakening of Weakening of the fibrous capthe fibrous capnThrombogenicity of the lipid coreIllustration courtesy of Michael J.Davies,M.D.Matrix Metabolism and Integrity of the Plaques Fibrous CapLibby P.Circulation 1995;
15、91:2844-2850.+SynthesisBreakdownLipid coreIL-1TNF-MCP-1M-CSFFibrouscapIFN-IFN-CD-40LCollagen-degradingCollagen-degradingProteinasesProteinasesTissue FactorTissue FactorProcoagulantProcoagulantIncreased Expression of Interstitial Collagenase(CL)by Smooth Muscle Cells(SMC)and Macrophages(M)in Human At
16、heromaGalis ZS et al.J Clin Invest 1994;94:2493-2503.Plaque Rupture with ThrombosisThrombusFibrous cap1 mmLipid coreIllustration courtesy of Frederick J.Schoen,M.D.,Ph.D.Thrombosis of a Disrupted Atheroma,the Cause of Most Acute Coronary Syndromes,Results from:nWeakening of the fibrous capn nThrombo
17、genicityThrombogenicity of the lipid coreof the lipid coreIllustration courtesy of Michael J.Davies,M.D.CD40 and Tissue Factor in AtheromaCD40Mach F et al.Circulation 1997;96:396-399.Tissue FactorCD40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived MacrophagesLog FluorescenceCell
18、 Numbers1601208040016012080400100101102103100101102103rCD40L/-CD40LrCD40LT cell/membranes/-CD40LT cell/membranesMach F et al.Circulation 1997;96:396-399.CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cellsHenn V et al.Nature 1998;391:591-594.Inflammation Can Prom
19、ote ThrombosisPlateletPlateletTissueTissueFactorFactorFibrinogenFibrinogenVia Via gp llbgp llb/lllalllaFibrinCD40LCD40LPlatelet-Platelet-FibrinFibrinThrombusThrombusFibrinopeptidesFibrinopeptidesPlateletPlateletInflammation Participates in All Phases of Atherothrombotic DiseasenLesion initiationnLesion progressionnThrombotic complications