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nullInflammation and the Pathogenesis of Atherothrombotic Disease Peter Libby, M.D.Inflammation and the Pathogenesis of Atherothrombotic Disease Peter Libby, M.D.Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis:Atheroma are not merely filled with lipid, but contain cells whose functions critically influence atherogenesis:Intrinsic Vascular Wall Cells: Endothelium Smooth Muscle Cells Inflammatory Cells: Macrophages T Lymphocytes Mast CellsCell Types in the Human AtheromaCell Types in the Human AtheromaMonocyte/ MacrophageT-lymphocytesTunica MediaIntimaSmooth muscle cellsEndotheliumSchematic Time Course of Human AtherogenesisSchematic Time Course of Human AtherogenesisNo symptoms+ SymptomsTime (y)SymptomsLesion initiationIschemic Heart DiseaseCerebrovascular DiseasePeripheral Vascular DiseaseMacrophage Functions in AtherogenesisMacrophage Functions in AtherogenesisAttachmentLeukocyte–Endothelial Adhesion MoleculesLeukocyte–Endothelial Adhesion MoleculesMonoTBPMNVascular Cell Adhesion Molecule 1 (VCAM-1)Vascular Cell Adhesion Molecule 1 (VCAM-1)Binds monocytes and lymphocytes - Cells found in atheroma Expressed by endothelium over nascent fatty streaks Expressed by microvessels of the mature atheromaAn atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endotheliumAn atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endotheliumLi H et al. Arterioscler Thromb 1993;13:197-204.VCAM-1 Expression in Rabbit AortaVCAM-1 Expression in Rabbit AortaLi H et al. Arterioscler Thromb 1993;13:197-204.3 weeks on atherogenic dietMacrophage Functions in AtherogenesisMacrophage Functions in AtherogenesisPenetrationMonocyte Chemoattractant Protein 1 (MCP-1)Monocyte Chemoattractant Protein 1 (MCP-1)A potent mononuclear cell chemoattractant Produced by endothelial and smooth muscle cells Localizes in human and experimental atheromaAbsence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptor–deficient miceAbsence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptor–deficient miceGu L et al. Mol Cell 1998;2:275-281.Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceReduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceGu L et al. Mol Cell 1998;2:275-281.LDL-R –/– MCP-1 +/+LDL-R –/– MCP-1 –/–Reduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceReduced Lipid Deposition in MCP-1–Deficient Atherosclerotic MiceGu L et al. Mol Cell 1998;2:275-281.Oil Red Staining % Aortic Surface StainedTime on Diet:12 – 14 weeks+/+-/-***+/+-/-20 – 25 weeks *P = 0.001 compared to +/+ **p = 0.005 compared to +/+Macrophage Functions in AtherogenesisMacrophage Functions in AtherogenesisActivationMacrophage Functions in AtherogenesisMacrophage Functions in AtherogenesisDivisionMacrophage Colony-Stimulating Factor (M-CSF)Macrophage Colony-Stimulating Factor (M-CSF)A potent monocyte activator and co-mitogen Produced by endothelial and smooth muscle cells Localizes in human and experimental atheromaAugmented M-CSF gene expression in human and experimental atherogenesisAugmented M-CSF 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 Atheroma M-CSF Expression in Atheroma Intimal M-CSF in AtheromaM-CSF Promotes AtherogenesisM-CSF Promotes AtherogenesisSmith JD et al. Decreased atherosclerosis in 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. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor–deficient mice. J Clin Invest 1998;101:2702-2710. M-CSF Deficiency (op mutation) Reduces Atheroma in LDL Receptor–Knockout MiceM-CSF Deficiency (op mutation) Reduces Atheroma in LDL Receptor–Knockout MiceRajavashisth T et al. J Clin Invest 1998;101:2702-2710.+/+op/+op/opM-CSF Gene Dosage Relates to Atheroma Size in LDLR –/– MiceM-CSF Gene Dosage Relates to Atheroma Size in LDLR –/– MiceRajavashisth T et al. J Clin Invest 1998;101:2702-2710.107Fatty Lesions in Aortic Root (m2/section)106105104103Genotypeop/++/+op/opMolecular Mediators of AtherogenesisMolecular Mediators of AtherogenesisM-CSFMCP-1VCAM-1Anatomy of the Atherosclerotic PlaqueAnatomy of the Atherosclerotic PlaqueLumenLipid CoreFibrous capShoulderIntimaMediaElastic laminæInternalExternalSchematic Time Course of Human AtherogenesisSchematic Time Course of Human AtherogenesisTransition from chronic to acute atheromaIschemic Heart DiseaseCerebrovascular DiseasePeripheral Vascular DiseaseThrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from:Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from:Weakening of the fibrous cap Thrombogenicity of the lipid coreIllustration courtesy of Michael J. Davies, M.D.Matrix Metabolism and Integrity of the Plaque’s Fibrous CapMatrix Metabolism and Integrity of the Plaque’s Fibrous CapLibby P. Circulation 1995;91:2844-2850.++++++–SynthesisBreakdownLipid coreIL-1 TNF- MCP-1 M-CSFFibrous capIFN-CD-40LCollagen-degrading ProteinasesTissue Factor ProcoagulantIncreased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M) in Human AtheromaIncreased Expression of Interstitial Collagenase (CL) by Smooth Muscle Cells (SMC) and Macrophages (M) in Human AtheromaGalis ZS et al. J Clin Invest 1994;94:2493-2503.Plaque Rupture with ThrombosisPlaque 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:Thrombosis of a Disrupted Atheroma, the Cause of Most Acute Coronary Syndromes, Results from:Weakening of the fibrous cap Thrombogenicity of the lipid coreIllustration courtesy of Michael J. Davies, M.D.CD40 and Tissue Factor in AtheromaCD40 and Tissue Factor in AtheromaCD40Mach F et al. Circulation 1997;96:396-399.Tissue FactorCD40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived MacrophagesCD40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived MacrophagesLog FluorescenceCell Numbers160 120 80 40 0160 120 80 40 0100101102103100101102103rCD40L/-CD40LrCD40LT cell/membranes/ -CD40LT cell/ membranesMach F et al. Circulation 1997;96:396-399.nullCD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cellsHenn V et al. Nature 1998;391:591-594.nullInflammation Can Promote ThrombosisTissue FactorFibrinogenVia gp llb/lllaCD40LPlatelet- Fibrin ThrombusFibrinopeptidesnullInflammation Participates in All Phases of Atherothrombotic DiseaseLesion initiation Lesion progression Thrombotic complicationsnull