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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Inflammation and the Pathogenesis of Atherothrombotic Disease,Peter Libby,M.D.,Inflammation and the Pathogene,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 Cells,Atheroma are not merely filled,Cell Types in the Human Atheroma,Monocyte/Macrophage,T-lymphocytes,TunicaMedia,Intima,Smooth musclecells,Endothelium,Cell Types in the Human Athero,No symptoms,+,Symptoms,Schematic Time Course of Human Atherogenesis,Time(y),Symptoms,Lesion initiation,Ischemic HeartDisease,CerebrovascularDisease,Peripheral VascularDisease,No symptoms+SymptomsSchemati,Macrophage Functions in Atherogenesis,Attachment,Macrophage Functions in Athero,LeukocyteEndothelial Adhesion Molecules,Mono,T,B,PMN,LeukocyteEndothelial Adhesion,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 atheroma,Vascular Cell Adhesion Molecul,An atherogenic diet rapidly induces VCAM-1,a cytokine-regulatable mononuclear leukocyte adhesion molecule,in rabbit aortic endothelium,Li H et al.,Arterioscler Thromb,1993;13:197-204.,An atherogenic diet rapidly in,VCAM-1 Expression in Rabbit Aorta,Li H et al.,Arterioscler Thromb,1993;13:197-204.,3 weeks on atherogenic diet,VCAM-1 Expression in Rabbit Ao,Penetration,Macrophage Functions in Atherogenesis,PenetrationMacrophage Function,Monocyte Chemoattractant Protein 1(MCP-1),A potent mononuclear cell chemoattractant,Produced by endothelial and smooth muscle cells,Localizes in human and experimental atheroma,Monocyte Chemoattractant Prote,Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density lipoprotein receptordeficient mice,Gu L et al.,Mol Cell,1998;2:275-281.,Absence of monocyte chemoattra,Reduced Lipid Deposition in MCP-1Deficient Atherosclerotic Mice,Gu L et al.,Mol Cell,1998;2:275-281.,LDL-R/MCP-1+/+,LDL-R/MCP-1/,Reduced Lipid Deposition in MC,Gu L et al.,Mol Cell,1998;2:275-281.,Reduced Lipid Deposition in MCP-1Deficient Atherosclerotic Mice,Oil Red Staining,%Aortic Surface Stained,Time on Diet:,12 14 weeks,+/+,-/-,*,*,+/+,-/-,20 25 weeks,*P=0.001 compared to+/+*p=0.005 compared to+/+,Gu L et al.Mol Cell 1998;2:27,Macrophage Functions in Atherogenesis,Activation,Macrophage Functions in Athero,Macrophage Functions in Atherogenesis,Division,Macrophage Functions in Athero,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 atheroma,Macrophage Colony-Stimulating,Augmented M-CSF gene expression in human and experimental atherogenesis,Rosenfeld ME et al.,Am J Pathol,1992;140:291-300.,Clinton SK et al.,Am J Pathol,1992;140:301-316.,Augmented M-CSF gene expressio,M-CSF Expression in Atheroma,IntimalM-CSFinAtheroma,M-CSF Expression in AtheromaI,M-CSF Promotes Atherogenesis,Smith 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 receptordeficient mice.,J Clin Invest,1998;101:2702-2710.,M-CSF Promotes AtherogenesisSm,M-CSF Deficiency(,op,mutation)Reduces Atheroma in LDL ReceptorKnockout Mice,Rajavashisth T et al.,J Clin Invest,1998;101:2702-2710.,+/+,op/+,op/op,M-CSF Deficiency(op mutation),M-CSF Gene Dosage Relates to Atheroma Size in LDLR/Mice,Rajavashisth T et al.,J Clin Invest,1998;101:2702-2710.,10,7,Fatty Lesions in Aortic Root(,m,2,/section),10,6,10,5,10,4,10,3,(10),*,(4),*,(12),Genotype,op/+,+/+,op/op,M-CSF Gene Dosage Relates to A,Molecular Mediators of Atherogenesis,M-CSF,MCP-1,VCAM-1,Molecular Mediators of Atherog,Anatomy of the Atherosclerotic Plaque,Lumen,Lipid,Core,Fibrous cap,Shoulder,Intima,Media,Elastic,lamin,Internal,External,Anatomy of the Atherosclerotic,Schematic Time Course of Human Atherogenesis,Transition from chronic to acute atheroma,Ischemic HeartDisease,CerebrovascularDisease,Peripheral VascularDisease,Schematic Time Course of Human,Thrombosis of a Disrupted Atheroma,the Cause of Most Acute Coronary Syndromes,Results from:,Weakening of the fibrous cap,Thrombogenicity of the lipid core,Illustration courtesy of Michael J.Davies,M.D.,Thrombosis of a Disrupted Athe,Matrix Metabolism and Integrity of the Plaques Fibrous Cap,Libby P.,Circulation,1995;91:2844-2850.,+,+,+,+,+,+,Synthesis,Breakdown,Lipid core,IL-1TNF-,MCP-1M-CSF,Fibrouscap,IFN-,CD-40L,Collagen-degrading,Proteinases,Tissue Fac
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