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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:EndotheliumSmooth Muscle CellsInflammatory Cells:MacrophagesT LymphocytesMast C
2、ells,Cell Types in the Human Atheroma,Monocyte/Macrophage,T-lymphocytes,TunicaMedia,Intima,Smooth musclecells,Endothelium,No symptoms,+Symptoms,Schematic Time Course of Human Atherogenesis,Time(y),Symptoms,Lesion initiation,Ischemic HeartDisease,CerebrovascularDisease,Peripheral VascularDisease,Macr
3、ophage Functions in Atherogenesis,Attachment,LeukocyteEndothelial Adhesion Molecules,Mono,T,B,PMN,Vascular Cell Adhesion Molecule 1(VCAM-1),Binds monocytes and lymphocytes-Cells found in atheromaExpressed by endothelium over nascent fatty streaksExpressed by microvessels of the mature atheroma,An at
4、herogenic 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.,VCAM-1 Expression in Rabbit Aorta,Li H et al.Arterioscler Thromb 1993;13:197-204.,3 weeks on atherogenic diet,Penetration,
5、Macrophage Functions in Atherogenesis,Monocyte Chemoattractant Protein 1(MCP-1),A potent mononuclear cell chemoattractantProduced by endothelial and smooth muscle cellsLocalizes in human and experimental atheroma,Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low-density li
6、poprotein receptordeficient mice,Gu L et al.Mol Cell 1998;2:275-281.,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/,Gu L et al.Mol Cell 1998;2:275-281.,Reduced Lipid Deposition in MCP-1Deficient Atherosclerotic Mice,Oil
7、 Red Staining%Aortic Surface Stained,Time on Diet:,12 14 weeks,+/+,-/-,*,*,+/+,-/-,20 25 weeks,*P=0.001 compared to+/+*p=0.005 compared to+/+,Macrophage Functions in Atherogenesis,Activation,Macrophage Functions in Atherogenesis,Division,Macrophage Colony-Stimulating Factor(M-CSF),A potent monocyte
8、activator and co-mitogenProduced by endothelial and smooth muscle cellsLocalizes in human and experimental atheroma,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.,M-CSF Expression
9、in Atheroma,IntimalM-CSFinAtheroma,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 ath
10、erosclerosis: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 Deficiency(op mutation)Reduces Atheroma in LDL ReceptorKnockout Mice,Raj
11、avashisth T et al.J Clin Invest 1998;101:2702-2710.,+/+,op/+,op/op,M-CSF Gene Dosage Relates to Atheroma Size in LDLR/Mice,Rajavashisth T et al.J Clin Invest 1998;101:2702-2710.,107,Fatty Lesions in Aortic Root(m2/section),106,105,104,103,Genotype,op/+,+/+,op/op,Molecular Mediators of Atherogenesis,
12、M-CSF,MCP-1,VCAM-1,Anatomy of the Atherosclerotic Plaque,Lumen,LipidCore,Fibrous cap,Shoulder,Intima,Media,Elasticlamin,Internal,External,Schematic Time Course of Human Atherogenesis,Transition from chronic to acute atheroma,Ischemic HeartDisease,CerebrovascularDisease,Peripheral VascularDisease,Thr
13、ombosis of a Disrupted Atheroma,the Cause of Most Acute Coronary Syndromes,Results from:,Weakening of the fibrous capThrombogenicity of the lipid core,Illustration courtesy of Michael J.Davies,M.D.,Matrix Metabolism and Integrity of the Plaques Fibrous Cap,Libby P.Circulation 1995;91:2844-2850.,+,+,
14、+,+,+,+,Synthesis,Breakdown,Lipid core,IL-1TNF-MCP-1M-CSF,Fibrouscap,IFN-,CD-40L,Collagen-degradingProteinases,Tissue FactorProcoagulant,Increased Expression of Interstitial Collagenase(CL)by Smooth Muscle Cells(SMC)and Macrophages(M)in Human Atheroma,Galis ZS et al.J Clin Invest 1994;94:2493-2503.,
15、Plaque Rupture with Thrombosis,Thrombus,Fibrous cap,1 mm,Lipid core,Illustration courtesy of Frederick J.Schoen,M.D.,Ph.D.,Thrombosis of a Disrupted Atheroma,the Cause of Most Acute Coronary Syndromes,Results from:,Weakening of the fibrous capThrombogenicity of the lipid core,Illustration courtesy o
16、f Michael J.Davies,M.D.,CD40 and Tissue Factor in Atheroma,CD40,Mach F et al.Circulation 1997;96:396-399.,Tissue Factor,CD40 Ligation Induces Tissue Factor Expression in Human Monocyte-Derived Macrophages,Log Fluorescence,Cell Numbers,16012080400,16012080400,100,101,102,103,100,101,102,103,rCD40L/-C
17、D40L,rCD40L,T cell/membranes/-CD40L,T cell/membranes,Mach F et al.Circulation 1997;96:396-399.,CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells,Henn V et al.Nature 1998;391:591-594.,Inflammation Can Promote Thrombosis,TissueFactor,Fibrinogen,Via gp llb/llla,CD40L,Platelet-FibrinThrombus,Fibrinopeptides,Inflammation Participates in All Phases of Atherothrombotic Disease,Lesion initiationLesion progressionThrombotic complications,
