2012-9-27 Pathogenesis Pathogenesis with positional signals and a mechanical scaffold Guo and Friedman. Senn L/ Dis, 2007 Pathways of Stellate cell Activation Hepatic Stellate cell Activation A Central Event in Liver Fibrosis INJURY Normal Liver with Fibro REVERSAON2 RESOLUTON THE HEPATIC PERISINUSOIDAL (DISSE)SPACE ③999 Sinusoid LIPOCYTE一一 MYOFIBROBLAST2012-9-27 5 Pathogenesis  Fibrogenic stimuli from injured liver Oxidative stress; Hypoxia; Inflammation and immune responses; Apoptosis; Steatosis; Senecense and autopathy  Imbalance between the accumulation and degradation of ECM Tissue inhibitors of metalloproteinases (TIMPs)  The biologic activity of ECM in fibrogenesis Dramatic changes of ECM components in the quality, quantity, and distribution provides cells with positional signals and a mechanical scaffold Provide “biological signals” with a resultant fibrogenic response and angiogenesis  Cellular responses and behavior  Capillarization of the sinusoids, Angiogenesis vascularized fibrotic septa intrahepatic shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) vessels of the liver  Cirrhosis may lead to liver failure, portal hypertension, or development of hepatocellular carcinoma Injured hepatocytes Kupffer cell activation Stellate cell activation Inflammation Matrix production, degradation and remodeling Fibrosis ROS/NOS, cytokines (PDGF TGF-1, MCP-1) Cytokines (MCP- 1, MIP-2, IL-1 ) Cytokines (MCP-1, TNF-, IL-1 MIP-2) Denatured proteins ROS apoptotic bodies ROS/NOS Degraded collagen, hyaluronic acid MMPs/TIMPs Endothelial cells EIIIA isoform, ET-1, VEGF PDGF Type IV collagen, laminin Lipid peroxides, apopttoic bodies, cytokines (VEGF, IGF-1) Endothelial cells Pathogenesis Guo and Friedman, Senim Liv Dis, 2007 Hepatic Stellate cell Activation - A Central Event in Liver Fibrosis Normal Liver Activated HSC with Fibrosis Friedman SL and Arthur, Science and Medicine, 2002 RESOLUTION APOPTOSIS? REVERSION? INJURY PDGF ET-1 TGF-1 PDGF, MCP-1 PDGF, Serum MCP-1 Proliferation Fibrogenesis HSC Chemotaxis Retinoid Loss WBC Chemoattraction Matrix Degradation Oxidative Stress, cFn MMP-2 Initiation Perpetuation Contractility Pathways of Stellate cell Activation Friedman SL, J Biol Chem, 2000