Mechanisms of fibrosis in pediatric liver diseases

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Pediatric liver diseases, most notably biliary atresia, and biliary fibrosis in general differ significantly from other forms of liver fibrosis resulting from parenchymal damage, particularly at the cellular level. Cholangiocyte rather than hepatocyte damage is likely to be the primary event driving the disease, and portal fibroblasts rather than hepatic stellate cells are the primary fibrogenic cells. Preliminary data from our laboratory and others have shown 1) that cholangiocyte dysfunction, namely the acquisition of mesenchymal characteristics including expression of vimentin, is typical of pediatric biliary fibrosis;2) that cholangiocytes are mechanosensitive, and that their responses to various stimuli are different when cultured on mechanically physiologic substrates versus tissue culture plastic or glass;3) that the chemokine MCP-1 is a major cholangiocyte product and is important for portal fibroblast differentiation;4) that portal fibroblasts are the primary fibrogenic effector cells;and 5) that interactions between cholangiocytes and portal fibroblasts are mediated at least in part by Kupffer cells. We hypothesize that cholangiocyte dysfunction and the resulting cholangiocyte/portal fibroblast interactions drive fibrosis in pediatric and other forms of biliary disease. The overall goal of this proposal is to determine the cellular basis of fibrosis in cell culture models of biliary injury, specifically the mechanism whereby cholangiocyte damage results in the myofibroblastic differentiation of portal fibroblasts. This will be achieved through the following two specific aims: 1) To determine the role of vimentin expression in cholangiocyte dysfunction and fibrosis;and 2) To determine direct and Kupffer cellmediated interactions between cholangiocytes and portal fibroblasts that lead to portal fibroblast myofibroblastic differentiation and fibrogenesis.