Pathologic fibrosis in the liver is mediated by activated hepatic stellate cells (lipocytes, lto cells). These cells have a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. A number of factors have been proposed to perpetuate the fibrogenic process in activated stellate cells, including inflammatory cytokines, alterations in the extracellular matrix, oxidative stress and growth factors. However, the intracellular signaling pathways that are activated by these factors in stellate cells are poorly understood. The overall goal of this research project is to gain a better understanding of the intracellular signaling mechanisms that may perpetuate the fibrogenic process in hepatic stellate cells, focusing on the potential roles of two serine/threonine kinases, c- Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), and their ability to upregulate AP-l-responsive gene expression. Therefore, l will investigate whether certain inflammatory mediators and extracellular matrix components activate JNK and BRK in hepatic stellate cells, with a resultant increase in AP- I-dependent gene expression. This project will identify basic biochemical processes that are important to improved understanding of the mechanisms of perpetuation of hepatic fibrogenesis.
| Khan, M A; Poulos, J E; Brunt, E M et al. (2001) Hepatic alpha-smooth muscle actin expression in hepatitis C patients before and after interferon therapy. Hepatogastroenterology 48:212-5 |
