DAMPs in hepatic fibrogenesis and carcinogenesis.

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Chronic liver injury of infectious, toxic or metabolic origin often leads to a maladaptive wound healing process with accumulation of connective tissue (fibrosis) and an increased risk for the development of hepatocellular carcinoma (HCC). The mechanisms by which chronic hepatocellular injury initiates and sustains inflammation and fibrosis remain incompletely understood. Here we hypothesize that molecules released from dying hepatocytes termed damage-associated molecular patterns (DAMPS) stimulate inflammatory and fibrogenic cells and thereby promote liver fibrosis and HCC. In this proposal, we will investigate whether deletion of the DAMP high mobility group box 1 (HMGB1) or deletion of a receptor for the DAMP ATP, termed P2X7, attenuate inflammation, fibrosis and carcinogenesis in genetic (hepatocyte-specific TAK1-deletion) and chemical (diethylnitrosamine plus carbontetrachloride) models of chronic liver injury. Positive findings would identify HMGB1 and ATP as potential targets for the prevention of liver fibrosis and HCC.