DAMPs in hepatic fibrogenesis and carcinogenesis.

感染性、毒性或代谢性慢性肝损伤通常会导致伤口愈合过程不适应，伴有结缔组织（纤维化）的积累，并增加发生肝细胞癌（HCC）的风险。慢性肝细胞损伤引发和维持炎症和纤维化的机制仍不完全清楚。在这里，我们假设从死亡的肝细胞释放的称为损伤相关分子模式（DAMPS）的分子刺激炎症和纤维化细胞，从而促进肝纤维化和HCC。在这项提议中，我们将研究在慢性肝损伤的遗传（肝细胞特异性tak1缺失）和化学（二乙基亚硝胺加四氯化碳）模型中，删除DAMP高迁移率组盒1 （HMGB1）或删除DAMP ATP受体P2X7是否会减轻炎症、纤维化和癌变。阳性结果将确定HMGB1和ATP是预防肝纤维化和HCC的潜在靶点。

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.