DAMPs in hepatic fibrogenesis and carcinogenesis.

感染性、中毒性或代谢性慢性肝损伤往往会导致创面愈合不良，伴随结缔组织的堆积(纤维化)，并增加发生肝细胞癌的风险。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，我们假设死亡的肝细胞释放的分子被称为损伤相关分子模式(DAMP)，刺激炎症和纤维化细胞，从而促进肝纤维化和肝细胞癌。在这项研究中，我们将研究在遗传性(肝细胞特异性TAK1缺失)和化学性(二乙基亚硝胺+四氯化碳)慢性肝损伤模型中，缺失潮湿的高迁移率族蛋白1(HMGB1)或缺失潮湿的ATP受体(称为P2X7)是否能够减轻慢性肝损伤的炎症、纤维化和癌变。阳性结果将确定HMGB1和ATP是预防肝纤维化和肝细胞癌的潜在靶点。

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.