肝星状细胞（HSC）是形成肝纤维化的关键效应细胞，HSC激活、迁移和增殖均与损伤所致的炎症相关。肝损伤诱导环氧化酶II（COX-2）表达，催化产生炎性因子—前列腺素（PGs），然而PGs调控肝损伤修复或纤维化的机理有待阐明。我们在胆汁阻塞诱导小鼠肝损伤模型中发现：COX-2表达于肝细胞；一种自主研发的新型COX-2抑制剂显著抑制HSC积聚和纤维化形成；细胞实验揭示COX-2抑制剂有效阻止损伤的肝细胞对HSC的募集。结合文献报道：HSC表达环PGs受体，我们推测PGs可调控HSC对肝损伤的修复和纤维化效应。本项目拟研究：1）损伤诱导肝脏产生的效应PGs分子和HSC的相应受体；2）PGs对HSC激活、迁移和增殖的作用机理；3）抑制COX-2缓解肝纤维化的调控机制。深入揭示肝损伤诱导的PGs在肝损伤修复和纤维化中的分子机理，将为COX-2抑制剂用于抗肝纤维化治疗及新药研发提供理论基础和潜在靶标。

Hepatic stellate cell (HSC) is a critical player in liver fibrosis, and the activation, migration and proliferation of HSC are associated to injury caused inflammation. Liver injury induces the expression of cyclooxygenase II (COX-2), which catalyze the production of inflammatory factor, prostaglandin (PGs), and the mechanism of PGs involved in repairing injury or leading to fibrosis remains to be clarified. We found that bile obstruction caused hepatocyte injury that induces COX-2 expression in mouse model, and a novel Cox 2 inhibitor significantly inhibited the accumulation of HSC in the necro-inflammation lesions and its fibrosis severity. In vitro cell co-culture experiments revealed that Cox 2 inhibitor effectively prevented the recruitment of HSC by injured hepatocytes. Considering with the already reported evidence that HSC expresses the prostacyclin receptor, we hypothesize that the PGs regulate the HSC behaviors that participating the processes of liver injury repair and/or fibrosis. This hypothesis will be verified by three aims: 1) To elucidate liver injury induced what kind of PGs effect ligand(s) and the corresponding receptor(s) on HSC; 2) To dissect the mechanisms of PGs on regulating the activation, migration and proliferation of HSC; 3) To determine whether inhibition of COX-2 diminishes liver fibrosis and the roles behind. To reveal the molecular basis of liver injury-induced PGs regulating the process of liver injury repair and hepatic fibrosis, not only to accumulate data for underlining the antifibrogenic usage of this COX-2 inhibitor, but also to provide potential targets for developing new anti-hepatic-fibrogengesis drugs.