前列腺素调控肝星状细胞积聚于肝损伤灶的机理

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.

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。

1.背景：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。.2.目标与内容：解析肝组织损伤及纤维化条件下表达COX-2的细胞类型，产生的PGs种类，以及HSC表达的PGs效应受体类型；深入剖析PGs对HSC激活、迁移和增殖等行为的影响；探究抑制COX-2缓解或阻止肝纤维化的机理。.3.结果：1）阐明了小鼠胆管结扎（BDL）肝损伤模型中，表达环氧化酶Ⅱ型（COX-2）和产生前列腺素PGE2的主要细胞类型；2)发现BDL肝损伤模型中前列腺素PGE2的受体EP1-4表达量均有上升；原代HSC的前列腺素受体在自然激活的过程中，9类前列腺素受体呈三类表达模式。3)探讨了不同前列腺素分子类型对HSC株的激活及增殖的影响和效应阈值，发现TXB2和PGJ2显著抑制HSC的增殖，并显著抑制原代HSC增殖与活化；4)在BDL肝损伤模型上，进行了COX-2抑制剂（GIBH-1014和Celecoxib）的干预实验，发现GIBH-1014有效抑制胆管结扎导致的肝组织坏死灶的数量、HSC的积聚和肝纤维化程度，并明显改善肝功能指标。5) 诱导性PGE2在疾病发生的早期于肝内积聚，并在后来发展成全身系统性的增高。肝脏细胞在损伤刺激下PGE2水平增加的主要贡献者是肝脏星型细胞，诱导性PGE2水平的增加能激活肝脏星型细胞的增殖和胞外基质的堆积，以及抑制巨噬细胞的CD163表达。.4.总结与意义：本课题的研究结果阐述了PGE2、COX-2与肝纤维化形成的可能性关系，不仅为COX-2抑制剂用于治疗肝纤维化疾病临床实验提供基础，而且为抗肝纤维化新药研发提供潜在靶标。

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