抗氧化蛋白Prx1对肝纤维化的作用及机制研究

Liver fibrosis is a serious public health problem world-widely, and preventing liver fibrosis is a key point to prevent liver cirrhosis from occurring and developing. Since oxidative stress plays an important role in the pathogenesis of liver fibrosis, it could be a potential therapeutic target. Peroxiredoxin 1(Prx1) is a newly discovered peroxidase with important anti-oxidative activity. Previous study of our group showed that the expression of Prx1 was significantly decreased in DMN-induced liver fibrosis rats, and Prx1 levels in hepatic stellate cells(HSC) were decreased after stimulation by LPS or AngII. However, treatment of the anti-fibrosis new drug- - Fluorofenidone(AKF-PD) greatly increased the expression of Prx1 and remarkably improved liver fibrosis compared to controls. Thus, we hypothesized that Prx1 may play an important protective role in liver fibrosis, and could be a promising target of the anti-fibrosis drug AKF-PD. Based on the above work, the researches we want to conduct in this project are as follow: I. clarifying the effect of Prx1 in HSC activation and proliferation as well as liver fibrosis; II. illustrating the specific mechanism of the protective role of Prx1 in liver fibrosis; III. exploring whether Prx1 is a target of AKF-PD.

肝纤维化是严重危害人类健康的公共卫生问题，控制肝纤维化是控制肝硬化发生发展的关键。氧化应激是肝纤维化的重要发病机制和治疗的重要靶点。Peroxiredoxin 1（Prx1）是新近发现的一种过氧化物酶，具有重要的抗氧化活性，本课题组前期研究发现DMN肝纤维化大鼠模型组Prx1表达明显降低；LPS、AngII刺激肝星状细胞（HSC）后，Prx1的表达也明显减少；应用抗肝纤维化新药氟非尼酮治疗后Prx1的表达明显上调，肝纤维化程度也较模型组显著改善。由此，我们提出设想：Prx1可能在肝纤维化过程中对肝脏起重要保护作用，它可能是氟非尼酮治疗肝纤维化的潜在靶点。基于以上研究，本课题组拟对以下问题进行探讨：①明确Prx1对HSC活化增殖及肝纤维化的影响；②明确Prx1在肝纤维化中对肝脏起保护作用的具体机制；③明确Prx1是否为氟非尼酮的作用靶点。

肝纤维化是严重危害人类健康的公共卫生问题，控制肝纤维化是控制肝硬化发生发展的关键。氧化应激是肝纤维化的重要发病机制和治疗的重要靶点。Peroxiredoxin 1（Prx1）是新近发现的一种过氧化物酶，具有重要的抗氧化活性。本课题旨在探讨Prx1在肝纤维化中的作用以及Prx1是否为氟非尼酮（AKF-PD）治疗肝纤维化的作用靶点。本课题体外细胞实验显示：Prx1可抑制肝星状细胞内TGF-β/Smads信号通路，抑制肝星状细胞活化,具有抗氧化作用；AKF-PD对细胞内Prx1的蛋白表达无显著影响。动物实验显示：Prx1在CCl4诱导的肝纤维化模型中的mRNA及蛋白表达水平无明显变化，敲除Prx1后对CCl4诱导的肝纤维化并无明显影响。在本研究的基础上，我们发现在CCl4诱导的小鼠急性肝损伤模型中，敲除Prx1后能减轻急性肝损伤的病变程度,并且外源性重组的Prx1可促进肝星状细胞及原代腹腔巨噬细胞分泌多种炎症因子，提示细胞外的Prx1具有促炎作用。总结：Prx1在肝星状细胞活化和急性肝损伤中发挥重要作用，其在肝纤维化中的作用有待进一步研究。