基于RAAS,Lipoxin抗肝纤维化机制研究

Hepatic fibrosis is the repairing response to chronic inflammation and other damage repair. It was discovered recently that inflammation is a programmed process from onset to resolution, and the strategies of anti-inflammation are blocking inflammatory resolution timely, so the strategies of promoting resolution is getting more and more importance. Our research group has confirmed that Lipoxin significantly decreased carbon tetrachloride induced liver fibrosis in rats. The protective effects were the results of promoting inflammatory resolution promptly, decreasing the expressions of TGF-β1 and PDGF, and inhibition the activation of hepatic stellate cell. On the other hand, the role of renin-angiotensin aldosterone system (RAAS) in the formation of liver fibrosis is increasingly highlighted, especially the anti-fibrosis effects of ACE2-Ang(1-7)-Mas receptor axis. Our earlier research showed, Lipoxin decreased AngII but increase ACE2 expression in the rat liver fibrosis model induced by carbon tetrachloride. On this basis, we plan to systematically study the relation between Lipoxin and RAAS, and determine whether Lipoxin protected carbon tetrachloride induced liver fibrosis through regulating the balance of ACE-AngII-AT1R and ACE2-Ang(1-7)-Mas in rats.

肝纤维化是肝脏对慢性炎症或其他损伤的修复反应。新近发现炎症是从启动到消退的程序化过程，抑制炎症发生的抗炎策略同时蕴藏着阻碍炎症消退之隐患，促进炎症消退的治疗策略越来越受重视。本课题组已经证实促炎症缓解介质脂氧素（Lipoxin）明显减轻大鼠肝纤维化，其保护效应与促进炎症及时消退、下调TGF-β1和PDGF，抑制HSC活化相关。肾素-血管紧张素-醛固酮系统(RAAS)在肝纤维化形成过程中的作用日益突显，尤其是ACE2-Ang(1-7)-Mas轴的抗肝纤维化作用已经成为研究焦点。本课题组的前期研究表明，Lipoxin抑制四氯化碳诱导的血管紧张II（AngII）却促进肝组织表达ACE2。在此基础上，本课题拟继续采用四氯化碳建立大鼠肝纤维化模型，系统地研究Lipoxin对RAAS的影响，并明确脂氧素抗肝纤维化效应与ACE-AngII-AT1R轴和ACE2-Ang(1-7)-Mas轴之间的关系。

本课题建立了4个体内模型：CCL4诱导的肝纤维化模型，LPS诱导的急性肺损伤模型，LPS/D-GAL诱导急性肝损伤模型以及CCL4诱导的急性肝损伤模型，并完成了体外实验，探讨了LXA4及其受体激动剂BML-111抗肝纤维化效应，抗急性和慢性损伤效应，及其与RAAS的关系。研究结果发现LXA4及其受体激动剂BML-111抗纤维化作用与其调节ACE-AngⅡ-AT1R 轴和 ACE2-Ang-(1-7)-Mas轴平衡相关，LXA4及其受体激动剂BML-111保护急性损伤效应也可以通过调节RAAS实现。本研究采用促炎症消退介质脂氧素受体激动剂BML-111治疗肝纤维化，并首次从RAAS的角度探讨了其抗肝纤维化的机制；同时发现LXA4及其受体激动剂BML-111通过激活ACE2-Ang-(1-7)-Mas负轴发挥其抗急性损伤效应。本项目的研究结果为慢性肝纤维化，急性损伤的治疗提供了新思路和研究方向。