基于氧化应激拮抗作用他莫昔芬抗Gal/LPS诱导的急性肝损伤研究

项目名称： 基于氧化应激拮抗作用他莫昔芬抗Gal/LPS诱导的急性肝损伤研究

项目编号： No.81460555

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 罗满生

作者单位： 井冈山大学

项目金额： 45万元

中文摘要： G-菌内毒素等引发的急性肝损伤（ALI）是一种严重的临床综合症，病死率达80-90%，除肝移植外目前尚无其它对策。因此，探讨ALI 预防或治疗的新方法具有重要意义。和其它研究相似，本课题组前期研究表明TNFα及其诱导的早期细胞凋亡在内毒素主要成分LPS诱导的ALI发病过程中起关键作用。研究发现氧化应激产物活性氧对于该凋亡的启动和维持具有促进作用。因此，抗氧化应激有望成为ALI治疗的新方向。研究表明他莫昔芬可经调节Mmd2表达而拮抗氧化应激，保护另一种ALI，但Mmd2的肝脏细胞来源和抗氧化应激机制尚未阐明。基于这些，我们推测他莫昔芬可经此作用拮抗Gal/LPS诱发的ALI。为此，本项目拟通过细胞和动物实验探讨他莫昔芬对Gal/LPS诱导ALI的保护作用，明确他莫昔芬给药后肝脏Mmd2的细胞来源，并阐明其抗氧化应激机制，为将来G-菌引起的ALI深入研究及Mmd2的保护性机制研究奠定前期基础。

中文关键词： 脂多糖；他莫昔芬；急性肝损伤；氧化应激；细胞凋亡

英文摘要： Acute liver injury (ALI) induced endotoxin of G- bacteria is a severe clinical syndrome which account 80-90% mortality. Till now, no other strategy is available for this disease apart from liver transplantation. Therefore, it would be particularly meaningful to find out novel pathway for the prevention or therapy of it. As other research results, in our pioneering investigation it was demonstrated that the early apoptosis induced by TNFα played a pivotal role during the development of some kinds of ALI, particularly ALI given rise by endotoxin. It was reported in some studies that oxidative stress was required for the initiation and maintain of TNFα induced hepatocellular apoptosis. Thus, inhibition of oxidative stress will be a promising direction for the therapy of ALI associated with early hepatocellular apoptosis. Some investigation turned out that Tamoxifen was implicated for the effective protection of another kind of ALI by regulation of the expression of hepatic Mmd2, which antagonize oxidative stress. However, which kind of cell produce this molecule remains to be unknown. Furthermore, the mechanism by which Mmd2 counteracts oxidative stress requires futher study. Based upon these, we suppose that Tamoxifen could prevent or alleviate ALI provoked by the administration of Gal/LPS via the similar action. To this end, in vitro and in vivo assays will be carried out to testify our hypothesis and elucidate the producing cell of Mmd2 after Tamoxifen administration, which followed by clarifying the anti oxidative stress mechanism of this molecule. Hopefully, accomplishment of this programme will not only deep into the mechanistic investigation of ALI induced by invading G- bacteria, but also make some preparations for the coming research(es) about the hepatoprotective effect of Mmd2 during ALI.

英文关键词： lipopolysaccharide;tamoxifen;acute liver injury;oxidative stress;apoptosis