补体C3介导苄醇对急性暴发型肝功能衰竭的治疗作用

Acute fulminant liver failure (AFLF) is still a challenge to modern medical society. We recently discovered a significant effect of benzyl alcohol (BA) on a mouse model of acute hepatic injury, which was shown to be toll-like receptor 4 -dependent (Hepatology, 2014). In the preliminary experiment, we firstly observed BA exerted significantly protective effects in mouse AFLF model, which were shown to be complement factor 3-dependent. However, the underlying mechanism remains unclear. To further address this issue, we plan to examine and compare the ultrastructural and histological changes, cellular metabolism, oxygen species levels, anti-inflammatory, anti-oxidant, and anti-apoptotic activities together with systemic inflammatory responses and activation of NF-κB, MAP kinases, and STAT3 signaling pathways between wild type and C3-knockout mice with or without BA treatment, by using both in vivo and in vitro models. Moreover, complement activation blockage or certain immune response cells will be investigated. Our study may be beneficial to understand the mechanisms of BA's protection on AFLF and contribute to the improved management of AFLF.

急性暴发性肝衰竭的治疗是目前医学难点。申请者最近研究证实，苄醇能够通过TLR4信号通路显著改善小鼠急性肝损伤的程度（Hepatology，2014）。另外，申请者在预实验研究中首次发现，苄醇能够显著抑制野生型小鼠急性暴发性肝衰竭，而该保护效应在C3-/-小鼠缺失，提示补体C3也参与了苄醇介导的保护过程，但具体机制不明。为此，本研究拟通过整体动物模型检测和离体细胞培养两个方面，从超微与组织病理、细胞代谢、氧自由基与抗炎、抗氧化、抗凋亡机制、NF-κB、MAPK及STAT3信号传导通路、机体炎性反应等不同角度，在LPS/D-GalN造成急性暴发性肝衰竭模型中，进一步分析苄醇治疗所引起的病理改变，并检测上述改变在野生型和C3-/-小鼠上的差异；通过在不同水平阻断补体激活，观察免疫效应细胞变化，探讨苄醇对急性暴发性肝衰竭的保护机制以及补体C3作用的靶点，为急性暴发性肝衰竭的治疗提供新的思路和方法。

急性爆发性肝衰竭会产生严重的氧化应激、炎症和细胞凋亡，从而导致肝细胞死亡进而肝脏的坏死，其治疗是是目前的医学难点。Sirtuin1（SIRT1）被认为在细胞增殖、衰老等过程中具有多种重要作用。卞醇醇是一种广泛存在于水果、茶叶等植物的天然化合物，对外伤、缺血再灌注损伤、失血性休克等具有一定保护作用，其对急性爆发性肝衰竭的保护作用机制尚不清楚。因此，在本项目中，我们从超微与组织病理、细胞代谢、氧自由基与抗炎、抗氧化、抗凋亡机制、NF-κB、MAPK及STAT3信号传导通路、机体炎性反应等不同角度，在LPS/D-GalN造成急性暴发性肝衰竭模型中，进一步分析苄醇治疗所引起的病理改变，并检测上述改变在野生型和SIRT1-/-小鼠上的差异；观察免疫效应细胞变化，探讨苄醇对急性暴发性肝衰竭的保护机制为急性暴发性肝衰竭的治疗提供新的思路和方法。