vWF（血管性血友病因子）抑制FGL2表达的分子机制及其在急性肝衰竭中的作用研究

Acute liver failure is a serious disease harm to people’s health and it is a syndrome characterized associated with the liver inflammation, necrosis of liver cells, intrahepatic blood coagulation, liver cell regeneration and Extrahepatic complications. In our previous study, we proved the expression of vWF (von Willebrand Factor) was significantly increased in ALF patients compared with healthy control. In addition, we found that wildtype littermates displayed augmented liver damage and extensive deposition of FGL2 compared with vWF-/- mice 24h after treated by a single intraperitoneal injection of carbon tetrachloride (CCl4). Furthermore, Chip and western blot showed higher activation of MAPK signal pathway in vWF-/- mice compared to the control after CCl4 infected 24h, suggested vWF could inhibit the activation of downstream MAPK signal pathway which regulate the expression of FGL2, reduced the degree of ALF. This study was based the pathological changes of ALF and the recent investigation of vWF in a mouse ALF model has provided insights into mechanisms underlying the disease pathogenesis and resulted in some novel treatment strategies.

急性肝衰竭（Acute liver failure，ALF）是以肝脏炎症、肝细胞坏死、肝内凝血加重及肝外并发症为特征的综合病症，是严重危害人类健康的疾病之一。对其研究时我们发现ALF病人外周血中，vWF（血管性血友病因子）的表达较正常对照组代偿性增高且与疾病的严重程度密切关联，表明vWF在急性肝衰竭发病中起着重要作用；CCl4诱导小鼠急性肝衰竭模型中亦证实阻断vWF能加重小鼠肝脏病损指标，致使更高肝损程度及更广泛的FGL2（纤维蛋白样蛋白）沉积；芯片结果提示CCl4诱导vWFKO小鼠24小时后，肝组织MAPK信号途径活化程度较诱导后WT小鼠高近10倍，表明保护性因子vWF能通过抑制性活化下游MAPK信号途径，抑制FGL2表达，进而减轻急性肝衰竭疾病程度。本研究基于ALF的病理变化作为研究基础，有望找出ALF发生的病理成因，对ALF的早期诊断、临床治疗及预后的判断提供新的思路及理论依据。

急性肝衰竭是指由多种因素引起的严重肝脏损害，导致其合成、解毒、排泄和生物转化等功能发生严重障碍或失代偿，其主要病理表现为黄疸、肝性脑病、腹水，伴随凝血功能障碍，肝细胞的大面积坏死及炎症的产生，死亡率高达80-90%，是严重危害人类健康的疾病之一。在研究中，我们通过体内外实验验证急性肝衰竭发生进展中vwf分子的重要作用和在疾病进程中的重要意义。运用vwfKO小鼠和WT小鼠作为研究对象，比较CCL4诱导急性肝衰竭模型中肝组织形态变化和肝损程度，明确vwf分子缺失对急性肝衰竭发病的重要促进作用，抑制该分子表达能一定程度上抑制急性肝衰竭发病进程，揭示vwf分子在急性肝衰竭模型中的重要保护作用及重要地位，通过实验，我们最终证明在ALF发病中vwf/GPIB通路可以抑制下游MAPK信号途径降低FGL2的表达，减轻ALF的发病症状和程度，进一步揭示vwf的保护作用；同时结合课题组研究方向，我们在完成对vwf调控FGL2参与急性肝衰竭发病的研究之后，将目光转移到了肿瘤研究上，我们课题组通过实验佐证在胃癌的发病过程中，补体C5a/C5aR通路能调节细胞周期调控蛋白P21，参与胃癌发病，抑制C5a/C5aR通路能缓解胃癌细胞生长和增殖。