Clinical and experimental study for regulation of apoptosis and necrosis in acute liver failure

(1)临床研究：测定急性肝炎（AH）和暴发性肝炎（FH）患者血清可溶性Fas、Fas配体（FasL）、肿瘤坏死因子α (TNF α)和TNF受体-1（TNFR1）水平。我们还评估了这些参数与疾病预后之间的关系。与正常人相比，AH和FH患者血清sFas和sFasL水平显著升高。然而，AH和FH之间没有差异。AH和FH患者血清TNF a和TNFR1也显著升高。特别是FH患者血清TNFR1水平明显高于AH患者，反映了肝损害的严重程度和肝炎的预后。我们的数据表明，Fas-FasL系统和TNFα和TNFR1与肝坏死早期过程密切相关。(2)实验研究：评价糖皮质激素和环孢素A对半乳糖胺和脂多糖所致大鼠急性肝损伤的保护作用。糖皮质激素同时抑制TNFα的产生和细胞凋亡，从而保护肝坏死的发展。另一方面，环孢菌素A对急性肝损伤也有保护作用，如果在肝损伤过程中的适当时间给予。环孢素A虽不抑制TNFα的产生和细胞凋亡，但能抑制中性粒细胞向肝组织的浸润。这些药物对急性肝损伤模型的作用机制有待进一步研究。

(1) Clinical study: we measured the serum levels of soluble Fas, Fas ligand(FasL), tumor necrosis factor alfa (TNF α) and TNF receptor-1(TNFR1) in patients with acute hepatitis (AH) and fulminant hepatitis(FH). We also evaluated the relationship between these parameters and the prognosis of disease. The serum sFas and sFasL levels were significantly increased in patients with AH and FH compared to that in normal subjects. However, there were no differences between AH and FH. The serum TNF a and TNFR1 were also significantly increased in patients with AH and FH. In paticular, the serum TNFR1 levels were significantly increased in patients with FH compared to that of AH patients, and it reflected the severity of liver damage and the prognosis of hepatitis. Our data suggest that the Fas-FasL system and TNFα and TNFR1 are closely associated with the early process of massive hepatic necrosis.(2) Experimental study: we evaluated whether the administration of glucocorticoid and cyclosporin A could protect acute liver injury induced by galactosamin and lipopolysaccharide in rats. The glucocorticoid inhibited both TNFα production and apoptosis, resulting in the protection of the development of massive liver necrosis. On the other hand, cyclospolin A was also protective against acute liver injury, if it is administered at an apopriate time during the course of liver injury. Although cyclosporin A did not inhibit both TNFα production and apoptosis, it inhibited the neutrophil infiltration into the liver tissue. Further studies are needed to clarify the mechanisms of the effect of these druges on acute liver injury model.