Effect of Pirfenidone on Endotoxin-induced Liver Injury after Partial Hepatectomy in Rats

背景资料。在活体供肝移植中，对移植物大小的限制是扩大成年受体适应症的严重障碍。革兰氏阴性菌感染、败血症和多器官衰竭是肝移植术后早期死亡的最常见原因。供肝扩大切除后的内毒素血症或受体小体积肝移植后的内毒素血症尚无有效的治疗方法。吡非尼酮(PFD)是一种新型抗纤维化实验药物。我们观察了白藜芦醇提取物对内毒素诱导的肝部分切除后肝损伤的影响。雄性SD大鼠于70%肝切除后48h静脉注射脂多糖(LPS)。内毒素注射前，给予PFD(300 mg/kg)或其载体(0.5%羧甲基纤维素)两次口服。PFD治疗组小鼠的存活率明显高于对照组。对血清AST、ALT、LDH活性和总胆红素的升高有明显的抑制作用。治疗组大鼠血清和肝组织中肿瘤坏死因子-α、白介素1-β、干扰素-γ和白介素6水平明显低于对照组。此外，与对照组相比，PFD治疗组大鼠残肝坏死程度明显减轻。这些结果表明，PFD通过抑制剩余肝脏炎性细胞因子的产生来减轻内毒素所致的肝部分切除后肝损伤。PFD对预防肝切除术后内毒素所致的肝损伤有一定的作用。

Background. In living donor liver transplantation, restrictions on graft size are a serious obstacle for the expansion of indications for adult recipients. The sequence of gram-negative infection, septicemia, and multiple organ failure is the most common cause of early mortality after liver transplantation. An effective therapy is not still established in endotoxemia following extended hepatectomy in donor or small for size graft in recipient. Pirfenidone (PFD) is a new experimental drug used as an antifibrotic agent. We investigated the effect of PFD on endotoxin-induced liver injury following partial hepatectomy.Methods. Male Sprague-Dawley rats were intravenously administered with lipopolysaccharide (LPS) 48 h after 70% hepatectomy. Prior to LPS administration, PFD (300 mg/kg) or its vehicle (0.5% carboxymethylcellulose) was given orally twice.Results. The survival rate of the PFD-treated group was markedly improved as compared with that of controls. PFD prevented the increases in activities of serum enzymes (AST, ALT, LDH) and total bilirubin. The levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β interferon-γ and interleukin-6 in serum and liver tissue were significantly lower in the PFD-treated group than in the control group. Furthermore, the degree of necrosis in remnant liver significantly decreased in the PFD-treated rats as compared with controls.Conclusion. These results indicate that PFD alleviates endotoxin-induced liver injury after partial hepatectomy through the inhibition of production of inflammatory cytokines in the remaining liver. PFD may be useful to prevent endotoxin-induced liver injury after hepatectomy.