Chen Geng, Wang Shuguang, Bie Ping, Li Xiaowu, Dong Jiahong
Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
Transplantation. 2009 Feb 15;87(3):330-9. doi: 10.1097/TP.0b013e3181954fee.
Nonanastomotic biliary strictures are a serious complication after orthotopic liver transplantation (OLT) and are difficult to cure. We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT.
A total of 90 Sprague-Dawley rats were divided into three groups: Sham-operated group (Sham, n=30), OLT group with 1 hr donor liver preservation (OLT-1h, n=30), and OLT group with 12 hr donor liver preservation (OLT-12h, n=30). Bile was collected and analyzed biochemically. The histopathologic study was performed to determine the intrahepatic bile duct morphologic changes. Hepatic expressions of bile transporters Ntcp, Bsep, Mdr2, and Oatps were detected.
During the first 2 weeks after transplantation, bile salt secretion was not parallel with phospholipid secretion, resulting in high biliary bile salt-to-phospholipid (BS:PL) ratio. The expression of bile transporters was consistent with the change of bile composition. Bile duct injury correlated significantly with bile salt secretion and BS:PL ratio. Moreover, OLT group with longer donor liver preservation time (OLT-12h) had significantly lower Mdr2 messenger RNA/protein level, higher BS:PL ratio, and better correlation between BS:PL ratio and bile duct injury compared with those of OLT-1h.
The unparallel secretion of bile salts and phospholipids results in cytotoxic bile formation with high BS:PL ratio after liver transplantation. Longer donor liver preservation time will increase graft bile cytotoxicity. The results of this study suggest that endogenous bile salts play a role in the pathogenesis of bile duct injury after OLT.
非吻合口胆管狭窄是原位肝移植（OLT）后一种严重的并发症，且难以治愈。我们研究了内源性胆汁盐毒性在OLT后胆管损伤发病机制中的作用。
总共90只Sprague-Dawley大鼠被分为三组：假手术组（假手术组，n = 30）、供肝保存1小时的OLT组（OLT-1h，n = 30）和供肝保存12小时的OLT组（OLT-12h，n = 30）。收集胆汁并进行生化分析。进行组织病理学研究以确定肝内胆管的形态学变化。检测胆汁转运蛋白Ntcp、Bsep、Mdr2和Oatps的肝脏表达。
移植后的前2周内，胆汁盐分泌与磷脂分泌不平行，导致胆汁中胆汁盐与磷脂（BS:PL）比值升高。胆汁转运蛋白的表达与胆汁成分的变化一致。胆管损伤与胆汁盐分泌和BS:PL比值显著相关。此外，与OLT-1h组相比，供肝保存时间较长的OLT组（OLT-12h）的Mdr2信使核糖核酸/蛋白水平显著降低，BS:PL比值更高，且BS:PL比值与胆管损伤之间的相关性更好。
肝移植后胆汁盐和磷脂的不平行分泌导致形成具有高BS:PL比值的细胞毒性胆汁。供肝保存时间延长会增加移植物胆汁的细胞毒性。本研究结果表明内源性胆汁盐在OLT后胆管损伤的发病机制中起作用。
