Effects of biliary drainage on the impaired functions of organs and immunity in obstructive cholestasis

1. 梗阻性黄疸患者的肝脏MRP2表达受损可通过胆道引流恢复。采用免疫染色和Western blotting检测胆道癌患者剖腹取肝组织中肝脏MRP2（一种胆红素转运蛋白）的小管表达。7例左、右肝管梗阻患者的胆汁淤积叶MRP2表达量为非胆汁淤积叶的46±26%。9例肝门胆管梗阻患者，有胆道引流的胆叶中表达量为无引流的156%（90 ~ 360%）。最终发展为肝功能衰竭的患者在肝切除术前MRP2表达受损。梗阻性黄疸小鼠的免疫功能障碍(1)与假手术小鼠相比，胆管结扎小鼠腹腔感染大肠杆菌后的杀菌活性严重受损。胆道引流后7天细菌清除率完全恢复。库普弗细胞衍生的IL-10对胆管结扎小鼠的细菌清除受损负责。fas突变小鼠没有表现出与肝损伤和少量IL-10产生相关的大肠杆菌杀灭能力受损。这些结果提示，fas介导的胆汁淤积肝细胞凋亡可能参与了胆汁淤积小鼠库普弗细胞免疫功能障碍。此外，TLR2配体刺激NK T细胞至少在一定程度上促进了梗阻性黄疸小鼠肠道易位大肠杆菌引起的肝细胞凋亡。(2)胆管结扎小鼠Peyer’s patches的萎缩是肠道细菌易位的部分原因。toll样受体4激活诱导B细胞凋亡可能是胆管结扎诱导Peyer斑块萎缩的机制之一。

1. Impaired hepatic MRP2 expression in obstructive jaundice is restored by biliary drainageThe canalicular expression of hepatic MRP2, a bilirubin transporter, in the liver tissue taken at laparotomy for patients with biliary carcinoma was evaluated with immunostaining and Western blotting. The MRP2 expression levels in the cholestatic lobes were 46±26% of those in the non-cholestatic lobes of 7 patients in which either right or left hepatic ducts were obstructed. The expression levels in the lobes with biliary drainage were 156% (90-360%) of those without drainage of 9 patients whose hilar bile ducts were obstructed. The MRP2 expression before hepatectomy had been impaired in patients who eventually developed liver failure.2. Immune dysfunction in mice with obstructive jaundice(1) Bactericidal activity after intraperitoneal infection with E.coli was severely impaired in mice with bile duct ligation as compared with sham mice. The decreased bacterial clearance was completely restored 7days after biliary drainage. Kupffer cell-derived IL-10 is responsible for impaired bacterial clearance in bile duct-ligated mice. Fas-mutated mice did not exhibit impairment in E.coli killing in association with little hepatic injury and a small amount of IL-10 production. These results suggest that Fas-mediated hepatocyte apoptosis in cholestasis may be involved in the immune dysfunction of Kupffer cells in cholestatic mice. Moreover, NK T cells stimulated with a ligand for TLR2 at least partly contribute to hepatocyte apoptosis caused by E.coli translocated from gut in mice with obstructive jaundice.(2) Atrophy of Peyer's patches in mice with bile duct ligation was partly responsible for bacterial translocation from the gut. Activation-induced apoptosis of B cells through Toll-like receptor 4 could be a mechanism whereby bile duct ligation induces atrophy of Peyer's patches.