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

胆汁引流对梗阻性胆汁淤积脏器及免疫功能受损的影响

基本信息

批准号：
14571192
负责人：
ARAI Toshiyuki
金额：
$ 2.24万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571192/
关键词：
obstructive cholestasis IL-10 IL-12 Kupffer cell apoptosis biliary dramage Toll-like receptor Peyer's patch 感染免疫 kupffer細胞胆汁内瘻 bacterial translocation

项目摘要

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.

1.胆道引流可恢复梗阻性黄疸患者受损的肝脏MRP 2表达。采用免疫染色和Western印迹法对胆道癌患者剖腹取肝组织中肝脏MRP 2（一种胆红素转运蛋白）的小管表达进行了评价。在7例左、右肝管阻塞的患者中，胆汁淤积性肝叶的MRP 2表达水平为非胆汁淤积性肝叶的46±26%。9例肝门部胆管梗阻患者中，有引流胆管的肝叶表达水平为无引流肝叶的156%（90-360%）。肝切除术前MRP 2的表达在最终发展为肝功能衰竭的患者中已经受损.梗阻性黄疸小鼠的免疫功能障碍（1）与假手术小鼠相比，胆道结扎小鼠腹腔感染大肠杆菌后，其杀菌活性严重受损。胆道引流后7天细菌清除率完全恢复。枯否细胞来源的IL-10是造成胆管结扎小鼠中细菌清除受损的原因。Fas突变小鼠没有表现出大肠杆菌杀伤受损，肝损伤很少，产生少量IL-10。这些结果表明，Fas介导的肝细胞凋亡可能参与了胆汁淤积小鼠枯否细胞的免疫功能障碍。此外，用TLR 2的配体刺激的NK T细胞至少部分地促进了阻塞性黄疸小鼠中由从肠道易位的大肠杆菌引起的肝细胞凋亡。(2)胆管结扎小鼠Peyer集合淋巴结的萎缩是肠道细菌移位的部分原因。Toll样受体4激活诱导B细胞凋亡可能是胆管结扎诱导派尔集合淋巴结萎缩的机制之一。