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

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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.