Effect of Glutathione Depletion and Hydrophilic Bile Acids on Hepatic Acute Phase Reaction in Rats with Extrahepatic Cholestasis

Abstract

Background: Extrahepatic cholestasis by biliary obstruction induces an acute phase reaction in the liver. It is a complex process involving cytokines, hormones and growth factors. To determine whether the regulation of acute phase proteins (APP) in cholestasis depends on glutathione (GSH), the effect of buthionine sulfoximine-induced (BSO-induced) GSH depletion on the expression of various APP was studied. In addition, we determined the influence of hepatoprotective bile acids on hepatic APP and underlying cytokine events. Methods: Liver samples of bile-duct-ligated or sham-operated rats were examined. mRNA expression was quantified by densitometric analysis of Northern blots. Results: Expression of APP increased 2-5-fold in bile-duct-ligated rats as compared to sham-operated controls. This acute phase reaction remained similar independently of whether cholestasis occurred for 5 days or 3 weeks. In contrast to ! 2-macroglobulin and tissue inhibitor of metalloproteinases-1 (TIMP-1), mRNA levels of both # -fibrinogen and haptoglobin were significantly up-regulated after GSH depletion by BSO in cholestasis. Feeding of ursodeoxycholic and iso-ursodeoxycholic acid markedly down-regulated ! 2-macroglobulin and TIMP-1 expression in cholestasis but did not affect overexpression of # -fibrinogen and haptoglobin. Cholestasis leads to an increased APP expression accompanied by an increased expression of inflammatory cytokines (IL-6, TNF- ! ). After feeding of hydrophilic bile acids, increases in inflammatory cytokines were abrogated. Conclusions: We show that GSH is involved in the acute phase reaction during obstructive cholestasis. In addition, bile acids might selectively ameliorate the acute phase response by reducing expression of the APP not affected by GSH depletion ( ! 2-macroglobulin and TIMP-1).