The Therapeutic Potential of Toll‐like Receptor 4 Antagonists in Preventing Liver Injury Induced by Biliary Obstruction and Subsequent Endotoxemia

Abstract

ObjectiveThe objective of this study was to elucidate the efficacy of toll‐like receptor 4 (TLR4) antagonists in preventing liver injury induced by biliary obstruction and subsequent intra‐portal lipopolysaccharide (LPS) infusion in rats.BackgroundBiliary obstruction often leads to the development of bacterial translocation and subsequent endotoxemia. Both biliary obstruction and endotoxemia lead to a severe liver injury.Materials and MethodsRats were subjected to either a sham operation (Sham group) or bile duct ligation for 7 days (BDL group). Seven days after each operation, LPS (0.5 μg) was injected through the ileocecal vein. In other experiments, rats that had undergone BDL were pretreated, prior to LPS challenge, with intravenous TAK‐242, a TLR4 inhibitor.ResultsThe expression of the TLR4 protein as well as the number of Kupffer cells in the liver were significantly increased in the BDL group compared with the Sham group. The expression of TLR4 co‐localized with Kupffer cells, which was confirmed by double immunofluorescence staining. Serum levels of liver enzymes and proinflammatory cytokines after intra‐portal LPS injection were significantly higher in the BDL group than in the Sham group. However, pretreatment with TAK‐242 strongly attenuated these changes.ConclusionsThese results imply that blocking TLR4 signaling effectively attenuates liver damage in rats with BDL and subsequent intra‐portal LPS infusion. TAK‐242 treatment may be used for patients who are susceptible to liver damage by biliary obstruction and endotoxemia.