Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection

Abstract

Oya S, Yokoyama Y, Kokuryo T, Uno M, Yamauchi K, Nagino M. Inhibition of Toll-like receptor 4 suppresses liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide injection. Am J Physiol Gastrointest Liver Physiol 306: G244 -G252, 2014. First published December 19, 2013 doi:10.1152/ajpgi.00366.2013The objective of this study was to elucidate the role of Toll-like receptor 4 (TLR4) in liver injury induced by biliary obstruction and subsequent intraportal lipopolysaccharide (LPS) infusion in rats. Biliary obstruction often leads to the development of bacterial translocation. Rats 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 g) was injected through the ileocecal vein. In other experiments, rats that had undergone BDL were pretreated, before LPS challenge, with internal biliary drainage (Drainage group); intravenous TAK-242, a TLR4 inhibitor (TAK group); or intravenous GdCl3, a Kupffer cell deactivator (GdCl3 group). The expression of the TLR4 protein and the number of Kupffer cells in the liver were significantly increased in the BDL group compared with the Sham group. These changes were normalized after biliary drainage. The expression of TLR4 colocalized with Kupffer cells, which was confirmed by double immunostaining. Serum levels of liver enzymes and proinflammatory cytokines after intraportal LPS injection were significantly higher in the BDL group than in the Sham group. However, pretreatment with TAK-242 or GdCl 3 strongly attenuated these changes to levels similar to those seen with biliary drainage. These results imply that blocking TLR4 signaling effectively attenuates liver damage to the same level as that observed with biliary drainage in rats with BDL and subsequent intraportal LPS infusion. TAK-242 treatment may be used for patients who are susceptible to liver damage by biliary obstruction and endotoxemia. bile duct ligation; bacterial translocation; TAK-242; biliary drainage; Kupffer cell PATIENTS WITH CHOLANGIOCARCINOMA or pancreatic head cancer often develop biliary obstruction. Biliary obstruction leads to impaired intestinal barrier function and the translocation of enteric bacteria to the systemic circulation (10, 26, 31). Thus, patients with biliary obstruction are susceptible to septic complications not only with cholangiovenous reflux but also with increased bacterial translocation (BT) from the gut to the systemic circulation (1,11,21). Severe liver damage has been shown using a model of biliary obstruction [bile duct ligation (BDL)] followed by endotoxin challenge by duodenal, intravenous, or intraperitoneal lipopolysaccharide (LPS) administration (2, 6, 18). However, no study has ever administered LPS through portal circulation (which mimics the conditions of BT) in BDL rats.A previous report demonstrated that intraportal LPS administration induces severe liver injury via Toll-like receptor 4 (TLR4) activation on Kupffer cells and the production of excessive a...

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