Obstructive jaundice increases sensitivity to lipopolysaccharide via TLR4 upregulation: Possible involvement in gut-derived hepatocyte growth factor-protection of hepatocytes

Background: Patients with obstructive jaundice are prone to sepsis after biliary tract surgery. The present study was designed to determine the effect of biliary obstruction on cytokine responses to lipopolysaccharide (LPS). Methods: Wister rats were allocated into two groups; the BDL group underwent bile duct ligation, followed 2 weeks later by administration of LPS into the duodenum. The control group underwent sham operation, and similarly received enteral LPS. Specimens were collected serially, and applied for the assays. Results: Serum aspartate aminotransferase and alanine aminotransferase levels were significantly increased in BDL rats. High tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 levels in peripheral blood were observed 2 h after LPS administration in BDL rats. In contrast, no increases in both cytokines were noted in peripheral and portal blood in control rats. Baseline HGF levels in portal and peripheral blood in BDL rats were significantly higher than in control rats. LPS significantly increased hepatocyte growth factor (HGF) levels in portal blood and decreased in peripheral blood in BDL rats, but not in control rats. Immunohistochemical analysis revealed that BDL increased expressions of Toll-like receptor (TLR)4, CD14 and CD68 both in the small intestine and liver. Both TLR4 and CD14 mRNAs were upregulated in the small intestine and liver after LPS administration in BDL rats. Conclusion: Obstructive jaundice and LPS stimulation induced TLR4 upregulation both in the liver and small intestine, which led to increased TNF-alpha and IL-6 production in liver and HGF production in the small intestine. The upregulation of TLR4 may lead to pathological and host defense reactions in obstructive jaundice complicated with Gram-negative bacterial infection. (C) 2005 Blackwell Publishing Asia Pty Ltd.