Hepatic tumor necrosis factor-alpha production and distant organ dysfunction in a murine model of obstructive jaundice

Abstract

Background: Multisystem organ dysfunction frequently occurs following obstructive jaundice, but its etiology remains unclear. This study was undertaken to evaluate the role for endogenous tumor necrosis factor-alpha (TNF-alpha) production in the renal and pulmonary injury that accompanies obstructive jaundice.

Methods: Two hundred and twenty C57BL/6 mice underwent ligation and division of the common bile duct or a sham celiotomy. The animals were randomized to receive either placebo or 1 mg/kg BW (low dose) or 15 mg/kg BW (high dose) of a novel TNF-alpha inhibitor comprised of two extracellular domains of the p55 TNF receptor linked together with polyethylene glycol. Serum bilirubin, creatinine, and urea nitrogen were determined. TNF-alpha bioactivity in plasma and organs was determined using the WEHI 164 clone 13 cytotoxicity assay. The TNF-alpha messenger RNA was detected by reverse transcriptase-polymerase chain reaction. Neutrophil infiltration into the lungs and kidney were quantitated by the myeloperoxidase assay.

Results: Common bile duct ligation and division resulted in rapid and sustained increases in serum bilirubin, creatinine, and urea nitrogen, peaking 2 to 5 days later. Hepatic TNF-alpha production was detected in the liver within 8 hours following obstructive jaundice, but TNF-alpha production could not be detected in the kidney or lung at any time point. Increased neutrophil infiltration occurred in the lung following obstructive jaundice peaking 5 days after obstructive jaundice. This neutrophil infiltration into the lungs could be partially inhibited (62%, P < 0.05) by administration of the novel TNF inhibitor. In contrast, neither renal nor hepatic dysfunction were affected by TNF-alpha blockade.

Conclusions: Hepatic TNF-alpha production is an integral component of the response to obstructive jaundice. A TNF-alpha-mediated inflammatory response occurs in the lungs as a result of obstructive jaundice; however, renal and hepatic dysfunction do not appear to be TNF-alpha dependent since they cannot be affected by TNF-alpha blockade.