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

Academic Article

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-α (TNF- α) 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-α 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-α bioactivity in plasma and organs was determined using the WEHI 164 clone 13 cytotoxicity assay. The TNF-α 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-α production was detected in the liver within 8 hours following obstructive jaundice, but TNF-α 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-α blockade. CONCLUSIONS: Hepatic TNF-α production is an integral component of the response to obstructive jaundice. A TNF-α-mediated inflammatory response occurs in the lungs as a result of obstructive jaundice; however, renal and hepatic dysfunction do not appear to be TNF-α dependent since they cannot be affected by TNF-α blockade.
  • Published In

    Digital Object Identifier (doi)

    Author List

  • Beierle EA; Vauthey JN; Moldawer LL; Copeland EM
  • Start Page

  • 202
  • End Page

  • 206
  • Volume

  • 171
  • Issue

  • 1