Hepatic tumor necrosis factors production and distant organ dysfunction in a murine model of obstructive jaundice

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 cellotomy. 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 cytotoxiclty 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.