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.
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 ureanitrogen 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 ureanitrogen, 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.
Authors: Zenichi Morise; Masakazu Ueda; Masaki Kitajima; Charles J Epstein; D Neil Granger; Matthew B Grisham Journal: Dig Dis Sci Date: 2002-03 Impact factor: 3.199
Authors: Francisco J Padillo; Jordi Muntane; Jose L Montero; Javier Briceño; Gonzalo Miño; Guillermo Solorzano; Antonio Sitges-Serra; Carlos Pera-Madrazo Journal: World J Surg Date: 2002-09-26 Impact factor: 3.352
Authors: Isao Nozaki; John G Lunz; Susan Specht; Jong-In Park; Andrew S Giraud; Noriko Murase; Anthony J Demetris Journal: Am J Pathol Date: 2004-12 Impact factor: 4.307