Hepatic tumor necrosis factor-alpha 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-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.
Beierle
E A
EA
Department of Surgery, University of Florida College of Medicine, Gainesville 32610, USA.
Vauthey
J N
JN
Moldawer
L L
LL
Copeland
E M
EM
D000818:Animals; D001663:Bilirubin / Q000097:blood; D001806:Blood Urea Nitrogen; D002779:Cholestasis / Q000378:metabolism* / Q000503:physiopathology*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D007668:Kidney / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism*; D008168:Lung / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D011092:Polyethylene Glycols; D003404:Creatinine; D001663:Bilirubin