CONTRIBUTION OF TUMOR-NECROSIS-FACTOR-ALPHA TO ENDOTOXIN-INDUCED MUCOSAL DYSFUNCTION IN THE FELINE JEJUNUM

Tumor necrosis factor alpha (TNF alpha) occupies a pivotal role in the development of shock and tissue injury during endotoxemia and septice mia, and may be an important trigger in the pathogenesis of endotoxin- induced intestinal mucosal dysfunction. This study investigated the co ntribution of TNF alpha to endotoxin-induced mucosal dysfunction and t he efficacy of polyclonal anti-TNF alpha antibody in preventing endoto xin-induced mucosal dysfunction. To evaluate mucosal dysfunction, jeju nal blood-to-lumen clearances of chromium 51-labeled ethylenediaminete traacetate ([Cr-51]-EDTA) were measured in cats administered fetal cal f serum (controls), endotoxin, TNF alpha, or polyclonal anti-TNF alpha antibody and endotoxin. Serum TNF alpha activity was determined using a modified in vitro cytotoxicity bioassay using the murine fibrosarco ma cell line, WEHI-164 clone 13. Endotoxin and TNF alpha induced jejun al mucosal dysfunction as indicated by increases in [Cr-51]-EDTA clear ance. Mucosal dysfunction was accompanied by marked increases in serum TNF alpha activity. Furthermore, pretreatment with polyclonal anti-TN F alpha antibody prevented endotoxin-induced mucosal dysfunction and m arkedly reduced the associated increase in serum TNF alpha activity. T he findings of this study suggest that TNF alpha is an important media tor of endotoxin-induced mucosal epithelial barrier dysfunction.