Contribution of tumor necrosis factor alpha to endotoxin-induced mucosal dysfunction in the feline jejunum

Abstract

Tumor necrosis factor α (TNFα) occupies a pivotal role in the development of shock and tissue injury during endotoxemia and septicemia, and may be an important trigger in the pathogenesis of endotoxin-induced intestinal mucosal dysfunction. This study investigated the contribution of TNFα to endotoxin-induced mucosal dysfunction and the efficacy of polyclonal anti-TNFα antibody in preventing endotoxin-induced mucosal dysfunction. To evaluate mucosal dysfunction, jejunal blood-to-lumen clearances of chromium 51-labeled ethylenediaminetetraacetate ([51Cr]-EDTA) were measured in cats administered fetal calf serum (controls), endotoxin, TNFα, or polyclonal anti-TNFα antibody and endotoxin. Serum TNFα activity was determined using a modified in vitro cytotoxicity bioassay using the murine fibrosarcoma cell line, WEHI-164 clone 13. Endotoxin and TNFα induced jejunal mucosal dysfunction as indicated by increases in [51 Cr]-EDTA clearance. Mucosal dysfunction was accompanied by marked increases in serum TNFα activity. Furthermore, pretreatment with polyclonal anti-TNFα antibody prevented endotoxin-induced mucosal dysfunction and markedly reduced the associated increase in serum TNFα activity. The findings of this study suggest that TNFα is an important mediator of endotoxin-induced mucosal epithelial barrier dysfunction.