Relationships between tumour necrosis factor, eicosanoids and platelet-activating factor as mediators of endotoxin-induced shock in mice.

1. The toxicity of intravenous recombinant human tumour necrosis factor (rhTNF), a TNF fragment (TNF114-130), endotoxin and combinations of rhTNF or TNF114-130 were tested in mice. Neither rhTNF nor TNF114-130 was lethal alone, but when combined with a non-lethal dose of endotoxin, rhTNF provoked dose-dependent mortality, as did higher doses of endotoxin alone. 2. Both the toxicity and the vasopermeability changes induced by endotoxin alone were blocked by the platelet-activating factor (PAF) antagonist BN52021, indomethacin or the dual cyclo-oxygenase/lipoxygenase inhibitor BW755C. 3. The lethality of the combined low dose endotoxin/rhTNF challenge was unaffected by pretreatment with BN52021, indomethacin or BW755C, or by treatment at 6 h intervals with BN52021 or BW755C. 4. The results of these studies suggest that TNF, a putative, early mediator of septic or endotoxin shock, cannot by itself mimic all of the effects of bacterial endotoxin in the model used in this study. Apparently, TNF works synergistically with other mediators whose release is stimulated by endotoxin. 5. The results also suggest that the mechanism of shock production by the rhTNF/endotoxin combination in mice is not dependent on the early stimulation of eicosanoid or PAF synthesis by rhTNF.