Tumor necrosis factor (TNF) and endotoxin prime effects of PAF in vivo.

The purpose of the present study in NMRI mice was to investigate the action of platelet-activating factor (PAF) on mortality and intestinal transit velocity, the interaction of endotoxin or tumor necrosis factor (TNF) with the effect of PAF on these parameters and the effect of the PAF antagonist WEB 2086 on the endotoxin/TNF- and PAF-induced changes. PAF at a high dose (200 micrograms/kg i.v.) increased mortality and reduced transit velocity. This effect was inhibited by WEB 2086 (0.01-0.5 mg/kg i.p.) in a dose-dependent manner. Pretreatment with endotoxin (S. typhosa; 10 micrograms/kg i.v.) or TNF (40 micrograms/kg i.v.) enhanced the activity of PAF resulting in increased mortality and reduced transit velocity. This enhanced activity of PAF in the case of pretreatment with endotoxin or TNF occurred at doses at which PAF, endotoxin or TNF given alone did not significantly affect these parameters. The ability of endotoxin or TNF to enhance the effect of PAF was maximal, if the time delay between endotoxin and subsequent PAF administration was about 1-2 h. WEB 2086 (0.01-1 mg/kg i.p.) inhibited this priming in a dose-dependent fashion. These findings support suggestions of a role for PAF in endotoxin shock and TNF-associated shock-like syndrome.