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Tumor necrosis factor (TNF) and endotoxin prime effects of PAF in vivo
H O Heuer1, G Letts, C J Meade
1Department of Pharmacology, Boehringer Ingelheim, Ingelheim/Rhein, F.R.G.
Abstract:
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.
Insights
Platelet-activating factor (PAF) increases mortality and slows intestinal transit. PAF
Area of Science:
- Pharmacology
- Immunology
- Gastroenterology
Background:
- Platelet-activating factor (PAF) is implicated in inflammatory conditions.
- Endotoxin and tumor necrosis factor (TNF) are key mediators in sepsis and shock.
- Understanding the interplay between PAF, endotoxin, and TNF is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the effects of PAF on mortality and intestinal transit in mice.
- To examine how endotoxin and TNF modulate PAF's actions.
- To evaluate the efficacy of the PAF antagonist WEB 2086 in counteracting these effects.
Main Methods:
- Administration of PAF, endotoxin, and TNF to NMRI mice.
- Assessment of mortality rates and intestinal transit velocity.
- Dose-response studies with the PAF antagonist WEB 2086.
- Evaluation of time-dependent interactions between endotoxin/TNF and PAF.
Main Results:
- High-dose PAF increased mortality and reduced intestinal transit velocity, effects blocked by WEB 2086.
- Endotoxin or TNF pretreatment potentiated PAF's effects on mortality and transit, even at doses ineffective alone.
- This potentiation was maximal 1-2 hours post-endotoxin/TNF and was dose-dependently inhibited by WEB 2086.
Conclusions:
- PAF plays a significant role in endotoxin and TNF-induced shock-like syndromes.
- The PAF antagonist WEB 2086 demonstrates therapeutic potential in mitigating these conditions.
- These findings highlight PAF as a potential therapeutic target in sepsis and inflammatory shock.