Cyclooxygenase inhibitors enhance tumour necrosis factor production and mortality in murine endotoxic shock

Intraperitoneal administration of E. coli lipopolysaccharide (5-15 mg/kg) produced a dose-related increase in mortality which was maximal 72 h after induction of shock. Using a suboptimal dose of LPS (10 mg/kg i.p.), pretreatment with indomethacin (0.1-10 mg/kg p.o) or ibuprofen (1-100 mg/kg p.o) 30 min prior to induction of shock led to a significant enhancement of mortality. This enhancement was associated with a 2-3 fold increase in the peak circulating levels of tumour necrosis factor (TNF-alpha) in the serum of animals treated with indomethacin or ibuprofen compared to vehicle-treated control animals. These results indicate that TNF-alpha production is modulated by endogenous prostaglandins in vivo and that enhanced production of TNF-alpha by cyclooxygenase inhibitors may lead to exacerbation of some inflammatory processes.