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.
Pettipher
E R
ER
Department of Immunology and Infectious Diseases, Pfizfer Inc., Groton, CT 06340.
Wimberly
D J
DJ
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003643:Death; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli; D007052:Ibuprofen / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis*
D016861:Cyclooxygenase Inhibitors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007052:Ibuprofen; D007213:Indomethacin