Evidence for tumor necrosis factor alpha as a mediator of the toxicity of a cyclooxygenase inhibitor in Gram-negative sepsis.
To investigate the effect of cyclooxygenase inhibition in experimental Gram-negative sepsis, indomethacin was administered to mice at different times (1 or 5 days, or 1 h) before sublethal infection with an intravenous inoculum of Pseudomonas aeruginosa Early indomethacin exposure did not alter the outcome of infection, yet treatment at the time of bacterial challenge resulted in a high mortality rate. Polymerase chain reaction-assisted mRNA amplification in the spleens of infected mice revealed that tumor necrosis factor alpha (TNF-alpha) messenger was selectively expressed by the drug-treated and infected mice during the 24 h preceding death. Higher TNF-alpha levels were found in sera from these mice, whose macrophages produced increased levels of nitric oxide in vitro. Both pentoxifylline, an inhibitor of TNF-alpha synthesis, and an inhibitor of nitric oxide production improved survival in the indomethacin-treated and infected mice, although no such effect followed the administration of TNF-neutralizing antibodies. These data support the notion that cyclooxygenase inhibitors may exert both positive and negative effects in Gram-negative sepsis, the latter presumably involving overproduction of TNF-alpha.
Campanile
F
F
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
Giampietri
A
A
Grohmann
U
U
Belladonna
M L
ML
Fioretti
M C
MC
Puccetti
P
P
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D007213:Indomethacin / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009569:Nitric Oxide / Q000096:biosynthesis; D010431:Pentoxifylline / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011552:Pseudomonas Infections / Q000503:physiopathology; D011550:Pseudomonas aeruginosa; D012333:RNA, Messenger / Q000235:genetics; D012772:Shock, Septic / Q000503:physiopathology* / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D010431:Pentoxifylline; D007213:Indomethacin