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 differ ent times (1 or 5 days, or 1 h) before sublethal infection with an int ravenous inoculum of Pseudomonas aeruginosa. Early indomethacin exposu re did not alter the outcome of infection, yet treatment at the time o f bacterial challenge resulted in a high mortality rate. Polymerase ch ain reaction-assisted mRNA amplification in the spleens of infected mi ce revealed that tumor necrosis factor alpha (TNF-alpha) messenger was selectively expressed by the drug-treated and infected mice during th e 24 h preceding death. Higher TNF-alpha levels were found in sera fro m these mice, whose macrophages produced increased levels of nitric ox ide 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 follo wed the administration of TNF-neutralizing antibodies. These data supp ort the notion that cyclooxygenase inhibitors may exert both positive and negative effects in Gram-negative sepsis, the latter presumably in volving overproduction of TNF-alpha.