Tumor Necrosis Factor-Induced Mortality Is Reversed with Cyclooxygenase Inhibition

Abstract

Objective The authors hypothesized that TNF would induce eicosanoid synthesis, and a cyclooxygenase inhibitor would attenuate both eicosanoid synthesis and improve survival in an LD90 TNF-induced (150 ng/kg/IV/5 min) mortality model. Summary Background Data Tumor necrosis factor is a cardinal mediator in sepsis; however, little is known about its effects on arachidonate metabolism. Methods Conscious male rats with carotid arterial and jugular venous catheters were randomized for mortality: group I. TNF alone (150 kg/IV/15 min, n = 30); group II, ibuprofen (30 mg/kg/IV at t = −20 and +240 min), plus TNF, (n = 28); and for hemodynamics, eicosanoid synthesis, blood gases: group II, TNF alone, (n = 8); group IV, ibuprofen + TNF (n = 8); group V, monoclonal antibody to TNF plus TNF (n = 8). Mortality was determined at 4–72 hr. Other parameters determined over 4 hours (0,5, 60, 120, 240 min). Results TNF stimulated synthesis of (a) TXB₂ (71 ± 30 pg/ml, mean ± SE at base vs. 117 ± 18 at 4 hr, p < 0.02); (b) PGE₂ (70 ± 6 pg/ml at base vs. 231 ± 68 at 4 hr. p < 0.02); (c) 6PGF (52 ± 6 pg/ml at base vs. 250 ± 80 at 4 hr, p < 0.02). Ibuprofen significantly (p < 0.05) inhibited eicosanoid synthesis from TNF. TNF-induced mortality (87%, 26/30) was dramatically decreased with lbuprofen (11%, 3/28), at 4, 24, and 72 hr (p < 0.01). Monoclonal antibody to TNF prevented all abnormalities and had 100% survival. Hemodynamic events were similar in both groups, but metabolic acidosis was attenuated with ibuprofen. Conclusions TNF stimulates arachidonic acid metabolism in vivo. A cyclooxygenase inhibitor attenuates elcosanoid synthesis and dramatically improves survival. TNF appears to have different effect on tissues that synthesize certain elcosanoids. Hypotension from TNF is not mediated via the eteosanoids. TNF-induced mortality, like endotoxemia/sepsis may be mediated, in part, via arachidonic add metabolites. These new findings support the notion that cyclooxygenase inhibitors may be used as adjunctive therapy in clinical sepsis.