CGS 8515 and indomethacin attenuate cytokine-induced cardiopulmonary dysfunction in pigs.

Abstract

We evaluated the effect of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 alpha (IL-1 alpha) on pig cardiopulmonary function by intravenously infusing each cytokine individually or in combination (0.5 microgram/kg from 0 to 0.5 h + 5 ng.kg-1 x min-1 from 0.5 to 6 h for each cytokine). The role of eicosanoids in mediating the TNF-alpha + IL-1 alpha-induced cardiopulmonary dysfunction was also investigated by pretreating cytokine-infused pigs with CGS 8515 (5-lipoxygenase inhibitor) or indomethacin (cyclooxygenase inhibitor). Coinfusion of TNF-alpha with IL-1 alpha caused additive increases (P < 0.05) in total peripheral resistance and plasma concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha). The increases in mean pulmonary arterial pressure (Ppa), pulmonary vascular resistance (PVR), alveolar-arterial O2 gradient (AaDO2), alveolar dead space-to-tidal volume ratio (VD/VT), and plasma concentrations of thromboxane B2 were either additive or synergistic. CGS 8515 blocked the TNF-alpha + IL-1 alpha-induced increases (P < 0.05) in mean aortic pressure, total peripheral resistance (4-6 h), VD/VT (5-6 h), and, at 6 h, attenuated the increases in Ppa, PVR, and AaDO2. Indomethacin blocked or attenuated the cytokine-induced increases (P < 0.05) in Ppa, PVR, AaDO2, VD/VT, and plasma concentrations of thromboxane B2 and 6-keto-PGF1 alpha. The 1-to 2-h systemic hypotension, caused by TNF-alpha + IL-1 alpha, was not abrogated by either indomethacin or CGS 8515. The cytokines did not alter plasma concentrations of leukotriene B4 or 5-hydroxyeicosatetraenoic acid. We conclude that coinfusion of TNF-alpha with IL-1 alpha induces physiological responses that are additive or synergistic and that cyclooxygenase and 5-lipoxygenase products (other than leukotriene B4 and 5-hydroxyeicosatetraenoic acid) importantly mediate cardiopulmonary dysfunction in pigs infused with TNF-alpha + IL-1 alpha.