CGS 8515 and indomethacin attenuate cytokine-induced cardiopulmonary dysfunction in pigs.
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.
Department of Anatomy, Physiological Sciences, and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
K T
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Kruse-Elliott
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NC
Olson
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000418:Albumins / Q000032:analysis; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000009:adverse effects*; D015237:Dinoprost / Q000097:blood; D004357:Drug Synergism; D015777:Eicosanoids / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006331:Heart Diseases / Q000139:chemically induced / Q000503:physiopathology; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D007213:Indomethacin / Q000494:pharmacology*; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000008:administration & dosage / Q000494:pharmacology; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000737:chemistry / Q000503:physiopathology*; D008171:Lung Diseases / Q000139:chemically induced / Q000503:physiopathology; D009285:Naphthoquinones / Q000494:pharmacology*; D013552:Swine / Q000502:physiology*; D013929:Thromboxane B2 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D000418:Albumins; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D007375:Interleukin-1; D016859:Lipoxygenase Inhibitors; D009285:Naphthoquinones; D014409:Tumor Necrosis Factor-alpha; D062367:ortho-Aminobenzoates; C055523:methyl 2-((3,4-dihydro-3,4-dioxo-1-naphthalenyl)amino)benzoate; D007975:Leukotriene B4; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D015237:Dinoprost; D007213:Indomethacin