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.