EFFECT OF PAF RECEPTOR ANTAGONISM ON CARDIOPULMONARY ALTERATIONS DURING COINFUSION OF TNF-ALPHA AND IL-1-ALPHA IN PIGS

We examined the possibility that platelet-activating factor (PAF) might be a mediator of cardiopulmonary alterations induced by a 6-h coinfusion of human recombinant tumor necrosis factor (TNF-a) and interleukin-1alpha (IL-1alpha) in anesthetized pip. Our hypothesis was tested by pretreating TNF-alpha + IL-1alpha-infused pip with WEB 2086 (3 mg/kg from -0.5 to 0 h + 0.75 mg.kg-1.h-1 from 0-6 h), a specific PAF receptor antagonist. Each cytokine was infused intravenously at 0.5 mug/kg from 0-0.5 h + 5 ng. kg-1.min-1 from 0.5-6 h. WEB 2086 attenuated the early (0.25 h) cytokine-induced increases in mean pulmonary arterial pressure and pulmonary vascular resistance and blocked or markedly attenuated the later occurring (4-6 h) systemic hypertension and increased systemic vascular resistance. WEB 2086 lessened the severity of TNF-alpha + IL-1alpha-induced hemoconcentration and airway constriction, but did not modify leukopenia, granulocytopenia, or the cytokine-induced increases in plasma concentrations of thromboxane B2, prostaglandin F2alpha, and 6-ketoprostaglandin F1alpha. Microscopically, WEB 2086 did not modify the increased number of granulocytes present in lung tissue derived from pigs infused with TNF-alpha + IL-1alpha. We conclude that PAF occupies a physiological role in modulating TNF-alpha + IL-1alpha-induced hemoconcentration, the early changes in pulmonary hemodynamics, and the later alterations in systemic hemodynamics.