Effect of PAF receptor antagonism on cardiopulmonary alterations during coinfusion of TNF-alpha and IL-1 alpha in pigs

• Published in: The American journal of physiology Vol. 264; no. 2 Pt 1; p. L175
• Main Authors: Kruse-Elliott, K T, Pino, M V, Olson, N C
• Format: Journal Article
• Language: English
• Published: United States 01.02.1993
• Subjects: Animals; Azepines - pharmacology; Blood Cells - drug effects; Drug Combinations; Eicosanoids - blood; Heart - drug effects; Hemodynamics - drug effects; Interleukin-1 - pharmacology; Lung - drug effects; Lung - pathology; Myocardium - pathology; Platelet Membrane Glycoproteins; Pulmonary Gas Exchange - drug effects; Receptors, Cell Surface - antagonists & inhibitors; Receptors, G-Protein-Coupled; Swine; Triazoles - pharmacology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0002-9513; 2163-5773
• DOI: 10.1152/ajplung.1993.264.2.L175

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-alpha) and interleukin-1 alpha (IL-1 alpha) in anesthetized pigs. Our hypothesis was tested by pretreating TNF-alpha + IL-1 alpha-infused pigs 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 microgram/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-1 alpha-induced hemoconcentration and airway constriction, but did not modify leukopenia, granulocytopenia, or the cytokine-induced increases in plasma concentrations of thromboxane B2, prostaglandin F2 alpha, and 6-ketoprostaglandin F1 alpha. Microscopically, WEB 2086 did not modify the increased number of granulocytes present in lung tissue derived from pigs infused with TNF-alpha + IL-1 alpha. We conclude that PAF occupies a physiological role in modulating TNF-alpha + IL-1 alpha-induced hemoconcentration, the early changes in pulmonary hemodynamics, and the later alterations in systemic hemodynamics.