Thromboxane A2 mediates augmented polymorphonuclear leukocyte adhesiveness

Abstract

We examined the role of prostaglandins and thromboxanes as mediators of plasma-dependent increased polymorphonuclear leukocyte adhesiveness induced by Escherichia coli lipopolysaccharide. The cyclo-oxygenase inhibitors-indomethacin and d,l-6-chloro-alpha-methyl-carbozole-2-acetic acid (R020-5720)-reduced lipopolysaccharide-induced adherence of polymorphonuclear leukocytes by 74 and 62%, respectively. In addition, inhibitors of thromboxane synthetase-imidazole, 9,11-azoprosta-5,13-dienoic acid, and 1-benzylimidazole-suppressed the stimulation of adherence by 31, 66, and 83%, respectively. Exogenous prostaglandins E(1), E(2), and F(2)alpha did not increase polymorphonuclear leukocyte adherence, nor were they detected in significant quantities in supernates of polymorphonuclear leukocytes exposed to lipopolysaccharide. However, inhibitors of both cyclo-oxygenase and thromboxane synthetase reduced increases in adherence induced by arachidonic acid (10 mug/ml), suggesting that lipopolysaccharide-mediated increases in adherence were due to an arachidonic acid product other than prostaglandin E(2) or F(2)alpha. 8,11,14-Eicosatrienoic acid, a precursor of monoenoic prostaglandins, did not enhance polymorphonuclear leukocyte adhesiveness. We next demonstrated lipopolysaccharide-stimulated generation, by polymorphonuclear leukocytes, of a labile, low molecular weight, dialyzable substance capable of enhancing the adherence of unstimulated leukocytes. In parallel experiments, a 10-fold increase in immunoreactive thromboxane B(2) over basal levels was detected after exposure of leukocytes to lipopolysaccharide. The inhibition of lipopolysaccharide enhancement of adherence by specific rabbit antibodies to thromboxane B(2) strongly supported a primary role for thromboxane A(2) as the mediator of the observed increases in adherence. Lipopolysaccharide-stimulated purified platelets did not increase leukocyte adherence, whereas thrombin-stimulated platelets did increase adherence. These studies suggest that lipopolysaccharide stimulates polymorphonuclear leukocytes to produce thromboxane A(2), which enhances their adhesiveness to nylon.