Although the pathogenetic mechanisms underlying indomethacin-induced mucosal injury remain undefined, the results from recent studies suggest that leukocyte adherence in gastric microvessels may be an important component of this injury process. The objective of this study was to determine whether clinically relevant plasma concentrations of indomethacin promote leukocyte-endothelial cell adhesive interactions in postcapillary venules. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 s) and emigrated leukocytes were measured in rat mesenteric venules. Repeat measurements of all parameters were obtained within 20 min after addition of either 2.5 or 25 micrograms/ml indomethacin to the mesenteric superfusate. In some experiments, rats were pretreated with either a leukotriene (LT) synthesis inhibitor (L 663,536), an LTD4 (MK-571) or LTB4 (SC 41930) receptor antagonist, misoprostol, or prostacyclin (PGI2). Indomethacin alone increased the number of adherent leukocytes, reduced both leukocyte rolling velocity and venular shear rate, but did not promote leukocyte emigration. L 663,536 and SC 41930 prevented all of the adhesive and hemodynamic alterations induced by indomethacin; misoprostol and PGI2, but not MK-571, exerted similar beneficial effects. These results indicate that indomethacin promotes leukocyte adherence in postcapillary venules through an LTB4-dependent mechanism.
The objective of this study was to define the nature, magnitude, and mechanisms of histamine-induced leukocyte-endothelial cell interactions in postcapillary venules of the rat mesentery using intravital microscopic techniques. Superfusion ofthe mesentery with histamine (10-7-10-M) resulted in a dose-related increase in the number of rolling leukocytes, a reduction in rolling velocity, and an increased clearance of FITC-labeled rat albumin from blood to superfusate. The histamine-induced recruitment of rolling leukocytes and increased albumin clearance were prevented by histamine H1 (hydroxyzine, diphenhydramine) but not H2 (cimetidine) receptor antagonists. Because histamine induces expression of the adhesion molecule P-selectin in cultured endothelial cells, a monoclonal antibody directed against rat P-selectin and soluble sialyl-LewisX oligosaccharide (the carbohydrate ligand to P-selectin) were also tested as inhibitors. Both were effective in preventing the histamine-induced recruitment of rolling leukocytes, but neither agent attenuated the increased albumin clearance. These observations suggest that (a) histamine recruits rolling leukocytes and increases albumin leakage in postcapillary venules via H1 receptor activation, (b) histamine-induced recruitment of rolling leukocytes is mediated in part by P-selectin expressed on the endothelial cell surface, and (c) the histamine-induced vascular albumin leakage is unrelated to leukocyte-endothelial cell adhesion. Our results are consistent with the view that histamine may act as a mediator of acute inflammatory reactions. (J. Clin. Invest. 1994.93:1508-1515.) Key words: leuko-
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