Abstract
Whether migration of granulocytes across pulmonary vascular endothelium in the absence of structural evidence of endothelial injury causes increased production of thromboxane or prostacyclin is not known. Using bovine pulmonary artery intimal explants mounted in Boyden chambers and homologous separated granulocytes, concentrations of thromboxane B2 and 6-keto-PGF1 alpha in the upper-well fluid were measured by radioimmunoassay over a three-hour period under the following conditions: (1) granulocyte chemotaxis (zymosan-activated plasma in the lower well, granulocytes in the upper well); (2) unstimulated granulocyte migration (serum or plasma in the lower well, granulocytes in the upper well); (3) granulocyte activation without migration (zymosan-activated plasma and granulocytes in the upper well); (4) granulocyte chemotaxis in the absence of endothelium (identical to condition 1 above except that endothelium was scraped from the explant surface); and (5) explants incubated in the absence of granulocytes. Minimal increases in thromboxane B2 concentrations in upper-well fluid occurred under all conditions. In contrast, granulocyte chemotaxis was accompanied by large increases in concentrations of 6-keto-PGF1 alpha evident by two hours of incubation and increasing markedly by three hours, to 524.3 +/- 69.0 ng/mL (m +/- SEM). Unstimulated migration of granulocytes toward serum or plasma and granulocyte activation without migration were accompanied, at three hours, by more modest increases in 6-keto-PGF1 alpha (296.5 +/- 46.4; 128.0 +/- 38.6, and 236.7 +/- 47.0 ng/mL, respectively) and, in the absence of granulocytes or in the absence of endothelium, only minimal increases in this prostacyclin metabolite occurred (137.2 +/- 16.9 and 53.9 +/- 12.6 ng/mL, respectively). The large rises in prostacyclin metabolite occurred at a time when the majority of granulocytes had migrated through the endothelial layer rather than during their adherence or transendothelial passage. We conclude that chemotaxis of granulocytes through pulmonary vascular endothelium causes endothelial production of large amounts of prostacyclin, but this occurs late in the chemotactic process, after granulocytes have transversed the endothelium.
MOLECULAR IMAGING OF THE HUMAN PULMONARY VASCULAR ENDOTHELIUM IN PULMONARY HYPERTENSION: THE PULMOBIND SAFETY AND PROOF OF PRINCIPLE TRIAL
