Release of isoprostanes by human pulmonary artery in organ culture: a cyclo-oxygenase and nitric oxide dependent pathway.

Isoprostanes are prostaglandin (PG)-like compounds initially described as formed by a direct action of radicals on arachidonic acid. However, the isoprostane 8-iso PGF2 alpha, is released by platelets and monocytes by cyclo-oxygenase dependent pathways. The free radical NO can modulate arachidonic acid metabolism in some cells, but its potential role in isoprostane formation has not been studied. Using human pulmonary artery in organ culture (24 h), we therefore investigated the role of cyclo-oxygenase and NO in 8-iso PGF2 alpha release. In endothelium-denuded segments of pulmonary artery, the inflammatory agennts tumor necrosis factor alpha, interleukin-1 beta, interferon gamma, and lipopolysaccharide stimulated the release of PGE2 and 8-iso PGF2 alpha, which were attenuated in both cases by the cyclo-oxygenase inhibitor indomethacin. By contrast, the NO synthase inhibitor L-N(G)-intro-L-arginine methyl ester inhibited 8-iso PGF2 alpha but not PGF2 release. Thus, we show for the first time that human pulmonary vessels can produce isporostanes and that NO synthase and cyclo-oxygenase pathways are involved in their release.