ENDOGENOUS NITRIC-OXIDE DECREASES XANTHINE OXIDASE-MEDIATED NEUTROPHIL ADHERENCE - ROLE OF P-SELECTIN

The oxygen radical-producing enzyme xanthine oxidase (XO) can promote neutrophil adherence to endothelium. Recognizing that a balance often exists in inflammatory processes, we sought to determine whether XO in itiates antiadherent pathways. We found that bovine pulmonary arterial endothelial cells (EC) exposed to XO released increased amounts of ni trite into the media, reflecting an increased production of nitric oxi de (NO). When EC were subjected to shear stress, treatment with XO and /or the NO synthase inhibitor N-omega-nitro-L-arginine (L-NNA) increas ed neutrophil rolling behavior and firm neutrophil adherence to EC in an additive fashion. Both rolling and adherent interactions were aboli shed by monoclonal antibodies directed against P-selectin. In addition , treatment of EC with XO and/or L-NNA increased both surface expressi on of P-selectin and release of von Willebrand factor into media. Fina lly, treatment of EC with the NO donor sodium nitroprusside decreased XO-mediated neutrophil rolling and adherence. We conclude that XO stim ulates EC to produce NO and that NO decreases the P-selectin-dependent neutrophil adhesion initiated by XO. Such increases in endogenous NO may constitute an important negative-feedback response to the acute pr oadhesive effects of XO.