Na+ /H+ exchange inhibitors attenuate human polymorphonuclear leukocyte adhesion to human endothelial cells and H_2 O_2 production

Ischemia-reperfusion injury is largely attributed to activated leukocytes. We investigated the effects of the Na^+ /H^+ exchange (NHE) inhibitors SM-20220 and SM-20550 on the adhesion and H_2 O_2 production of human polymorphonuclear leukocytes (PMN) co-cultured with human umbilical vein endothelial cells (HUVECs). The adhesion of PMN to HUVECs stimulated with phorbol myristate acetate, a protein kinase C activator, was abolished by anti-CD18 antibody. This adhesion was attenuated by the NHE inhibitors. We also investigated the effect of these inhibitors on TNF-α-induced H_2 O_2 production from PMN cocultured with HUVECs. The inhibitors strongly suppressed TNF-α-induced H_2 O_2 production, which is reported to require CD18-mediated adhesion. These findings suggest that NHE inhibitors work by attenuating the CD18-mediated leukocyte-endothelial cell interaction and its downstream events. The inhibition of leukocyte activities such as adhesion and H_2 O_2 production may be one of the important mechanisms by which NHE inhibitors protect against ischemia-reperfusion injury.