THERAPEUTIC POTENTIAL OF INHIBITING LEUKOCYTE ROLLING IN ISCHEMIA REPERFUSION/

Leukocyte rolling has been postulated to be mandatory for subsequent l eukocyte adhesion and tissue injury observed during ischemia/reperfusi on. The objective of this study was to systematically assess this hypo thesis at the microvascular level by examining the effects of various concentrations of a selectin-binding carbohydrate (fucoidin) on the in creased rolling and adhesion of leukocytes in postischemic venules. Th e contribution of L-selectin and/or P-selectin to leukocyte rolling we re also assessed in this model, Using intravital microscopy we observe d that 60 min of ischemia followed by reperfusion caused a profound in crease in leukocyte rolling and adhesion, A high dose of fucoidin (25 mg/kg) reduced leukocyte rolling by > 90% and significantly reduced le ukocyte adhesion, whereas a lower dose of fucoidin still reduced leuko cyte rolling by 60% but had no effect on leukocyte adhesion, Moreover, despite the profound reduction in leukocyte rolling with fucoidin, th e remaining rolling cells were able to firmly adhere via a CD18-depend ent mechanism, particularly in those postcapillary venules with reduce d (30-50 %) shear rates, The increased rolling was also reduced 60% by either an anti-P-selectin antibody, an anti-L-selectin antibody, or a combination of the two antibodies, but this reduction in rolling cell s did not translate into significantly reduced leukocyte adhesion, Our data suggest that L-selectin, P-selectin, and a fucoidin-sensitive pa thway contribute to the significant increase in reperfusion-induced le ukocyte rolling, However, targeting leukocyte rolling Its a form of th erapy requires very significant efficacy (> 90%) to achieve reasonable (similar to 50%) attenuation in leukocyte adhesion in postischemic ve nules.