Therapeutic potential of inhibiting leukocyte rolling in ischemia/reperfusion.
Leukocyte rolling has been postulated to be mandatory for subsequent leukocyte adhesion and tissue injury observed during ischemia/reperfusion. The objective of this study was to systematically assess this hypothesis at the microvascular level by examining the effects of various concentrations of a selectin-binding carbohydrate (fucoidin) on the increased rolling and adhesion of leukocytes in postischemic venules. The contribution of L-selectin and/or P-selectin to leukocyte rolling were also assessed in this model. Using intravital microscopy we observed that 60 min of ischemia followed by reperfusion caused a profound increase in leukocyte rolling and adhesion. A high dose of fucoidin (25 mg/kg) reduced leukocyte rolling by > 90% and significantly reduced leukocyte adhesion, whereas a lower dose of fucoidin still reduced leukocyte rolling by 60% but had no effect on leukocyte adhesion. Moreover, despite the profound reduction in leukocyte rolling with fucoidin, the remaining rolling cells were able to firmly adhere via a CD18-dependent mechanism, particularly in those postcapillary venules with reduced (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 cells did not translate into significantly reduced leukocyte adhesion. Our data suggest that L-selectin, P-selectin, and a fucoidin-sensitive pathway contribute to the significant increase in reperfusion-induced leukocyte rolling. However, targeting leukocyte rolling as a form of therapy requires very significant efficacy (> 90%) to achieve reasonable (approximately 50%) attenuation in leukocyte adhesion in postischemic venules.
Kubes
P
P
Department of Medical Physiology, University of Calgary, Alberta, Canada.
Jutila
M
M
Payne
D
D
D000818:Animals; D002415:Cats; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000502:physiology; D002465:Cell Movement; D006439:Hemodynamics; D066298:In Vitro Techniques; D019041:L-Selectin; D007962:Leukocytes / Q000166:cytology*; D009504:Neutrophils / Q000166:cytology; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011134:Polysaccharides / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D012212:Rheology; D013997:Time Factors
D015815:Cell Adhesion Molecules; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D011134:Polysaccharides; D019041:L-Selectin; C007789:fucoidan