ANTI-SELECTIN THERAPY MODIFIES SKELETAL-MUSCLE ISCHEMIA AND REPERFUSION INJURY

Restoration of blood flow to ischemic skeletal muscle results in a rep erfusion injury characterized by permeability edema in part mediated b y neutrophils that adhere via the selectin family of adhesion molecule s. Rats underwent 4 h of hindlimb tourniquet ischemia followed by 4 h of reperfusion, The role of neutrophils was determined by rendering on e group of animals neutropenic before ischemia. In additional experime ntal groups, selectins were blocked with either a soluble form of the selectin counter-receptor, sialyl-lewis X (SLX) or a monoclonal antibo dy directed against P-selectin (PB1.3). Neutrophil depletion resulted in a 36.1% reduction in hindlimb permeability (p < .05). SU( reduced h indlimb permeability index (PI) 23.9% at 1 mg/kg and 36.1% at 10 mg/kg compared to a nonfucosylated oligosaccharide, sialyl-N-acetylactosami ne (p < .05). SLX also reduced neutrophil sequestration by 48.6% (p < .05). PB1.3 reduced hindlimb injury by 26.5% (p < .05) but did not red uce leukosequestration. We interpret these data to indicate that ische mia and reperfusion lead to selectin-mediated neutrophil sequestration . The oligosaccharide SU(, while moderately effective in limiting neut rophil sequestration was as effective as neutrophil depletion in reduc ing hindlimb permeability. The lack of concordance between the ability of SW and PB1.3 in limiting neutrophil sequestration and permeability indicate mechanisms of action of these two agents that are in additio n to the blocking of adhesion.