Anti-selectin therapy modifies skeletal muscle ischemia and reperfusion injury.
Restoration of blood flow to ischemic skeletal muscle results in a reperfusion injury characterized by permeability edema in part mediated by neutrophils that adhere via the selectin family of adhesion molecules. Rats underwent 4 h of hindlimb tourniquet ischemia followed by 4 h reperfusion. The role of neutrophils was determined by rendering one group of animals neutropenic before ischemia. In additional experimental groups, selectins were blocked with either a soluble form of the selectin counter-receptor, sialyl-Lewis X (SLX) or a monoclonal antibody directed against P-selectin (PB1.3). Neutrophil depletion resulted in a 36.1% reduction in hindlimb permeability (p < .05). SLX reduced hindlimb permeability index (PI) 23.9% at 1 mg/kg and 36.1% at 10 mg/kg compared to a nonfucosylated oligosaccharide, sialyl-N-acetylactosamine (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 reduce leukosequestration. We interpret these data to indicate that ischemia and reperfusion lead to selectin-mediated neutrophil sequestration. The oligosaccharide SLX, while moderately effective in limiting neutrophil sequestration was as effective as neutrophil depletion in reducing hindlimb permeability. The lack of concordance between the ability of SLX and PB1.3 in limiting neutrophil sequestration and permeability indicate mechanisms of action of these two agents that are in addition to the blocking of adhesion.
Weiser
M R
MR
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Gibbs
S A
SA
Valeri
C R
CR
Shepro
D
D
Hechtman
H B
HB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002199:Capillary Permeability; D002448:Cell Adhesion; D016256:Lewis X Antigen / Q000627:therapeutic use*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply*; D009844:Oligosaccharides / Q000627:therapeutic use*; D019007:P-Selectin / Q000276:immunology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology / Q000628:therapy*; D000080506:Sialyl Lewis X Antigen
D000911:Antibodies, Monoclonal; D016256:Lewis X Antigen; D009844:Oligosaccharides; D019007:P-Selectin; D000080506:Sialyl Lewis X Antigen; D009195:Peroxidase