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1 Department of Pathology, University of New Mexico Health Science Center, Albuquerque, New Mexico, USA
* To whom correspondence should be addressed. E-mail: rlarson{at}salud.unm.edu.
Neutrophils are pivotal in the pathogenesis of ischemia-reperfusion (IR) injury leading to muscle damage. Firm adhesion of neutrophils to endothelium is initiated by interaction between intercellular adhesion molecular-1 (ICAM-1) on endothelium and
2 integrins on neutrophils. Inhibition of ICAM-1-dependent binding using monoclonal antibodies has been shown to be efficacious in ameliorating ischemia-reperfusion injury by preventing the influx of neutrophils into the ischemic tissue. We recently described a cyclic peptide that is a potent, and selective inhibitor of ICAM-1 (IP25) in vitro. In this study, we tested the hypothesis that IP25-mediated blockade of ICAM-1 would inhibit neutrophil influx during reperfusion of ischemic tissue and consequently attenuate muscle injury in a tourniquet hindlimb murine model of IR injury. Varying amounts of peptide drug were injected at the beginning of the reperfusion period. The neutrophil influx and size of infarction at the end of 2 hours of reperfusion was compared with untreated control mice and contralateral non-ischemic limbs. Mice receiving IP25 immediately prior to reperfusion showed 56% reduction in neutrophil infiltration in the ischemic muscle, accompanied by a 40% reduction in the infarct size. No effect on IR injury was seen if IP25 administration was delayed for 60 min after reperfusion. We conclude that IP25 effectively inhibits ICAM-1 mediated adhesion of neutrophil to endothelium in mice leading to a protective effect and suggests that synthetic peptide antagonists have a potential role as therapeutic tools.
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