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Department of Pathology, University of New Mexico Health Science Center, Albuquerque, New Mexico 87131
Neutrophils are pivotal in the
pathogenesis of ischemia-reperfusion (I/R) injury leading to
muscle damage. Firm adhesion of neutrophils to the endothelium is
initiated by an interaction between intercellular adhesion molecular-1
(ICAM-1) on the endothelium and 
2-integrins on
neutrophils. Inhibition of ICAM-1-dependent binding using monoclonal
antibodies has been shown to be efficacious in ameliorating I/R 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 I/R 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 h of reperfusion were compared with
those in untreated control mice and contralateral nonischemic
limbs. Mice receiving IP25 immediately before reperfusion showed a 56%
reduction in neutrophil infiltration in the ischemic muscle,
accompanied by a 40% reduction in the infarct size. No effect on I/R
injury was seen if IP25 administration was delayed for 60 min after
reperfusion. We conclude that IP25 effectively inhibits ICAM-1-mediated
adhesion of neutrophils to the endothelium in mice leading to a
protective effect and suggests that synthetic peptide antagonists have
a potential role as therapeutic tools.
infarction; peptide antagonist; cell adhesion
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