Amelioration of ischemia-reperfusion injury with cyclic peptide blockade of ICAM-1.
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 beta(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.
Merchant
Shakil H
SH
Department of Pathology, University of New Mexico Health Science Center, Albuquerque, New Mexico 87131, USA.
Gurule
Debbie M
DM
Larson
Richard S
RS
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins / Q000737:chemistry / Q000627:therapeutic use*; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000737:chemistry / Q000473:pathology; D005260:Female; D006614:Hindlimb; D007150:Immunohistochemistry; D007238:Infarction; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis / Q000187:drug effects* / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000473:pathology; D009504:Neutrophils / Q000502:physiology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D010456:Peptides, Cyclic; C473032:cyclic nonapeptide IP25; D018799:Intercellular Adhesion Molecule-1; D007770:L-Lactate Dehydrogenase