Inhibition of neutrophil adhesion reduces myocardial infarct size

Neutrophil accumulation and activation within the myocardium during ischemia and reperfusion has been shown to play a prominent role in the development of myocardial stunning and infarction.To determine if a simple inhibitor of neutrophil adhesion could reduce myocardial infarct size, we administered NPC 15669 (a new antiinflammatory agent that inhibits neutrophil adhesion) to 12 pigs (6 controls, 6 NPC-treated) in a porcine model of ischemia and reperfusion injury.Each animal received a continuous infusion of either NPC (10 mg/kg intravenous bolus followed by 6 mgkg-' * h-' intravenous infusion) or an equal volume of normal saline solution during 1 hour of left anterior descending artery occlusion and 2 hours of reperfusion.There were no eutrophil accumulation and activation within myo-N cardium has been shown to play a prominent role in extension of myocardial infarction [ 1-61.Activated neutrophils release numerous cytotoxic metabolites, including oxygen free radicals and proteolytic enzymes that are highly damaging to tissue [7, 81.Recent work indicates that activated neutrophils have increased adhesiveness to endothelial cells after modulation of their cell surface adhesion molecules [9].Most notable among these adhesion molecules is a neutrophil membrane glycoprotein known as the Mac-1, or CDllb/CD18, adhesion molecule.Several studies have demonstrated that inhibition of neutrophil adherence by monoclonal antibodies directed against the Mac-1 protein attenuates myocardial infarction and stunning [3, 5, lo].Such antibodies, although important as research tools, are too costly and in limited supply to be useful as therapeutic agents.Recently, a new class of antiinflammatory agents that inhibit neutrophil recruitment was introduced into clinical trials for treatment of several inflammatory diseases.These "leumedins" are amino acids that have been shown in several animal models to reduce neutrophil recruitment and infiltration into areas of inflammation [ll, 121.One of the principal activities of leumedins appears to be inhibition of up-regulation of the Mac-1 adhesion molecule.In this present study, we report the use of the leumedin