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EXPERIMENTAL STUDIES

P-selectin inhibition prevents early neutrophil activation but provides only modest protection against myocardial injury in dogs with ischemia and forty-eight hours reperfusion

^a Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Manuscript received June 12, 1998; revised manuscript received February 3, 1999, accepted March 15, 1999.

Reprint requests and correspondence: Dr. Lewis C. Becker, Johns Hopkins Medical Institutions, 600 North Wolfe Street, Halsted 500, Baltimore, Maryland, 21287
lbecker{at}welchlink.welch.jhu.edu

OBJECTIVES

This study was designed to determine whether antibody neutralization of the adhesion protein P-selectin would prevent neutrophil activation and reduce myocardial reperfusion injury.

BACKGROUND

Although inhibition of P-selectin markedly reduces short-term myocardial injury after ischemia and reperfusion, it is unknown whether it can provide meaningful long-term protection and preserve left ventricular function.

METHODS

Closed-chest dogs underwent 90 min left anterior descending coronary artery occlusion and 48 h reperfusion, and were randomized to 1) a treatment group (n = 11) receiving 1 mg/kg of the blocking anti–P-selectin antibody PB1.3, or 2) a control group receiving 1 mg/kg PNB1.6 (nonblocking antibody against P-selectin, n = 7) or an equivalent volume of saline (n = 2) 10 min before reperfusion. Infarct size was assessed postmortem by triphenyl tetrazolium chloride staining. Contrast left ventriculography was used to measure left ventricular function. Activation of circulating polymorphonuclear neutrophils (PMNs) was assessed by an increase in surface CD18 expression.

RESULTS

Neutrophil activation was observed at 30 min after reperfusion in the control group, but was abolished in the treatment group. Infarct size was reduced about 25% in the treatment group after controlling for variations in ischemic blood flow (p = 0.003, by analysis of covariance). However, this protective effect was not associated with preservation of blood flow to the ischemic–reperfused myocardium, nor with any improvement in global or regional left ventricular function.

CONCLUSIONS

The anti–P-selectin antibody PB1.3 prevented early PMN activation, but had only a modest long-term infarct-limiting effect over 48 h reperfusion. Adhesion molecules other than P-selectin may mediate delayed PMN activation and accumulation in reperfused myocardium.

Abbreviations and Acronyms   ANCOVA = analysis of covariance   Ig = immunoglobulin   LAD = left anterior descending coronary artery   mAb = monoclonal antibody   MPO = myeloperoxidase   PAF = platelet-activating factor   PMN = polymorphonuclear neutrophil

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