Circulation, Vol 88, 1779-1787, Copyright © 1993 by American Heart Association
DJ Lefer, SM Shandelya, CV Serrano Jr, LC Becker, P Kuppusamy and JL Zweier
BACKGROUND. Previous studies have demonstrated that polymorphonuclear
leukocytes (PMNs) are locally activated in reperfused myocardium and
contribute to the myocardial cell injury associated with reperfusion. It
has been suggested that the adhesion of activated PMNs in reperfused
myocardium is mediated by the PMN adhesion molecule CD-18. In the present
study, we performed experiments to determine if the specific anti-CD-18
monoclonal antibody (MAb) R15.7 can prevent PMN adhesion and PMN-mediated
reperfusion injury in the heart. METHODS AND RESULTS. Studies were
performed with isolated, Langendorff-perfused rat hearts (nine per group)
in which the hearts were subjected to 20 minutes of global ischemia
followed by 45 minutes of reperfusion. Human PMNs (50 million) and rat
plasma (HNRP) were infused directly into the coronary circulation of
nonischemic and postischemic hearts. When HNRP was administered to
nonischemic hearts, no significant alterations in coronary flow, left
ventricular developed pressure, or left ventricular end-diastolic pressure
were observed. When hearts were reperfused in the presence of HNRP,
however, marked impairment of contractile function was observed with more
than 90% reduction in coronary flow throughout the reperfusion period (P
< .001 versus baseline). In addition, left ventricular developed
pressure was significantly depressed (P < .001 versus baseline)
throughout the reperfusion period in the HNRP group and recovered to only
13.0 +/- 3.0% at 45 minutes of reperfusion. Moreover, left ventricular
end-diastolic pressure was significantly elevated (P < .001) in the HNRP
group throughout the reperfusion period. Treatment with the anti-CD-18
monoclonal antibody MAb R15.7 (20 micrograms/mL) at the time of reperfusion
resulted in a 92.9 +/- 4.9% recovery of coronary flow (P < .001 versus
HNRP) as well as a 71.0 +/- 10.1% recovery of left ventricular developed
pressure (P < .001 versus HNRP). Administration of MAb R15.7 also very
significantly attenuated the elevation in left ventricular end- diastolic
pressure that was observed in the untreated HNRP (30.2 +/- 7.8 versus 110.3
+/- 10.3 mm Hg, P < .001) at 45 minutes of reperfusion. Cardiac
myeloperoxidase activity, an index of PMN accumulation, was markedly
reduced in the MAb R15.7 group at 45 minutes of reperfusion compared with
the HNRP group (0.03 +/- 0.01 versus 0.3 +/- 0.05, P < .001). To
determine that the protective effect of MAb R15.7 was based on functional
blocking of CD-18, additional experiments were performed with identical
concentrations of MAb 3.1, which binds to the alpha-subunit of LFA-1. This
PMN-binding but non-CD-18-blocking antibody had little effect on the
recovery of postischemic function or coronary flow and did not reduce
tissue myeloperoxidase activity. CONCLUSIONS. The administration of a
specific anti-CD-18 monoclonal antibody, MAb R15.7, attenuates much of the
PMN-mediated contractile dysfunction associated with this in vitro model of
myocardial ischemia- reperfusion injury by limiting PMN accumulation. We
conclude that CD-18- mediated adhesion may play a critical role in the
pathogenesis of PMN- induced myocardial injury.
ARTICLES
Cardioprotective actions of a monoclonal antibody against CD-18 in myocardial ischemia-reperfusion injury
Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
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