Evidence for an involvement of the neutrophil integrin lymphocyte function-associated antigen-1 in early failure of...

The adhesion of neutrophils to the coronary vascular wall contributes to reperfusion injury of cardiac allografts. This phenomenon involves interactions between neutrophil beta 2-integrins (CD11a/CD18 [lymphocyte function-associated antigen-1, or LFA-1], CD11b/CD18 [membrane attack complex-1, or MAC-1], and CD11c/CD18 [p150,95]) and their endothelial ligands. Whereas the roles of the common beta-chain (CD18) and of the alpha-subunit of MAC-1 (CD11b) have been studied extensively, the role of the alpha-subunit of LFA-1 (CD11a) remains less well defined. The objective of this study, therefore, was to assess the effects of CD11a blockade on postischemic function and neutrophil infiltration of cardiac allografts.

Twenty-six rat hearts were kept in cold storage for 4 hours, heterotopically transplanted in the abdomen of recipient rats, and reperfused for 1 hour. In 10 hearts, a monoclonal antibody against LFA-1 alpha was given as a single intravenous bolus (100 micrograms) 35 minutes before reperfusion. The control groups consisted of 10 hearts that received saline and 6 hearts treated with an isotype-matched, nonbinding antibody (OKT3) administered at the same dosage and schedule as in the anti-LFA-1 alpha group. Before reperfusion, all hearts were instrumented with an intraventricular balloon-tipped catheter to allow serial isovolumic measurements of left ventricular function during reperfusion, after which myocardial accumulation of neutrophils was measured by myeloperoxidase activity. Postischemic heart rate and diastolic pressure were comparable among groups. However, the best recovery of contractility was achieved with anti-LFA-1 alpha treatment. After 60 minutes of reperfusion, dP/dt values were 1680 +/- 66 mm Hg/s-1, 1733 +/- 25 mm Hg/s-1, and 2550 +/- 95 mm Hg/s-1 in the saline, OKT3, and anti-LFA-1 alpha groups, respectively (P < .0001 between anti-LFA-1 alpha and the two control groups). This correlated with a significant (P < .0001) reduction in myocardial accumulation of neutrophils in the anti-LFA-1 alpha group (3.3 +/- 0.1 versus 7.9 +/- 0.6 and 6.7 +/- 0.3 U/100 mg tissue in the saline and OKT3 groups, respectively).

These results suggest the involvement of the alpha-subunit of LFA-1 (CD11a) in neutrophil-mediated reperfusion injury incurred by transplanted hearts. This finding is clinically relevant in view of the recent development of an anti-LFA-1 alpha monoclonal antibody for human use, the cardioprotective effects of which might thus extend beyond the initially intended prevention of lymphocyte-mediated rejection.