SURVIVAL IN LUNG REPERFUSION INJURY IS IMPROVED BY AN ANTIBODY THAT BINDS AND INHIBITS L-SELECTIN AND E-SELECTIN

The selectins are a three-member family of leukocyte, platelet, and en dothelial cell adhesion proteins that mediate leukocyte traffic into n ormal and inflamed tissues. P-selectin is expressed by endothelial cel ls and platelets, E-selectin by endothelial cells, and L-selectin by c irculating leukocytes. To determine if selectin-mediated leukocyte adh esion influences the development of lung reperfusion injury, we studie d hemodynamics and respiratory and inert gas exchange in sheep subject ed to 3-hour in situ left lung ischemia followed by 6-hour left lung r eperfusion with the right lung excluded. Ten minutes before reperfusio n, eight animals received EL-246 (1 mg/kg intravenously), a novel anti human selectin antibody that recognizes and blocks both L- and E-selec tin and cross-reacts in sheep. Eight control animals with ischemia rec eived no treatment, whereas three received an isotype-matched antihuma n L-selectin antibody that does not cross-react in sheep (DREG-56, 1 m g/kg intravenously). Eight sham control sheep underwent an identical o perative procedure but were never subjected to ischemia. Volume-cycled , pressure-limited (20 cm H2O) mechanical ventilation was consistent i n all animals throughout the experiment. Six-hour survival in EL-246 r ecipients (100%) was significantly higher than in either ischemic cont rol sheep (37.5%) or DREG-56 recipients (33.3%), but gravimetric lung water was equivalent in EL-246 recipients (5.9 +/- 1.7 ml/kg), ischemi c control sheep (8.3 +/- 3.0 ml/kg), and DREG-56 recipients (9.1 +/- 2 .6 ml/kg). Although inert gas shunt at 1/2 hour of reperfusion was no different when contrasted in EL-246 recipients (15% +/- 8%), ischemic control sheep (30% +/- 25%), and DREG-56 recipients (35% +/- 21%), shu nts in EL-246 recipients resolved (4% +/- 4%) within the 6-hour study period and were associated with a concomitant improvement in respirato ry gas exchange. Peripheral blood neutrophil counts increased after bo th EL-246 and DREG-56 administration, suggesting that the beneficial e ffect of EL-246 was not incurred by leukocyte depletion. We conclude t hat mechanisms other than activated neutrophils may account for the in itial deterioration of respiratory gas exchange in lung reperfusion in jury and inhibition of selectin function improves survival by preventi ng leukocyte-mediated amplification of this early process.