Survival in lung reperfusion injury is improved by an antibody that binds and inhibits L- and E-selectin

The selectins are a three-member family of leukocyte, platelet, and endothelial cell adhesion proteins that mediate leukocyte traffic into normal and inflamed tissues. P-selectin is expressed by endothelial cells and platelets, E-selectin by endothelial cells, and L-selectin by circulating leukocytes. To determine if selectin-mediated leukocyte adhesion influences the development of lung reperfusion injury, we studied hemodynamics and respiratory and inert gas exchange in sheep subjected to 3-hour in situ left lung ischemia followed by 6-hour left lung reperfusion with the right lung excluded. Ten minutes before reperfusion, eight animals received EL-246 (1 mg/kg intravenously), a novel antihuman selectin antibody that recognizes and blocks both L- and E-selectin and cross-reacts in sheep. Eight control animals with ischemia received no treatment, whereas three received an isotype-matched antihuman L-selectin antibody that does not cross-react in sheep (DREG-56, 1 mg/kg intravenously). Eight sham control sheep underwent an identical operative procedure but were never subjected to ischemia. Volume-cycled, pressure-limited (20 cm H2O) mechanical ventilation was consistent in all animals throughout the experiment. Six-hour survival in EL-246 recipients (100%) was significantly higher than in either ischemic control 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), ischemic control sheep (8.3 +/- 3.0 ml/kg), and DREG-56 recipients (9.1 +/- 2.6 ml/kg).(ABSTRACT TRUNCATED AT 250 WORDS)