Carbohydrate selectin inhibitor CY-1503 reduces neutrophil migration and reperfusion injury in canine pulmonary allografts

Background: Neutrophil adhesion is initiated by the interaction of rapidly expressed endothelial selectins with oligosaccharide structures (sialyl Lewis(x)) on polymorphonuclear neutrophils (PMN). The carbohydrate sialyl Lewis X analogue CY-1503 blocks selectin receptors, thereby inhibiting PMN rolling and subsequent firm adhesion and migration. Methods: We evaluated the inhibitorY effect of CY-1503 on PMN migration and reperfusion injury in canine left lung allografts. Donor lungs were flushed with modified Euro- Collins solution (1500 ml, 4°C) and preserved for 21 hours at 1°C. Left lung allotransplantation was subsequently performed in 14 mongrel dogs. Immediately after transplantation and allograft reperfusion, the recipient contralateral right pulmonary artery and bronchus were ligated to permit assessment of isolated allograft function during a 6-hour postreperfusion period (FIO₂ = 1.0). Allograft gas exchange (q 15 minutes) and hemodynamics (q 60 minutes) were assessed. After sacrifice, allograft bronchoalveolar lavage fluid (BALF) PMN count and allograft tissue myeloperoxidase (MPO) activity were measured. Two groups were studied: In group I (n = 7) CY-1503 was added to the donor lung flush (20 mg/L) and given to the recipient (35 mg/kg intravenous bolus) before reperfusion, followed by a continuous infusion (5.25 mg/kg/h intravenously) during the 6-hour assessment period. Group II animals (n = 7) received no CY-1503. Results: Gas exchange in group I was superior throughout the assessment period (p < 0.01 at 6 hours after reperfusion). BALF PMN count in group I was reduced to 0.57 ± 0.3 x 10⁶ PMN/ml compared with 3.9 ± 1.3 x 10⁶ PMN/ml in group II (p < 0.05). Group I allograft MPO activity was 0.21 ± 0.06 compared with 0.40 ± 0.02 ΔOD/mg/min in controls (p < 0.02). Two animals in each group died early after reperfusion as a result of graft failure and were excluded from analysis. Conclusions: Our observations indicate that selectin inhibition effectively reduces PMN adhesion, migration, and subsequent reperfusion injury in preserved canine lung allografts.