CARBOHYDRATE SELECTIN INHIBITOR CY-1503 REDUCES NEUTROPHIL MIGRATION AND REPERFUSION INJURY IN CANINE PULMONARY ALLOGRAFTS

Background: Neutrophil adhesion is initiated by the interaction of rap idly expressed endothelial selectins with oligosaccharide structures ( sialyl Lewis(x)) on polymorphonuclear neutrophils (PMN). The carbohydr ate sialyl Lewis X analogue CY-1503 blocks selectin receptors, thereby inhibiting PMN rolling and subsequent firm adhesion and migration. Me thods: We evaluated the inhibitory effect of CY-1503 on PMN migration and reperfusion injury in canine left lung allografts. Donor lungs wer e flushed with modified Euro-Collins solution (1500 ml, 4 degrees C) a nd preserved for 21 hours at 1 degrees C. Left lung allotransplantatio n was subsequently performed in 14 mongrel dogs. Immediately after tra nsplantation and allograft reperfusion, the recipient contralateral ri ght pulmonary artery and bronchus were ligated to permit assessment of isolated allograft function during a 6-hour postreperfusion period (F IO2 = 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 (MP O) activity were measured. Two groups were studied: In group I (n = 7) CY-1503 was added to the donor lung hush (20 mg/L) and given to the r ecipient (35 mg/kg intravenous bolus) before reperfusion, followed by a continuous infusion (5.25 mg/kg/h intravenously) during the 6-hour a ssessment period. Group II animals (n = 7) received no CY-1503. Result s: Gas exchange in group I was superior throughout the assessment peri od (p < 0.01 at 6 hours after reperfusion). BALF PMN count in group I was reduced to 0.57 +/- 0.3 x 10(6) PMN/ml compared with 3.9 +/- 1.3 X 10(6) PMN/ml in group II (p < 0.05). Group I allograft MPO activity w as 0.21 +/- 0.06 compared with 0.40 +/- 0.02 Delta OD/mg/min in contro ls (p < 0.02). Two animals in each group died early after reperfusion as a result of graft failure and were excluded from analysis. Conclusi ons: Our observations indicate that selectin inhibition effectively re duces PMN adhesion, migration, and subsequent reperfusion injury in pr eserved canine lung allografts.