Endothelin receptor antagonist SB209670 decreases lung allograft apoptosis and improves lung graft function after prolonged ischemia

Apoptosis has been postulated as a contributing factor in ischemia-reperfusion graft dysfunction following lung transplantation. The purpose of this study was to determine whether treatment with an endothrlin-A/endothrlin-B- (ETA/ETB) receptor antagonist could reduce the level of apoptosis observed in the lung following ischemia-reperfusion injury. Eleven dogs were subjected to left lung allotransplantation. Heart-lung bloch were harvested from donor dogs and preserved with modified Eurocollins solution and stored at 4 degreesC for 18 to 20 h. We investigated the level of apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), in the lungs of animals receiving an intravenous infusion of saline (control, n = 5) or the ET receptor antagonist SB209670 (n = 6) (15 mug/kg/min). The infusion began 30 min prior to transplantation and continued for up to 6 h thereafter The TUNEL staining was significantly higher in the airway epithelium and the parenchyma of the saline (control) group (40.67 +/- 6.16), compared with native right lungs (5.00 +/- 0.56) and the treatment group (14.13 +/- 2.84). We conclude that treatment of lung allografts with the mixed ETA/ETB-receptor antagonist SB209670 can ameliorate lung injury by reducing the level of apoptosis seen in the allograft following ischemia-reperfusion injury.