Effect of endothelin receptor antagonist on lung allograft apoptosis and NOSII expression

Background. It is postulated that apoptosis contributes to ischemia-reperfu sion graft dysfunction after lung transplantation. The purpose of this stud y was to determine whether the improvement in lung function that we previou sly observed with the use of an endothelin-1 (ET-1) receptor antagonist aft er ischemia-reperfusion injury is associated with a reduction in inducible nitric oxide synthase (NOSII) expression and programmed cell death. Methods. Left lung canine allotransplantation was performed. Harvested lung blocks were preserved with modified Eurocollins solution and stored at 4 d egreesC for 18 to 20 hours. Lung allografts were tested for the expression of NOSH by immunohistochemistry, and extent of apoptosis by terminal dUTP n ick end-labeling (TUNEL). Animals blindly received either an intravenous in fusion of saline (control) or the ET-1 receptor antagonist (SB209670) (15 m ug/kg/min). Infusion began 30 minutes pretransplantation and continued to 6 hours posttransplantation. Results. Immunohistochemical analysis demonstrated significantly stronger N OSII immunostaining in the allografts of the saline control group (36.5% +/ - 3.6%) compared with native right lungs (6.9% +/- 1.3%, p < 0.001) or the ET-receptor antagonist treatment group (9.6% +/- 1.4%, p < 0.001). The TUNE L staining revealed a significantly stronger labeling in the allografts of the saline treatment control group (40.7% +/- 6.2%) compared with native ri ght lungs (5.0% +/- 0.6%, p < 0.005) or the ET receptor antagonist treatmen t group (14.1% +/- 2.8%, p < 0.01). Conclusions. We conclude that treatment of lung allografts with the ET-1 re ceptor antagonist SB209670 reduces the area of NOSH expression and the exte nt of apoptosis, factors known to contribute to the process of prolonged is chemia-reperfusion injury. (C) 2001 by The Society of Thoracic Surgeons.