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

Background. It is postulated that apoptosis contributes to ischemia-reperfusion graft dysfunction after lung transplantation. The purpose of this study was to determine whether the improvement in lung function that we previously observed with the use of an endothelin-1 (ET-1) receptor antagonist after 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°C for 18 to 20 hours. Lung allografts were tested for the expression of NOSII by immunohistochemistry, and extent of apoptosis by terminal dUTP nick end-labeling (TUNEL). Animals blindly received either an intravenous infusion of saline (control) or the ET-1 receptor antagonist (SB209670) (15 μg/kg/min). Infusion began 30 minutes pretransplantation and continued to 6 hours posttransplantation. Results. Immunohistochemical analysis demonstrated significantly stronger NOSII 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 TUNEL staining revealed a significantly stronger labeling in the allografts of the saline treatment control group (40.7% ± 6.2%) compared with native right lungs (5.0% ± 0.6%, p < 0.005) or the ET receptor antagonist treatment group (14.1% ± 2.8%, p < 0.01). Conclusions. We conclude that treatment of lung allografts with the ET-1 receptor antagonist SB209670 reduces the area of NOSII expression and the extent of apoptosis, factors known to contribute to the process of prolonged ischemia-reperfusion injury.