Am. J. Respir. Crit. Care Med., Volume 157, Number 6, June 1998, 1975-1981

Efficacy of Administering an Endothelin-receptor Antagonist (SB209670) in Ameliorating Ischemia-Reperfusion Injury in Lung Allografts

HANI SHENNIB, ALLAN G. L. LEE, JIN Q. KUANG, MASASHI YANAGISAWA, ELIOT H. OHLSTEIN, and ADEL GIAID

Montreal General Hospital, McGill University, Montreal, Quebec, Canada; Howard Hughes Medical Institute, Dallas, Texas; and Smith Kline-Beecham, Inc., King of Prussia, Pennsylvania

The purpose of this study was to determine whether treatment with an endothelin-1 (ET-1)-receptor antagonist could prevent ET-1-mediated ischemia-reperfusion injury and early allograft dysfunction. Eleven dogs were subjected to left lung allotransplantation. Donor lungs were preserved with modified Eurocollins solution and stored at 4° C for 18 to 20 h. Animals received an intravenous infusion of either the ET-receptor antagonist SB209670 (n = 6) (15 µg/kg/min) or saline (control, n = 5), in a blinded fashion. The infusion started 30 min before transplantation and continued for up to 6 h after transplantation. Hemodynamic measurements, blood gas tensions, and plasma samples were obtained with animals functioning solely on the transplanted lung. Open-lung biopsies were obtained for wet-to-dry-weight ratios and histologic and immunohistochemical analyses. Survival at 6 h after transplantation was 40% in the control group and 100% in the treatment group. Pulmonary vascular resistance and lung tissue wet-to-dry-weight ratio were significantly lower in treated animals at 3 and 6 h after transplantation. Histology of the transplanted lungs revealed more intense airway and interstitial inflammatory infiltration and edema in the control group. Arterial and venous plasma ET-1 concentrations increased after transplantation; however, they were significantly higher in the treatment group. Immunohistochemical analysis revealed more intense ET-1 immunostaining in the airways and parenchyma of the treatment group. We conclude that treatment of lung allografts with the mixed endothelin A/endothelin B (ETA/ETB) receptor antagonist SB209670 can ameliorate ischemia-reperfusion injury, resulting in improved graft function and survival after lung transplantation.

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