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J Thorac Cardiovasc Surg 2000;119:297-304
© 2000 Mosby, Inc.

CARDIOTHORACIC TRANSPLANTATION

IN VIVO ADENOVIRUS-MEDIATED ENDOTHELIAL NITRIC OXIDE SYNTHASE GENE TRANSFER AMELIORATES LUNG ALLOGRAFT ISCHEMIA-REPERFUSION INJURY

From the Division of Cardiothoracic Surgery,^a the Department of Surgery,^b Washington University School of Medicine, Barnes-Jewish Hospital, St Louis, Mo.

Supported by National Institutes of Health grant 1 R01 HL41281.

Address for reprints: G. Alexander Patterson, MD, Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, 3108 Queeny Tower, St Louis, MO 63110.

Objective: Nitric oxide regulates vascular tone, inhibits platelet aggregation, and inhibits leukocyte adhesion, all of which are important modulators of ischemia-reperfusion injury. This study aimed to determine the effects of endothelial constitutive nitric oxide synthase gene transfer on ischemia-reperfusion injury in a rat lung transplant model.
Methods: In group I, donor animals were injected intravenously with 5 x 10⁹ pfu of adenovirus-encoding endothelial constitutive nitric oxide synthase. Groups II and III served as controls, whereby donor animals were injected with either 5 x 10⁹ pfu of adenovirus encoding ß-galactosidase or saline solution, respectively. Twenty-four hours after injection, left lungs were harvested and preserved for 18 hours at 4°C, then implanted into isogeneic recipients, which were put to death 24 hours later. Recombinant endothelial constitutive nitric oxide synthase gene expression was evaluated by Western blotting and immunohistochemistry. Lung grafts were assessed by measuring arterial oxygenation, myeloperoxidase activity, and wet/dry weight ratios.
Results: Western blotting confirmed the overexpression of endothelial constitutive nitric oxide synthase in lungs so transfected compared with controls. Twenty-four hours after reperfusion, mean arterial oxygenation was significantly improved in group I compared with group II and III controls (189.4 ± 47.1 mm Hg vs 71.7 ± 8.9 mm Hg and 67.8 ± 12.2 mm Hg, P = .02, P = .01, respectively). Myeloperoxidase activity, a reflection of tissue neutrophil sequestration, was also significantly reduced in group I compared with groups II and III (0.136 ± 0.038 OD/mg/min vs 0.587 ± 0.077 and 0.489 ± 0.126 OD/mg/min, P = .001, P = .01, respectively).
Conclusion: Adenovirus-mediated gene transfer with endothelial constitutive nitric oxide synthase ameliorates ischemia-reperfusion injury as manifested by significantly improved oxygenation and decreased neutrophil sequestration in transplanted lung isografts. Endothelial constitutive nitric oxide synthase gene transfer may reduce acute lung dysfunction after lung transplantation.

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