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J Thorac Cardiovasc Surg 2002;123:795-802
© 2002 The American Association for Thoracic Surgery

Cardiothoracic Transplantation (TX)

Low-dose endobronchial gene transfer to ameliorate lung graft ischemia-reperfusion injury

From the Division of Cardiothoracic Surgery^a and 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.

Received for publication April 11, 2001. Revisions requested June 26, 2001; revisions received July 18, 2001. Accepted for publication July 18, 2001. 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 63110-1013 (E-mail: pattersona{at}msnotes.wustl.edu).

Objective: This study was undertaken to determine whether low-dose endobronchial transfer to the donor of the gene for human interleukin 10 would decrease ischemia-reperfusion injury in lung transplantation.
Methods: Experiments used male Fischer rats. Donor animals underwent right thoracotomy. A catheter was introduced into the left main bronchus, and vector was instilled. Group I (n = 6) received 2 x 10⁷ plaque-forming units of adenovirus encoding human interleukin 10, group II (n = 6) received an adenovirus control encoding ß-galactosidase, and group III (n = 6) received saline solution. After instillation the left main bronchus was clamped for 60 minutes. Lungs were removed 24 hours later and stored in low-potassium dextran glucose solution for 18 hours before left lung transplantation. Graft function was assessed at 24 hours immediately before the animals were killed. Ratio of wet to dry weight and tissue myeloperoxidase activity were measured. Transgenic expression of human interleukin 10 was evaluated by means of enzyme-linked immunosorbent assay and immunohistochemical assay.
Results: Arterial oxygenation was significantly improved in group I relative to groups II and III (257.6 ± 59.7 mm Hg vs 114.6 ± 66.9 mm Hg and 118.6 ± 91.1 mm Hg, P = .008 and P = .007, respectively). Neutrophil sequestration, as measured by myeloperoxidase activity, was also significantly reduced in group I relative to groups II and III (0.141 ± 0.025 vs 0.304 ± 0.130 and 0.367 ± 0.153 optical density units/[min · mg protein], P = .029 and P = .004, respectively). Enzyme-linked immunosorbent assay and immunohistochemical assay demonstrated the expression of human interleukin 10 in transfected lungs only.
Conclusions: Low-dose endobronchial transfer to the donor of the gene for human interleukin 10 ameliorated ischemia-reperfusion injury in rodent lung transplantation by improving graft oxygenation and reducing neutrophil sequestration. Only 2 x 10⁷ plaque-forming units of adenoviral vector were required for functional transgenic expression. Endobronchial gene transfer to lung grafts may be a useful delivery route even at low doses.

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