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Right arrow Lung - transplantation

J Thorac Cardiovasc Surg 2003;126:1147-1154
© 2003 The American Association for Thoracic Surgery

General thoracic surgery

Tumor necrosis factor inhibitor gene transfer ameliorates lung graft ischemia-reperfusion injury

Tsutomu Tagawa, MDa,b, Benjamin D. Kozower, MDa, Samer A. Kanaan, MDa, Niccolò Daddi, MDa, Takashi Suda, MDa, Tadayuki Oka, MDb, G. Alexander Patterson, MD, FRCS(C)a,*

a Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, Barnes Jewish Hospital, St Louis, Mo, USA
b First Department of Surgery, Nagasaki University School of Medicine, Nagasaki, Japan

Received for publication October 2, 2002; revisions received December 2, 2002; revisions received February 19, 2003; accepted for publication February 26, 2003.

* Address for reprints: G. Alexander Patterson, MD, FRCS(C), Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, 3108 Queeny Tower, St Louis, MO 63110-1013, USA
pattersona{at}msnotes.wustl.edu

OBJECTIVE: Tumor necrosis factor is an important mediator of lung transplant ischemia-reperfusion injury, and soluble type I tumor necrosis factor receptor binds to tumor necrosis factor and works as a tumor necrosis factor inhibitor. The objectives of this study were to demonstrate that gene transfer of type I tumor necrosis factor receptor–IgG fusion protein reduces lung isograft ischemia-reperfusion injury and to compare donor endobronchial versus recipient intramuscular transfection strategies.

METHODS: Three donor groups of Fischer rats (n = 6/group) underwent endobronchial transfection with either saline, 2 x 107 plaque-forming units of control adenovirus encoding ß-galactosidase, or 2 x 107 plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor–IgG fusion protein. Left lungs were harvested 24 hours later. Two recipient groups (n = 6/group) underwent intramuscular transfection with 2 x 107 plaque-forming units or 1 x 1010 plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor–IgG fusion protein 24 hours before transplantation. All donor lung grafts were stored for 18 hours before orthotopic lung transplantation. Graft function was assessed 24 hours after reperfusion. Transgene expression was evaluated by means of enzyme-linked immunosorbent assay and immunohistochemistry of type I tumor necrosis factor receptor.

RESULTS: Endobronchial transfection of donor lung grafts with 2 x 107 plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor–IgG fusion protein significantly improved arterial oxygenation compared with the saline and ß-galactosidase donor groups (366.6 ± 137.9 vs 138.8 ± 159.9 and 140.6 ± 131.4 mm Hg, P = .009 and .010, respectively). Recipient intramuscular transfection with 1 x 1010 plaque-forming units of adenovirus encoding type I tumor necrosis factor receptor–IgG fusion protein improved lung graft oxygenation compared with that seen in the low-dose intramuscular group (2 x 107; 320.3 ± 188.6 vs 143.6 ± 20.2 mm Hg, P = .038). Type I tumor necrosis factor receptor–IgG fusion protein was expressed in endobronchial transfected grafts. In addition, intramuscular type I tumor necrosis factor receptor–IgG fusion protein expression was dose dependent.

CONCLUSIONS: Donor endobronchial and recipient intramuscular adenovirus-mediated gene transfer of type I tumor necrosis factor receptor–IgG fusion protein improved experimental lung graft oxygenation after prolonged ischemia. However, donor endobronchial transfection required 500-fold less vector. Furthermore, at low vector doses, it does not create significant graft inflammation.




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