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

Tsutomu Tagawa, Benjamin D. Kozower, Samer A. Kanaan, Niccolò Daddi, Takashi Suda, Tadayuki Oka, G. Alexander Patterson

研究成果: Article

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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 × 107 plaque-forming units of control adenovirus encoding β-galactosidase, or 2 × 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 × 107 plaque-forming units or 1 × 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 × 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 β-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 × 10 10 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 × 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.

元の言語English
ページ(範囲)1147-1154
ページ数8
ジャーナルJournal of Thoracic and Cardiovascular Surgery
126
発行部数4
DOI
出版物ステータスPublished - 10-2003
外部発表Yes

All Science Journal Classification (ASJC) codes

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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