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

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1147-1154
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume126
Issue number4
DOIs
Publication statusPublished - 10-2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

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

Fingerprint Dive into the research topics of 'Tumor necrosis factor inhibitor gene transfer ameliorates lung graft ischemia-reperfusion injury'. Together they form a unique fingerprint.

  • Cite this