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J Thorac Cardiovasc Surg 2002;124:259-269
© 2002 The American Association for Thoracic Surgery

Cardiothoracic Transplantation (TX)

Recipient intramuscular cotransfection of naked plasmid transforming growth factor ß₁ and interleukin 10 ameliorates lung graft ischemia-reperfusion injury

From the Division of Cardiothoracic Surgery,^a Department of Pathology and Immunology,^b Washington University School of Medicine, St Louis Mo; Università degli Studi di Bologna,^c Bologna, Italy; and Genzyme Co,^d Framingham Mass.

This work was supported by National Institutes of Health (NIH) grant 1 R01 HL-41281. Dr T. Mohanakumar is supported by NIH grant HL-56643. Dr S. A. Kanaan is supported by individual NRSA-NIH grant 1 F32 HL-68401-01.

Received for publication Sept 14, 2001. Revisions requested Nov 19, 2001; revisions received Dec 6, 2001. Accepted for publication Dec 7, 2001. Address for reprints: G. Alexander Patterson, MD, 3108 Queeny Tower, One Barnes-Jewish Hospital Plaza, St Louis, MO 63110 (E-mail: pattersona{at}msnotes.wustl.edu).

Objective: Multiple gene transfer might permit modulation of concurrent biochemical pathways involved in lung graft ischemia-reperfusion injury. In this study we analyzed whether recipient intramuscular naked plasmid cotransfection of transforming growth factor ß₁ and interleukin 10 would result in amelioration of lung graft ischemia-reperfusion injury.
Methods: Forty-eight hours before transplantation, 6 groups (n = 6) of F344 rats received intramuscular injection of naked plasmid encoding chloramphenicol acetyltransferase, chloramphenicol acetyltransferase plus ß-galactosidase, transforming growth factor ß₁, interleukin 10, or transforming growth factor ß₁ plus interleukin 10 or were not treated. Donor lungs were flushed and stored for 18 hours at 4°C before transplantation. Twenty-four hours later, grafts were assessed immediately before the animals were killed. Arterial oxygenation, wet/dry ratio, myeloperoxidase, and proinflammatory cytokines (interleukin 1, tumor necrosis factor , interferon , and interleukin 2) were measured, and immunohistochemistry was performed.
Results: For lung graft function, the arterial oxygenation was considerably higher in the cotransfected group receiving transforming growth factor ß₁ plus interleukin 10 compared with that in all other groups (P .03). The wet/dry ratio, reflecting lung edema, was reduced in the cotransfected group compared with that in control animals (nontreated, P < .02; chloramphenicol acetyltransferase, P < .03; chloramphenicol acetyltransferase plus ß-galactosidase, P < .01). Myeloperoxidase, which measures neutrophil sequestration, was also reduced with cotransfection compared with that seen in control animals (P .03). All proinflammatory cytokines were decreased in the cotransfected group compared with those in all other groups (interleukin 1ß, P < .04; tumor necrosis factor , P < .002; interferon , P < .0001; interleukin 2, P < .03). These results indicate that cotransfection provides a synergistic benefit in graft function versus either cytokine alone, neutrophil sequestration, or inflammatory cytokine expression. Immunohistochemistry showed positive staining of transforming growth factor ß₁ plus interleukin 10 in type I and II pneumocytes and localized edema fluid.
Conclusions: Recipient intramuscular naked plasmid cotransfection of transforming growth factor ß₁ and interleukin 10 provides a synergistic effect in ameliorating lung reperfusion injury after prolonged ischemia.

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