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J Thorac Cardiovasc Surg 2000;120:947-956
© 2000 The American Association for Thoracic Surgery

General Thoracic Surgery

Adenovirus-mediated gene transfer of human interleukin 10 ameliorates reperfusion injury of rat lung isografts

Hideki Itano, MDa, Wanjiang Zhang, MDa, Jon H. Ritter, MDb, Timothy J. McCarthy, PhDc, T. Mohanakumar, PhDa, G. Alexander Patterson, MDa

From the Division of Cardiothoracic Surgery,a Departments of Pathologyb and Radiology,c Washington University School of Medicine, St Louis, Mo.

This work was supported by the National Institutes of Health grants RO1 HL 41281 (G.A.P.), HL 56643 (T.M.), and the Whitaker Foundation (T.J.M.). The nitric oxide analyzer was purchased through a grant from the Whitaker Foundation (T.J.M.). H.I. was supported by the Okayama University Medical School.

Received for publication May 4, 2000. Accepted for publication June 6, 2000. Address for reprints: G. Alexander Patterson, MD, 3108 Queeny Tower, One Barnes-Jewish Hospital Plaza, St Louis, MO 63110 (E-mail: Kellym{at}msnotes.wustl.edu).

Abstract

Objective: The objective of this study was to examine the feasibility of human interleukin 10 gene transfer into rat lung isografts and to investigate the effect of gene transfer on subsequent ischemia-reperfusion injury.
Methods: Male F344 rats were divided into 4 groups and underwent left lung isotransplantation. Twenty-four hours before harvest, 5 x 10E9 pfu (group I, n = 6) or 1 x 10E10 pfu (group II, n = 7) of AdRSVhIL-10 was intravenously administered to donor rats. In group I-C (n = 6) and group II-C (n = 6), serving as controls, 5 x 10E9 pfu and 1 x 10E10 pfu of AdCMVLacZ were administered, respectively. Grafts were preserved for 18 hours at 4°C before implantation and assessed 24 hours after reperfusion. Transgene expression of human interleukin 10 was assessed by both reverse transcriptase–polymerase chain reaction and immunohistochemistry. Graft inducible nitric oxide synthase, tumor necrosis factor {alpha}, intercellular adhesion molecule-1, growth-regulated gene product/cytokine-induced neutrophil chemoattractant-1, and monocyte chemotactic protein-1 mRNA expression were assessed by reverse transcriptase–polymerase chain reaction. Isograft gas exchange, exhaled nitric oxide, and myeloperoxidase activity were also analyzed.
Results: Dose-dependent transgene expression was detected by reverse transcriptase–polymerase chain reaction and immunohistochemistry. Arterial PO2 in groups I (164.72 ± 85.3 mm Hg) and II (153.19 ± 113 mm Hg) was significantly higher than in groups I-C (82.37 ± 19.1 mm Hg) and II-C (77.95 ± 33.4 mm Hg) (P = .022 and P = .031, respectively). Arterial PCO2 in group I (33.40 ± 6.80 mm Hg) was significantly lower than in group I-C (51.23 ± 11.9 mm Hg) (P = .0096). Myeloperoxidase activity in group II (0.083 ± 0.031 {Delta}OD · min–1 · mg–1) was significantly lower than in group II-C (0.117 ± 0.028 {Delta}OD · min–1 · mg–1) (P = .044). The inducible nitric oxide synthase mRNA expression in group II (0.627 ± 0.28) was significantly lower than in group II-C (1.125 ± 0.63) (P = .039).
Conclusion: Adenovirus-mediated human interleukin 10 gene transfer in vivo into lung isografts ameliorates subsequent ischemia-reperfusion injury. This results in improved graft gas exchange, reduced neutrophil sequestration, and down-regulation of graft inducible nitric oxide synthase mRNA expression.




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