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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 616-625, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.2002-0109OC

Impact of Human Interleukin-10 on Vector-Induced Inflammation and Early Graft Function in Rat Lung Transplantation

Marc de Perrot, Stefan Fischer, Mingyao Liu, Yumiko Imai, Saulo Martins, Shoji Sakiyama, Toshi Tabata, Xiao-Hui Bai, Thomas K. Waddell, Beverly L. Davidson and Shaf Keshavjee

Thoracic Surgery Research Laboratory, Toronto General Hospital Research Institute, University Health Network, University of Toronto, Ontario, Canada; and The Gene Transfer Vector Core, Department of Medicine, University of Iowa, Iowa City, Iowa

Address correspondence to: S. Keshavjee, M.D., Director, Thoracic Surgery Research Laboratory, Toronto General Hospital, 200 Elizabeth Street, EN 10-224, Toronto, Ontario, Canada M5G 2C4. E-mail: shaf.keshavjee{at}uhn.on.ca

This study was undertaken to examine the time course of human interleukin (hIL)-10 gene expression after transtracheal administration of adenoviral (Ad)hIL-10 and its effect on the early adenoviral proinflammatory cytokine response and on post-transplant lung function. Using a rat lung transplant model, we observed that lungs retrieved 12 h after the administration of AdhIL-10 were associated with significant improvement in post-transplant lung function. Shorter periods of transfection were associated with significantly elevated levels of tumor necrosis factor-{alpha} and macrophage inflammatory protein-2 in lung tissue, leading to an increased degree of injury. The release of proinflammatory cytokines secondary to the adenoviral vector was reduced by high-dose methylprednisolone (30 mg/kg) administered 3 h before transfection. Reduction in the early adenoviral inflammatory response was associated with significant improvement in post-transplant lung function when lungs were retrieved 6 or 12 h after transtracheal administration of AdhIL-10. Transtracheal administration of adenoviral-mediated hIL-10 to donor lungs is associated with a significant early inflammatory response that may enhance ischemia-reperfusion injury if insufficient hIL-10 is expressed in lung tissue before retrieval. The period between delivery of AdhIL-10 and lung retrieval can be reduced if the early inflammatory response is suppressed with methylprednisolone.

Abbreviations: cold ischemic time, CIT • human IL-10, hIL-10 • interferon, IFN • interleukin, IL • ischemia-reperfusion, IR • low-potassium dextran, LPD • main bronchus, MB • macrophage inflammatory protein, MIP • pulmonary artery, PA • partial pressure of oxygen, PaO2 • peak airway pressure, PawP • positive end-expiratory pressure, PEEP • pulmonary vein, PV • Rous sarcoma virus, RSV • tumor necrosis factor, TNF • wet-to-dry, W/D




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