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J Thorac Cardiovasc Surg 2005;130:194-201
© 2005 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Inhibition of nuclear factor {kappa}B by I{kappa}B superrepressor gene transfer ameliorates ischemia-reperfusion injury after experimental lung transplantation

Takaaki Ishiyama, MD a , Sekhar Dharmarajan, MD a , Makio Hayama, MD a , Hisao Moriya, PhD b , Kathleen Grapperhaus, BSc a , G. Alexander Patterson, MD, FRCS(C) a , *

a Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, Mo.
b Department of Genetics, Washington University School of Medicine, St Louis, Mo.

Received for publication July 16, 2004; revisions received February 2, 2005; accepted for publication February 16, 2005.

* Address for reprints: G. Alexander Patterson, MD, 3108 Queeny Tower, One Barnes-Jewish Hospital Plaza, St Louis, MO 63110-1013. (Email: pattersona{at}msnotes.wustl.edu).

OBJECTIVES: Ischemia-reperfusion injury after lung transplantation is associated with significant morbidity and mortality. The activation of the transcription factor nuclear factor {kappa}B is central to the 2 important pathways that characterize ischemia-reperfusion injury, namely the inflammatory response and apoptosis. The purpose of this study was to determine the effects of nuclear factor {kappa}B inhibition on experimental lung transplant ischemia-reperfusion injury with gene transfer of the nuclear factor {kappa}B inhibitor I{kappa}B in a superrepressor form (I{kappa}BSR).

METHODS: An orthotopic left lung transplant model in isogeneic rats was used, with 18 hours of prolonged cold storage of donor lung grafts used to create severe ischemia-reperfusion injury. Donor rats underwent endobronchial gene transfection with saline alone or adenovirus encoding either ß-galactosidase control or I{kappa}BSR 48 hours before harvest. The function of transplanted lung grafts was assessed on the basis of isolated graft oxygenation, wet/dry lung weight ratio, and myeloperoxidase activity. Nuclear factor {kappa}B activation was assessed by means of enzyme-linked immunosorbent assay. Apoptotic cell death was assessed by evaluating the levels of histone-associated DNA fragments and caspase-3 activity.

RESULTS: Treatment of donor lung grafts with I{kappa}BSR resulted in significantly improved oxygenation compared with that seen in control tissue 24 hours after transplantation. I{kappa}BSR-treated lungs also demonstrated less pulmonary edema and reduced neutrophil infiltration 24 hours after reperfusion. Nuclear factor {kappa}B activation and apoptotic cell death induction 2 hours after transplantation was significantly reduced in I{kappa}BSR-treated lungs compared with in control lungs.

CONCLUSIONS: Inhibition of nuclear factor {kappa}B activation by I{kappa}BSR gene transfer improves transplanted lung graft oxygenation, decreases pulmonary edema and neutrophil sequestration, and reduces apoptotic cell death after experimental lung transplantation.




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