Objectives: Ischemia-reperfusion injury after lung transplantation is associated with significant morbidity and mortality. The activation of the transcription factor nuclear factor κB 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 κB inhibition on experimental lung transplant ischemia-reperfusion injury with gene transfer of the nuclear factor κB inhibitor IκB in a superrepressor form (IκBSR). 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 β-galactosidase control or IκBSR 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 κB 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 IκBSR resulted in significantly improved oxygenation compared with that seen in control tissue 24 hours after transplantation. IκBSR-treated lungs also demonstrated less pulmonary edema and reduced neutrophil infiltration 24 hours after reperfusion. Nuclear factor κB activation and apoptotic cell death induction 2 hours after transplantation was significantly reduced in IκBSR-treated lungs compared with in control lungs. Conclusions: Inhibition of nuclear factor κB activation by IκBSR gene transfer improves transplanted lung graft oxygenation, decreases pulmonary edema and neutrophil sequestration, and reduces apoptotic cell death after experimental lung transplantation.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Cardiology and Cardiovascular Medicine