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A7603 - Nrf2 Promotes Recovery from Ischemia-Reperfusion Injury After Lung Transplantation
Author Block: T. Togo1, Y. Hoshikawa2, M. Noda1, H. Yabuki1, M. Hideki1, T. Watanabe1, F. Junichi1, Y. Okada1; 1Department of Thoracic Surgery, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan, 2Department of Thoracic Surgery, Fujita Health University School of Medicine, Toyoake, Japan.
Lung transplantation (LTx) has become the mainstay for treatment of end-stage respiratory diseases. However postoperative 90-day mortality rate is 11% according to the international registry data. The most major cause of early death after LTx is primary graft dysfunction (PGD) mainly due to ischemia-reperfusion (IR) lung injury. IR of the lung has been shown to induce overproduction of reactive oxygen species, which leads to the progression of severe lung injury and pulmonary edema. Nrf2 is a key transcription factor that activates many antioxidant enzymes. To test whether Nrf2 would be activated in the cold-preserved and transplanted lung grafts, and whether Nrf2 would protect lungs from IR injury, male F344 wild-type (WT) rats underwent left LTx from Nrf2 knockout (KO) or WT rats. Cold preservation for 6h followed by transplantation caused an increase in the proportion of Nrf2-nuclear staining positive alveolar cells and overexpressed Nrf2-regulated genes (NAD(P)H quinone oxidoreductase 1 [NQO1] and glutamate-cysteine ligase modifier subunit [GCLM]) in the WT lung grafts at 2h after LTx. Lung grafts from Nrf2 KO and WT rats exhibited comparable severity of lung injury assessed by wet to dry weight ratio, lung compliance, arterial blood gas, and histopathological findings at 2h after LTx. The Nrf2 KO grafts showed significantly higher gene expression of proinflammatory cytokines (interleukin-6 [IL-6], interleukin-1β [IL-1β], and tumor necrosis factor α [TNFα]) at 2h after LTx, lower gene expression of NQO1, higher proportion of TdT-mediated dUTP nick end labeling(TUNEL)-positive apoptotic alveolar cells, and delayed recovery from lung injury at 24h after LTx than the WT grafts. In conclusion, Nrf2 is activated in the cold-preserved and transplanted lung grafts, and promotes recovery from IR injury after LTx.