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* Department of Environmental Health Sciences, Bloomberg School of Public Health, and
Department of Medicine, Johns Hopkins University, Baltimore, MD;
NIEHS, National Institutes of Health, Research Triangle Park, NC 27709; and
Department of Medical Biochemistry, Tohoku University, Sendai, Japan
Aberrant tissue repair and persistent inflammation following oxidant-mediated acute lung injury (ALI) can lead to the development and progression of various pulmonary diseases, but the mechanisms underlying these processes remain unclear. Hyperoxia is widely used in the treatment of pulmonary diseases, but the effects of this oxidant exposure in patients undergoing recovery from ALI are not clearly understood. Nrf2 has emerged as a crucial transcription factor that regulates oxidant stress through the induction of several detoxifying enzymes and other proteins. Using an experimental model of hyperoxia-induced ALI, we have examined the role of oxidant stress in resolving lung injury and inflammation. We found that when exposed to sublethal (72 h) hyperoxia, Nrf2-deficient, but not wild-type mice, succumbed to death during recovery. When both genotypes were exposed to a shorter period of hyperoxia-induced ALI (48 h), the lungs of Nrf2-deficient mice during recovery exhibited persistent cellular injury, impaired alveolar and endothelial cell regeneration, and persistent cellular infiltration by macrophages and lymphocytes. Glutathione (GSH) supplementation in Nrf2-deficient mice immediately after hyperoxia remarkably restored their ability to recover from hyperoxia-induced damage in a manner similar to that of wild-type mice. Thus, the results of the present study indicate that the Nrf2-regulated transcriptional response and, particularly GSH synthesis, is critical for lung tissue repair and the resolution of inflammation in vivo and suggests that a dysfunctional Nrf2-GSH pathway may compromise these processes in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was funded by National Institutes of Health Grants HL66109 and ES11863 (to SPR) and Specialized Centers of Clinically Oriented Research Grants P50 HL073994 (to S.P.R. and P.H.), HL049441 (to P.H.), and CA 94076 (to T.W.K).
2 Address correspondence and reprint requests to Dr. Sekhar P. Reddy, Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Room E7610.615, North Wolfe Street, Baltimore, MD 21205. E-mail address: sreddy{at}jhsph.edu
3 Abbreviations used in this paper: ALI, acute lung injury; HALI, hyperoxia-induced ALI; GSH, glutathione; BAL, broncho alveolar lavage; SPC, surfactin protein C.
4 The online version of this article contains supplemental material.
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