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* Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205;
University of Maryland School of Medicine, Baltimore, MD 21201;
Department of Medical Biochemistry, Tohoku University, Sendai, Japan;
Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205; and
¶ National Institute of Environmental Health Sciences, National Institutes of Health (NIH), Research Triangle Park, NC 27709
Oxygen supplementation is used as therapy to support critically ill patients with severe respiratory impairment. Although hyperoxia has been shown to enhance the lung susceptibility to subsequent bacterial infection, the mechanisms underlying enhanced susceptibility remain enigmatic. We have reported that disruption of NF-E2-related factor 2 (Nrf2), a master transcription regulator of various stress response pathways, enhances susceptibility to hyperoxia-induced acute lung injury in mice, and have also demonstrated an association between a polymorphism in the NRF2 promoter and increased susceptibility to acute lung injury. In this study, we show that Nrf2-deficient (Nrf2–/–) but not wild-type (Nrf2+/+) mice exposed to sublethal hyperoxia succumbed to death during recovery after Pseudomonas aeruginosa infection. Nrf2-deficiency caused persistent bacterial pulmonary burden and enhanced levels of inflammatory cell infiltration as well as edema. Alveolar macrophages isolated from Nrf2–/– mice exposed to hyperoxia displayed persistent oxidative stress and inflammatory cytokine expression concomitant with diminished levels of antioxidant enzymes, such as Gclc, required for glutathione biosynthesis. In vitro exposure of Nrf2–/– macrophages to hyperoxia strongly diminished their antibacterial activity and enhanced inflammatory cytokine expression compared with Nrf2+/+ cells. However, glutathione supplementation during hyperoxic insult restored the ability of Nrf2–/– cells to mount antibacterial response and suppressed cytokine expression. Thus, loss of Nrf2 impairs lung innate immunity and promotes susceptibility to bacterial infection after hyperoxia exposure, ultimately leading to death of the host.
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 NIH Grants HL66109 and ES11863 (to S.P.R.), HL049441 (to P.H.), SCCOR P50 HL073994 (to S.P.R. and P.H.), ES007141 (to S.V.), CA105005 (to D.V.K.), and CA94076 (to T.W.K.) and, in part, by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (to S.R.K.).
2 Address correspondence and reprint requests to Narsa M. Reddy or Sekhar P. Reddy, The Johns Hopkins Bloomberg School of Public Health, Department of Environmental Health Sciences, Room. E7610, 615 North Wolfe Street, Baltimore, MD 21205. E-mail addresses: nmachire{at}jhsph.edu or sreddy{at}jhsph.edu
3 Abbreviations used in this paper: ALI, acute lung injury; Nrf2, NF-E2-related factor 2; ARE, antioxidant response element; cfu, colony forming unit; BAL, bronchoalveolar lavage; MARCO, macrophage receptor with collagenous structure; MSR1, macrophage scavenger receptor 1; GSH, glutathione.
4 The online version of this article contains supplementary material.
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