Innate immunity against bacterial infection following hyperoxia exposure is impaired in NRF2-deficient mice

Narsa M. Reddy, Vegiraju Suryanarayana, Dhananjaya V. Kalvakolanu, Masayuki Yamamoto, Thomas W. Kensler, Paul M. Hassoun, Steven R. Kleeberger, Sekhar P. Reddy

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53 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)4601-4608
Number of pages8
JournalJournal of Immunology
Issue number7
Publication statusPublished - 2009 Oct 1


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