Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice

Tirumalai Rangasamy, Jia Guo, Wayne A. Mitzner, Jessica Roman, Anju Singh, Allison Fryer, Masayuki Yamamoto, Thomas W. Kensler, Rubin M. Tuder, Steve N. Georas, Shyam Biswal

Research output: Contribution to journalArticle

422 Citations (Scopus)

Abstract

Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2 -disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2 -directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma. JEM

Original languageEnglish (US)
Pages (from-to)47-59
Number of pages13
JournalJournal of Experimental Medicine
Volume202
Issue number1
DOIs
StatePublished - Jul 4 2005
Externally publishedYes

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Asthma
Antioxidants
Inflammation
Allergens
Basic-Leucine Zipper Transcription Factors
Genes
Lung
Interleukin-13
Ovalbumin
Bronchoalveolar Lavage Fluid
Mucus
Eosinophils
Interleukin-4
Oxidation-Reduction
Hyperplasia
Oxidative Stress
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. / Rangasamy, Tirumalai; Guo, Jia; Mitzner, Wayne A.; Roman, Jessica; Singh, Anju; Fryer, Allison; Yamamoto, Masayuki; Kensler, Thomas W.; Tuder, Rubin M.; Georas, Steve N.; Biswal, Shyam.

In: Journal of Experimental Medicine, Vol. 202, No. 1, 04.07.2005, p. 47-59.

Research output: Contribution to journalArticle

Rangasamy, T, Guo, J, Mitzner, WA, Roman, J, Singh, A, Fryer, A, Yamamoto, M, Kensler, TW, Tuder, RM, Georas, SN & Biswal, S 2005, 'Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice', Journal of Experimental Medicine, vol. 202, no. 1, pp. 47-59. https://doi.org/10.1084/jem.20050538
Rangasamy, Tirumalai ; Guo, Jia ; Mitzner, Wayne A. ; Roman, Jessica ; Singh, Anju ; Fryer, Allison ; Yamamoto, Masayuki ; Kensler, Thomas W. ; Tuder, Rubin M. ; Georas, Steve N. ; Biswal, Shyam. / Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. In: Journal of Experimental Medicine. 2005 ; Vol. 202, No. 1. pp. 47-59.
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