The Journal of Experimental Medicine
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Published 5 July 2005. doi:10.1084/jem.20050538
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 1, 47-59
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ARTICLE

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

Tirumalai Rangasamy1, Jia Guo3, Wayne A. Mitzner1, Jessica Roman3, Anju Singh1, Allison D. Fryer1, Masayuki Yamamoto1,5,6, Thomas W. Kensler1,2, Rubin M. Tuder1,4, Steve N. Georas3, and Shyam Biswal1,2

1 Department of Environmental Health Sciences, Bloomberg School of Public Health
2 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center
3 Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205
4 Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205
5 Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba, 305-8577, Japan
6 Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, 305-8577, Japan

CORRESPONDENCE Shyam Biswal: sbiswal{at}jhsph.edu

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.

Abbreviations used: AHR, airway hyperreactivity; ARE, antioxidant response element; BAL, bronchoalveolar lavage; EMSA, electrophoretic mobility shift assay; G6PD, glucose 6 phosphate dehydrogenase; {gamma} GCLm, {gamma} GCL modifier subunit; GCLc, GSH cysteine ligase catalytic subunit; GSH, glutathione; GSR, GSH S-reductase; GSSG, GSH disulfide; GST, glutathione S-transferase; H&E, hematoxylin and eosin; HO-1, heme oxygenase 1; MBP, major basophilic protein; NAC, N-acetyl L-cysteine; Nrf2, nuclear erythroid 2 p45-related factor 2; PAS, periodic acid–Schiff; ROS, reactive oxygen species; SOD, superoxide dismutase.


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