Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice.
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.
Rangasamy
Tirumalai
T
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Guo
Jia
J
Mitzner
Wayne A
WA
Roman
Jessica
J
Singh
Anju
A
Fryer
Allison D
AD
Yamamoto
Masayuki
M
Kensler
Thomas W
TW
Tuder
Rubin M
RM
Georas
Steve N
SN
Biswal
Shyam
S
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001249:Asthma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D005786:Gene Expression Regulation; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics*
D000975:Antioxidants; C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D015534:Trans-Activators; D010047:Ovalbumin; D000111:Acetylcysteine