title: Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function.
abstract: Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress. We previously demonstrated that Nrf2-deficient mice have heightened susceptibility to asthma, including elevated oxidative stress, inflammation, mucus, and airway hyperresponsiveness (AHR) (Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW, Tuder RM, Georas SN, Biswal S. J Exp Med 202: 47-59, 2005). Here we dissected the role of Nrf2 in lung epithelial cells and tested whether genetic or pharmacological activation of Nrf2 reduces allergic asthma in mice. Cell-specific activation of Nrf2 in club cells of the airway epithelium significantly reduced allergen-induced AHR, inflammation, mucus, Th2 cytokine secretion, oxidative stress, and airway leakiness and increased airway levels of tight junction proteins zonula occludens-1 and E-cadherin. In isolated airway epithelial cells, Nrf2 enhanced epithelial barrier function and increased localization of zonula occludens-1 to the cell surface. Pharmacological activation of Nrf2 by 2-trifluoromethyl-2'-methoxychalone during the allergen challenge was sufficient to reduce allergic inflammation and AHR. New therapeutic options are needed for asthma, and this study demonstrates that activation of Nrf2 in lung epithelial cells is a novel potential therapeutic target to reduce asthma susceptibility.
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and tsussan1@jhu.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Sussan
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Sachin
authors.initials: S
authors.lastname: Gajghate
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Samit
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Pooja
authors.initials: P
authors.lastname: Mandke
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: McCormick
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Kuladeep
authors.initials: K
authors.lastname: Sudini
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Sarvesh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Breysse
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Diette
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Venkataramana K
authors.initials: VK
authors.lastname: Sidhaye
authors.affiliation: Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
authors.forename: Shyam
authors.initials: S
authors.lastname: Biswal
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D016535:Bronchial Hyperreactivity / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D047188:Chalcones / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D019610:Cytoprotection; D003598:Cytoskeletal Proteins / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism; D007249:Inflammation / Q000276:immunology; D000072019:Kelch-Like ECH-Associated Protein 1; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010047:Ovalbumin; D018384:Oxidative Stress / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology; D018418:Th2 Cells / Q000276:immunology; D019108:Tight Junctions / Q000276:immunology*; D062826:Zonula Occludens-1 Protein / Q000378:metabolism*
chemical_list: C561055:2-trifluoromethyl-2'-methoxychalone; D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D047188:Chalcones; D016207:Cytokines; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D062826:Zonula Occludens-1 Protein; D010047:Ovalbumin
keywords: Th2; airway hyperresponsiveness; inflammation; ovalbumin; oxidative stress