title: Inflammation and airway hyperresponsiveness after chlorine exposure are prolonged by Nrf2 deficiency in mice.
abstract: Chlorine gas (Cl2) is a potent oxidant and trigger of irritant induced asthma. We explored NF-E2-related factor 2 (Nrf2)-dependent mechanisms in the asthmatic response to Cl2, using Nrf2-deficient mice, buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis and sulforaphane (SFN), a phytochemical regulator of Nrf2.
  
  
  
  Airway inflammation and airway hyperresponsiveness (AHR) were assessed 24 and 48h after a 5-min nose-only exposure to 100ppm Cl2of Nrf2-deficient and wild type Balb/C mice treated with BSO or SFN. Animals were anesthetized, paralyzed and mechanically ventilated (FlexiVent™) and challenged with aerosolized methacholine. Bronchoalveolar lavage (BAL) was performed and lung tissues were harvested for assessment of gene expression.
  
  
  
  Cl2exposure induced a robust AHR and an intense neutrophilic inflammation that, although similar in Nrf2-deficient mice and wild-type mice at 24h after Cl2exposure, were significantly greater at 48h post exposure in Nrf2-deficient mice. Lung GSH and mRNA for Nrf2-dependent phase II enzymes (NQO-1 and GPX2) were significantly lower in Nrf2-deficient than wild-type mice after Cl2exposure. BSO reduced GSH levels and promoted Cl2-induced airway inflammation in wild-type mice, but not in Nrf2-deficient mice, whereas SFN suppressed Cl2-induced airway inflammation in wild-type but not in Nrf2-deficient mice. AHR was not affected by either BSO or SFN at 48h post Cl2exposure.
  
  
  
  Nrf2-dependent phase II enzymes play a role in the resolution of airway inflammation and AHR after Cl2exposure. Moderate deficiency of GSH affects the magnitude of acute inflammation but not AHR.
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ano
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Alice
authors.initials: A
authors.lastname: Panariti
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Allard
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Sullivan
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Toby K
authors.initials: TK
authors.lastname: McGovern
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hamamoto
authors.affiliation: Department of Respiratory Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: William S
authors.initials: WS
authors.lastname: Powell
authors.affiliation: Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada. Electronic address: james.martin@mcgill.ca.
authors.forename: James G
authors.initials: JG
authors.lastname: Martin
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D019328:Buthionine Sulfoximine / Q000378:metabolism; D002713:Chlorine / Q000633:toxicity; D005786:Gene Expression Regulation / Q000235:genetics; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D017879:Isothiocyanates / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D016210:Methacholine Chloride / Q000378:metabolism; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012130:Respiratory Hypersensitivity / Q000378:metabolism* / Q000503:physiopathology; D013454:Sulfoxides
chemical_list: D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D013454:Sulfoxides; D016210:Methacholine Chloride; D002713:Chlorine; D019328:Buthionine Sulfoximine; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; C016766:sulforaphane; D005978:Glutathione
keywords: Buthionine sulfoximine; Irritant induced asthma; Nrf2; Phase II enzymes; Sulforaphane