title: The aryl hydrocarbon receptor suppresses cigarette-smoke-induced oxidative stress in association with dioxin response element (DRE)-independent regulation of sulfiredoxin 1.
abstract: The aryl hydrocarbon receptor (AhR) is a ubiquitously expressed receptor/transcription factor that mediates toxicological responses of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Emerging evidence indicates that the AhR suppresses apoptosis and proliferation independent of exogenous ligands, including suppression of apoptosis by cigarette smoke, a key risk factor for chronic obstructive pulmonary disease (COPD). As cigarette smoke is a potent inducer of oxidative stress, a feature that may contribute to the development of COPD, we hypothesized that the AhR prevents smoke-induced apoptosis by regulating oxidative stress. Utilizing primary lung fibroblasts derived from AhR(+/+) and AhR(-/-) mice as well as A549 human lung adenocarcinoma cells deficient in AhR expression (A549-AhR(ko)), we first show that AhR(-/-) fibroblasts and A549-AhR(ko) epithelial cells have a significant increase in cigarette smoke extract (CSE)-induced oxidative stress compared to wild type. CSE induced a significant increase in the mRNA expression of key antioxidant genes, including Nqo1 and Srxn1, predominantly in AhR(+/+) fibroblasts, with significantly less induction in AhR(-/-) cells. The induction of Srxn1, but not Nqo1, was independent of dioxin-response element (DRE) binding as AhR(DBD/DBD) lung fibroblasts, which express an AhR incapable of binding the DRE, increased Srxn1 to a degree similar to wild-type cells in response to CSE. There was no difference in Nrf2 expression or activation based on AhR expression. Lung fibroblasts derived from COPD subjects have significantly less AhR protein expression compared with both never-smokers (Normal) and smokers (At Risk). Consequently, COPD-derived fibroblasts were less robust in their induction of both Nqo1 and Srxn1 mRNA after exposure to CSE, which also failed to activate the AhR in the COPD fibroblasts. Taken together, these results support a new role for the AhR in regulating antioxidant defense in lung structural cells, such that low AhR expression may facilitate the development or progression of COPD.
authors.affiliation: Department of Medicine, Division of Experimental Medicine.
authors.forename: Miles
authors.initials: M
authors.lastname: Sarill
authors.affiliation: Research Institute of the McGill University Health Centre, McGill University, Centre for Translational Biology (CTB), Block E, 1001 Decarie Blvd., Montreal, QC H4A 3J1, Canada.
authors.forename: Michela
authors.initials: M
authors.lastname: Zago
authors.affiliation: Department of Medicine, Division of Experimental Medicine.
authors.forename: Jared A
authors.initials: JA
authors.lastname: Sheridan
authors.affiliation: Department of Medicine, McMaster University, Hamilton, ON, Canada.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Nair
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Alvin
authors.initials: A
authors.lastname: Gomez
authors.affiliation: Research Institute of the McGill University Health Centre, McGill University, Centre for Translational Biology (CTB), Block E, 1001 Decarie Blvd., Montreal, QC H4A 3J1, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Roussel
authors.affiliation: Research Institute of the McGill University Health Centre, McGill University, Centre for Translational Biology (CTB), Block E, 1001 Decarie Blvd., Montreal, QC H4A 3J1, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
authors.affiliation: Department of Medicine, Division of Experimental Medicine; Research Institute of the McGill University Health Centre, McGill University, Centre for Translational Biology (CTB), Block E, 1001 Decarie Blvd., Montreal, QC H4A 3J1, Canada.
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.affiliation: Department of Medicine, Division of Experimental Medicine; Research Institute of the McGill University Health Centre, McGill University, Centre for Translational Biology (CTB), Block E, 1001 Decarie Blvd., Montreal, QC H4A 3J1, Canada.
authors.forename: David H
authors.initials: DH
authors.lastname: Eidelman
authors.affiliation: Department of Medicine, Division of Experimental Medicine; Research Institute of the McGill University Health Centre, McGill University, Centre for Translational Biology (CTB), Block E, 1001 Decarie Blvd., Montreal, QC H4A 3J1, Canada. Electronic address: Carolyn.baglole@McGill.ca.
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Baglole
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D020218:Response Elements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012906:Smoke / Q000009:adverse effects*
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D012906:Smoke; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse
keywords: Aryl hydrocarbon receptor; Chronic obstructive pulmonary disease; Cigarette smoke; Fibroblasts; Lung; Oxidative stress; Sulfiredoxin