title: Airway smooth muscle NOX4 is upregulated and modulates ROS generation in COPD.
abstract: The burden of oxidative stress is increased in chronic obstructive pulmonary disease (COPD). However, whether the intra-cellular mechanisms controlling the oxidant/anti-oxidant balance in structural airway cells such as airway smooth muscle in COPD is altered is unclear. We sought to determine whether the expression of the NADPH oxidase (NOX)-4 is increased in airway smooth muscle in COPD both in vivo and primary cells in vitro and its role in hydrogen peroxide-induced reactive oxygen species generation. We found that in vivo NOX4 expression was up-regulated in the airway smooth muscle bundle in COPD (n = 9) and healthy controls with >20 pack year history (n = 4) compared to control subjects without a significant smoking history (n = 6). In vitro NOX4 expression was increased in airway smooth muscle cells from subjects with COPD (n = 5) compared to asthma (n = 7) and upregulated following TNF-α stimulation. Hydrogen peroxide-induced reactive oxygen species generation by airway smooth muscle cells in COPD (n = 5) was comparable to healthy controls (n = 9) but lower than asthma (n = 5); and was markedly attenuated by NOX4 inhibition. Our findings demonstrate that NOX4 expression is increased in vivo and in vitro in COPD and although we did not observe an intrinsic increase in oxidant-induced reactive oxygen species generation in COPD, it was reduced markedly by NOX4 inhibition supporting a potential therapeutic role for NOX4 in COPD.
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity & Inflammation, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK.
authors.forename: Fay
authors.initials: F
authors.lastname: Hollins
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity & Inflammation, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Sutcliffe
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity & Inflammation, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK.
authors.forename: Edith
authors.initials: E
authors.lastname: Gomez
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity & Inflammation, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK.
authors.forename: Rachid
authors.initials: R
authors.lastname: Berair
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity & Inflammation, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Russell
authors.affiliation: Genkyotex, Geneva, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Szyndralewiez
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity & Inflammation, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Saunders
authors.affiliation: Institute for Lung Health, Department of Infection, Immunity & Inflammation, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK. ceb17@le.ac.uk.
authors.forename: Christopher
authors.initials: C
authors.lastname: Brightling
mesh_terms: D001980:Bronchi / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D000074663:NADPH Oxidase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology* / Q000209:etiology / Q000503:physiopathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D000074663:NADPH Oxidase 4; C498910:NOX4 protein, human
keywords: Airway smooth muscle; COPD; NOX4; Oxidative stress; Reactive oxygen species