title: Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology.
  
  
  OBJECTIVE
  We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells.
  
  
  METHODS
  Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ.
  
  
  RESULTS
  Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β-induced ASM cell proliferation and CXCL8 release.
  
  
  CONCLUSIONS
  Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom. Electronic address: c.wiegman@imperial.ac.uk.
authors.forename: Coen H
authors.initials: CH
authors.lastname: Wiegman
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Michaeloudes
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Gulammehdi
authors.initials: G
authors.lastname: Haji
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Narang
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Clarke
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Kirsty E
authors.initials: KE
authors.lastname: Russell
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Wuping
authors.initials: W
authors.lastname: Bao
authors.affiliation: Janssen Research & Development, High Wycombe, United Kingdom.
authors.forename: Stelios
authors.initials: S
authors.lastname: Pavlidis
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.affiliation: Janssen Research & Development LLC, San Diego, Calif.
authors.forename: Justin
authors.initials: J
authors.lastname: Kanerva
authors.affiliation: Janssen Research & Development LLC, San Diego, Calif.
authors.forename: Anton
authors.initials: A
authors.lastname: Bittner
authors.affiliation: Janssen Research & Development LLC, San Diego, Calif.
authors.forename: Navin
authors.initials: N
authors.lastname: Rao
authors.affiliation: MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kirkham
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Kian Fan
authors.initials: KF
authors.lastname: Chung
authors.affiliation: Airway Disease Section, National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
mesh_terms: D000328:Adult; D000368:Aged; D056151:Airway Remodeling / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010126:Ozone; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012907:Smoking / Q000378:metabolism / Q000503:physiopathology; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D045222:Electron Transport Chain Complex Proteins; D009943:Organophosphorus Compounds; D017382:Reactive Oxygen Species; D014451:Ubiquinone; C429014:mitoquinone; D010126:Ozone; D006861:Hydrogen Peroxide
keywords: MitoQ; Ozone; airway hyperresponsiveness; airway smooth muscle; antioxidant; chronic obstructive pulmonary disease; inflammation; mitochondria; oxidative stress; proliferation
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