title: Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD.
abstract: BACKGROUND
  Respiratory virus infections are commonly associated with COPD exacerbations, but little is known about the mechanisms linking virus infection to exacerbations. Pathogenic mechanisms in stable COPD include oxidative and nitrosative stress and reduced activity of histone deacetylase-2 (HDAC2), but their roles in COPD exacerbations is unknown. We investigated oxidative and nitrosative stress (O&NS) and HDAC2 in COPD exacerbations using experimental rhinovirus infection.
  
  
  METHODS
  Nine subjects with COPD (Global Initiative for Chronic Obstructive Lung Disease stage II), 10 smokers, and 11 nonsmokers were successfully infected with rhinovirus. Markers of O&NS-associated cellular damage, and inflammatory mediators and proteases were measured in sputum, and HDAC2 activity was measured in sputum and bronchoalveolar macrophages. In an in vitro model, monocyte-derived THP-1 cells were infected with rhinovirus and nitrosylation and activity of HDAC2 was measured.
  
  
  RESULTS
  Rhinovirus infection induced significant increases in airways inflammation and markers of O&NS in subjects with COPD. O&NS markers correlated with virus load and inflammatory markers. Macrophage HDAC2 activity was reduced during exacerbation and correlated inversely with virus load, inflammatory markers, and nitrosative stress. Sputum macrophage HDAC2 activity pre-infection was inversely associated with sputum virus load and inflammatory markers during exacerbation. Rhinovirus infection of monocytes induced nitrosylation of HDAC2 and reduced HDAC2 activity; inhibition of O&NS inhibited rhinovirus-induced inflammatory cytokines.
  
  
  CONCLUSIONS
  O&NS, airways inflammation, and impaired HDAC2 may be important mechanisms of virus-induced COPD exacerbations. Therapies targeting these mechanisms offer potential new treatments for COPD exacerbations.
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England; Centre for Respiratory Infection, Imperial College, London, England.
authors: Joseph
authors: J
authors: Footitt
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England; Centre for Respiratory Infection, Imperial College, London, England.
authors: Patrick
authors: P
authors: Mallia
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Andrew L
authors: AL
authors: Durham
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors: W Eugene
authors: WE
authors: Ho
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England.
authors: Maria-Belen
authors: MB
authors: Trujillo-Torralbo
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Aurica G
authors: AG
authors: Telcian
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England.
authors: Ajerico
authors: A
authors: Del Rosario
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors: Cheng
authors: C
authors: Chang
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors: Hong-Yong
authors: HY
authors: Peh
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Tatiana
authors: T
authors: Kebadze
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Julia
authors: J
authors: Aniscenko
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Luminita
authors: L
authors: Stanciu
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Sarah
authors: S
authors: Essilfie-Quaye
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Kazuhiro
authors: K
authors: Ito
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Peter J
authors: PJ
authors: Barnes
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England.
authors: Sarah L
authors: SL
authors: Elkin
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England; Centre for Respiratory Infection, Imperial College, London, England.
authors: Onn M
authors: OM
authors: Kon
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore.
authors: W S Fred
authors: WS
authors: Wong
authors: Airways Disease Section, National Heart and Lung Institute, Imperial College, London, England.
authors: Ian M
authors: IM
authors: Adcock
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College, London, England; Imperial College Healthcare NHS Trust, London, England; Centre for Respiratory Infection, Imperial College, London, England. Electronic address: s.johnston@imperial.ac.uk.
authors: Sebastian L
authors: SL
authors: Johnston
mesh_terms: D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015538:Nitrosation / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology*; D010850:Picornaviridae Infections / Q000150:complications / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000378:metabolism*; D012229:Rhinovirus; D013183:Sputum; D019562:Viral Load
chemical_list: D018836:Inflammation Mediators; D056464:Histone Deacetylase 2
keywords: COPD; host defense; infection; viral disease