Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD

Chest. 2016 Jan;149(1):62-73. doi: 10.1378/chest.14-2637. Epub 2016 Jan 6.


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.

Keywords: COPD; host defense; infection; viral disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Disease Progression
  • Female
  • Histone Deacetylase 2 / metabolism*
  • Humans
  • Inflammation Mediators / metabolism
  • Male
  • Middle Aged
  • Nitrosation / physiology
  • Oxidative Stress / physiology*
  • Picornaviridae Infections / complications
  • Picornaviridae Infections / metabolism*
  • Pulmonary Disease, Chronic Obstructive / complications*
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Rhinovirus*
  • Sputum
  • Viral Load


  • Inflammation Mediators
  • Histone Deacetylase 2