Oxidative and Nitrosative Stress and Histone Deacetylase-2 Activity in Exacerbations of COPD.
File(s)
Accepted version
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2016-01-06
Date Acceptance
2016-01-01
Citation
Chest, 2016, 149 (1), pp.62-73
ISSN
1931-3543
Publisher
Elsevier
Start Page
62
End Page
73
Journal / Book Title
Chest
Volume
149
Issue
1
Copyright Statement
© 2016 The Authors. Published by Elsevier Inc. CC BY-NC-ND 3.0
Sponsor
Medical Research Council (MRC)
Wellcome Trust
Wellcome Trust
National Institute for Health Research
Identifier
PII: S0012-3692(15)00112-9
Grant Number
G0600879
083567/Z/07/Z
093080/Z/10/Z
NF-SI-0514-10092
Subjects
COPD
host defense
infection
viral disease
Publication Status
Published
Date Publish Online
2016-01-06