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

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

Joseph Footitt  1 , Patrick Mallia  1 , Andrew L Durham  2 , W Eugene Ho  3 , Maria-Belen Trujillo-Torralbo  4 , Aurica G Telcian  5 , Ajerico Del Rosario  4 , Cheng Chang  3 , Hong-Yong Peh  3 , Tatiana Kebadze  5 , Julia Aniscenko  5 , Luminita Stanciu  5 , Sarah Essilfie-Quaye  2 , Kazuhiro Ito  2 , Peter J Barnes  2 , Sarah L Elkin  4 , Onn M Kon  1 , W S Fred Wong  3 , Ian M Adcock  2 , Sebastian L Johnston  6
Affiliations

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

Joseph Footitt et al. Chest. 2016 Jan.

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.

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

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Figures

Figure 1
Figure 1
Time course of inflammatory cells, neutrophil elastase, and virus load in sputum during experimental rhinovirus infection. A, Total sputum inflammatory cells (neutrophils, macrophages/monocytes, lymphocytes, eosinophils). B, Sputum neutrophils. C, Sputum neutrophil elastase. D, Sputum virus load. All data are given as mean ± SEM. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001 vs baseline. †P < .05; ††P < .01 COPD vs nonsmokers. #P < .01; ##P < .01 COPD vs smokers.
Figure 2
Figure 2
Time course of inflammatory mediators in sputum during experimental rhinovirus infection in COPD. A, Sputum IL-1β. B, Sputum TNF-α. C, Sputum GM-CSF. D, Sputum CXCL8/IL-8. E, Sputum MMP-9. All data are given as median ± IQR. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001 vs baseline. †P < .05; ††P < .01 COPD vs nonsmokers. GM-CSF = granulocyte-macrophage colony-stimulating factor; IQR = interquartile range; MMP-9 = matrix metalloprotease-9; TNF-α = tumor necrosis factor-α.
Figure 3
Figure 3
Time course of oxidative and nitrosative stress markers in sputum and HDAC2 activity in sputum and BAL macrophages during experimental rhinovirus infection. A, Sputum 8-isoprostane. B, Sputum 8-hydroxy-2'-deoxyguanosine. C, Sputum 3-nitrotyrosine. D, Sputum nitrite. E, Sputum macrophage HDAC2 activity (change from baseline). F, BAL macrophage HDAC2 activity. All data are given as median ± IQR. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001 vs baseline. †P < .05; ††P < .01; †††P < .001 COPD vs nonsmokers. #P < .05; ##P < .01; ###P < .001 COPD vs smokers. HDAC2 = histone deacetylase-2. See Figure 2 legend for expansion of other abbreviation.
Figure 4
Figure 4
Rhinovirus infection of THP-1 cells in vitro. A, Induction of IL-6 by rhinovirus in THP-1 cells. B, Induction of CXCL-8 by rhinovirus in THP-1 cells. C, HDAC2 protein in THP-1 cells infected with rhinovirus. D, HDAC2 RNA in THP-1 cells infected with rhinovirus protein. E, HDAC2 activity in THP-1 cells infected with rhinovirus. F, HDAC2 nitrosylation in THP-1 cells infected with rhinovirus. G, Inhibition of rhinovirus-induced IL-6 by N-acetylcysteine (NAC). H, Inhibition of rhinovirus-induced CXCL8/IL-8 by NAC. Data given as mean ± SE of at least three independent experiments. ∗P < .05.
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