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Reduced Histone Deacetylase in COPD*: Clinical Implications

Peter J. Barnes, DM, DSc
Author and Funding Information

*From the National Heart and Lung Institute, Imperial College, London, UK.

Correspondence to: Peter J. Barnes, DM, DSc, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, UK; e-mail: p.j.barnes@imperial.ac.uk



Chest. 2006;129(1):151-155. doi:10.1378/chest.129.1.151
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COPD is characterized by progressive inflammation in the small airways and lung parenchyma, and this is mediated by the increased expression of multiple inflammatory genes. The increased expression of inflammatory genes is regulated by acetylation of core histones around which DNA is wound, and conversely these activated genes are switched off by deacetylation of these histones. Histone deacetylases (HDACs) suppress inflammatory gene expression, but their activity and expression (particularly of HDAC-2) is reduced in the peripheral lung and in alveolar macrophages of patients with COPD. This results in amplification of the inflammatory response as COPD progresses but also accounts for corticosteroid resistance in COPD, since HDAC-2 is required by corticosteroids to switch off activated inflammatory genes. The reduction in HDAC-2 appears to be secondary to the increased oxidative and nitrative stress in COPD lungs. Antioxidants and inhibitors of nitric oxide synthesis may therefore restore corticosteroid sensitivity in COPD, but this can also be achieved by low doses of theophylline, which is an HDAC activator. This mechanism is also relevant to asthmatic patients who smoke, patients with severe asthma and cystic fibrosis, in whom oxidative stress is also increased.

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