Oxidative stress and chromatin remodeling in chronic obstructive pulmonary disease and smoking-related diseases

• Published in: Antioxidants & redox signaling Vol. 18; no. 15; p. 1956
• Main Authors: Sundar, Isaac K, Yao, Hongwei, Rahman, Irfan
• Format: Journal Article
• Language: English
• Published: United States 20.05.2013
• Subjects: Acetylation; Chromatin Assembly and Disassembly; DNA Methylation; Histones - metabolism; Humans; Methylation; Oxidation-Reduction; Oxidative Stress; Phosphotransferases - metabolism; Pulmonary Disease, Chronic Obstructive - etiology; Signal Transduction; Smoking
• ISSN: 1557-7716
• DOI: 10.1089/ars.2012.4863

Chronic obstructive pulmonary disease (COPD) is predominantly a tobacco smoke-triggered disease with features of chronic low-grade systemic inflammation and aging (inflammaging) of the lung associated with steroid resistance induced by cigarette smoke (CS)-mediated oxidative stress. Oxidative stress induces various kinase signaling pathways leading to chromatin modifications (histone acetylation/deacetylation and histone methylation/demethylation) in inflammation, senescence, and steroid resistance. Histone mono-, di-, or tri-methylation at lysine residues result in either gene activation (H3K4, H3K36, and H3K79) or repression (H3K9, H3K27, and H3K20). Cross-talk occurs between various epigenetic marks on histones and DNA methylation. Both CS and oxidants alter histone acetylation/deacetylation and methylation/demethylation leading to enhanced proinflammatory gene expression. Chromatin modifications occur in lungs of patients with COPD. Histone deacetylase 2 (HDAC2) reduction (levels and activity) is associated with steroid resistance in response to oxidative stress. Histone modifications are associated with DNA damage/repair and epigenomic instability as well as premature lung aging, which have implications in the pathogenesis of COPD. HDAC2/SIRTUIN1 (SIRT1)-dependent chromatin modifications are associated with DNA damage-induced inflammation and senescence in response to CS-mediated oxidative stress. Understanding CS/oxidative stress-mediated chromatin modifications and the cross-talk between histone acetylation and methylation will demonstrate the involvement of epigenetic regulation of chromatin remodeling in inflammaging. This will lead to identification of novel epigenetic-based therapies against COPD and other smoking-related lung diseases. Pharmacological activation of HDAC2/SIRT1 or reversal of their oxidative post-translational modifications may offer therapies for treatment of COPD and CS-related diseases based on epigenetic histone modifications.