Oxidative Stress, Histone Deacetylase and Corticosteroid Resistance in Severe Asthma and COPD
Cigarette smoke-mediated oxidative stress enhances inflammation through the activation of stress kinases (JNK, ERK, p38) and redox-sensitive transcription factors such as NF-κ B and AP-1 resulting in increased expression of distinct pro-inflammatory mediators. Cigarette smoke and oxidants alter chromatin remodelling by targeted acetylation of histones and inhibition of histone deacetylase activity and in so doing further enhances inflammatory gene expression. Resistance to steroid therapy in patients with chronic obstructive pulmonary disease (COPD) and asthma has been attributed to the altered balance between oxidative stress and the acetylation-deacetylation states of histones. Corticosteroids/ glucocorticoids are potent anti-inflammatory hormones that mediate a vast array of tissue and cell specific pathways via different tissue specific co-activators or co-repressors. Glucocorticoids exert their effect via specific glucocorticoid receptors and involve modulation of the acetylation status of histones. Histone deacetylases (HDACs) are recruited by glucocorticoids which lead to deacetylation of histones and a subsequent switching off various inflammatory genes. Cigarette smoke-mediated oxidative stress alters HDAC levels by post-translational modifications with reactive aldehydes and NO present in cigarette smoke. Pharmacological agents and polyphenolic antioxidants, especially theophylline and curcumin are now known to assist glucocorticoid recruitment of HDACs, in particular HDAC2. Various therapeutic strategies are being employed either to control the activity of NF-κ B or to increase the activity of HDACs. Co-administration of theophylline, curcumin or its derivatives along with glucocorticoids could greatly overcome the resistance and enhance the therapeutic efficacy of the steroids in COPD and steroid resistant asthma.
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Document Type: Research Article
Department of Environmental Medicine, Division of Lung Biology and Disease, University of Rochester Medical Center, MRBX 3.11106, 601 Elmwood Avenue, P.O. Box 850; Rochester, NY 14642, USA.
Publication date: February 1, 2007
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