Deacetylases and NF-kappaB in redox regulation of cigarette smoke-induced lung inflammation: epigenetics in pathogenesis of COPD.
Oxidative stress has been implicated in the pathogenesis of several inflammatory lung disorders including chronic obstructive pulmonary disease (COPD), due to its effect on pro-inflammatory gene transcription. Cigarette smoke-mediated oxidative stress activates NF-kappaB-dependent transcription of pro-inflammatory mediators either through activation of inhibitor kappaB-alpha kinase (IKK) and/or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-kappaB-co-activator complex formation results in targeted increase in chromatin modifications, such as histone acetylation leading to inflammatory gene transcription. NF-kappaB-dependent gene expression, at least in part, is regulated by changes in deacetylases such as histone deacetylases (HDACs) and sirtuins. Cigarette smoke and oxidants also alter the activity of HDACs and sirtuins by post-translational modifications by protein carbonylation and nitration, and in doing so further induce gene expression of pro-inflammatory mediators by chromatin modifications. In addition, cigarette smoke/oxidants can reduce glucocorticoid sensitivity by attenuating HDAC2 activity and expression, which may account for the glucocorticoid insensitivity in patients with COPD. Understanding the mechanisms of NF-kappaB regulation, and the balance between histone acetylation and deacetylation may lead to the development of novel therapies based on the pharmacological manipulation of IKK and deacetylases in lung inflammation and injury.
Rajendrasozhan
Saravanan
S
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY, USA.
Yang
Se-Ran
SR
Edirisinghe
Indika
I
Yao
Hongwei
H
Adenuga
David
D
Rahman
Irfan
I
D044127:Epigenesis, Genetic; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010084:Oxidation-Reduction; D011014:Pneumonia / Q000209:etiology / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*
D016328:NF-kappa B; D006655:Histone Deacetylases