Deacetylases and NF-κB in Redox Regulation of Cigarette Smoke-Induced Lung Inflammation: Epigenetics in Pathogenesis of COPD

Abstract

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-κB-dependent transcription of pro-inflammatory mediators either through activation of inhibitor κB-α kinase (IKK) and/or the enhanced recruitment and activation of transcriptional co-activators. Enhanced NF-κB-co-activator complex formation results in targeted increase in chromatin modifications, such as histone acetylation leading to inflammatory gene transcription. NF-κB-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 levels/activity of HDAC by post-translational modifications and in doing so further induces gene expression of pro-inflammatory mediators. 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-κB 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.

Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease

“…Experiments were replicated at least two times. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3686 ARTICLE NF-kB via both the inhibition of HDAC2 and the stimulation of IkB-a degradation, with these mechanisms suggested to be important for inflammatory responses associated with COPD 12,14 . Therefore, we conclude that mepenzolate suppresses inflammatory responses in animal models of COPD due to its inhibitory effect on ROS production, its stimulatory effect on the expression of antioxidant proteins and the resulting inhibition of NF-kB, which is caused by the activation of HDAC2 and the inhibition of IkB-a degradation.…”

“…In contrast to this, the body contains a number of endogenous antioxidant proteins such as superoxide dismutase (SOD) and glutathione S-transferase (GST), with a decrease in these proteins reported to be involved in the pathogenesis of COPD 9,10 . The inflammatory responses associated with COPD are thought to be triggered by oxidative stress and mediated through the activation of nuclear factor-kB (NF-kB, a pro-inflammatory transcription factor) and inhibition of histone deacetylase 2 (HDAC2) [11][12][13][14] . Oxidative stress seems to activate NF-kB through the inhibition of HDAC activity and degradation of inhibitor of NF-kB (IkB)-a (refs 12,14,15).…”

“…Pro-inflammatory gene expression is normally silenced by the condensation of DNA; however, the acetylation of core histones opens up the condensed chromatin and induces the expression of these genes (refs 11,12,16). HDACs suppress the expression of proinflammatory genes not only by maintaining chromatin condensation but also by directly modifying pro-inflammatory transcription factors (such as NF-kB) 12 . Moreover, HDACs, and particularly HDAC2, seem to have important roles in the inflammatory responses associated with COPD 11,17,18 .…”

“…Moreover, HDACs, and particularly HDAC2, seem to have important roles in the inflammatory responses associated with COPD 11,17,18 . Furthermore, because corticosteroids use HDAC2 to suppress the activity of NF-kB 11,12,19 , the inhibitory effect of CS on HDAC2 may be responsible for the reduced sensitivity of COPD patients to steroid treatment 11 . Therefore, compounds that activate HDAC2 or inhibit ROS production and NF-kB may be effective for the treatment of inflammation associated with COPD.…”

Epigenetic and current treatment approaches in chronic obstructive pulmonary disease

“…Histona metil ve asetil grupları histon metil transferaz (HMT) ve histon asetil transferaz (HAT) enzimleri ile eklenirken histon demetilaz (HDM) ve histon deasetilaz (HDAC) ile uzaklaştırılır (10). Bu enzimler kromatin yapısını modifiye ederek inflamatuvar genlerin ekspresyonunu düzenlerler (11,12). DNA'da oluşan genomik hiper ya da hipometilasyonlar hücre düzeyinde fonksiyonel bozukluklara yol açmaktadır.…”