Effects of Carbocysteine and Beclomethasone on Histone Acetylation/Deacetylation Processes in Cigarette Smoke Exposed Bronchial Epithelial Cells

Abstract

Histone deacetylase expression/activity may control inflammation, cell senescence, and responses to corticosteroids. Cigarette smoke exposure, increasing oxidative stress, may negatively affect deacetylase expression/activity. The effects of cigarette smoke extracts (CSE), carbocysteine, and beclomethasone dipropionate on chromatin remodeling processes in human bronchial epithelial cells are largely unknown. The present study was aimed to assess the effects of cigarette smoke, carbocysteine, and beclomethasone dipropionate on histone deacetylase 3 (HDAC3) expression/activity, N-CoR (nuclear receptor corepressor) expression, histone acetyltransferases (HAT) (p300/CBP) expression, p-CREB and IL-1 m-RNA expression, neutrophil chemotaxis. Increased p-CREB expression was observed in the bronchial epithelium of smokers. CSE increased p-CREB expression and decreased HDAC3 expression and activity and N-CoR m-RNA and protein expression. At the same time, CSE increased the expression of the HAT, p300/CBP. All these events increased acetylation processes within the cells and were associated to increased IL-1 m-RNA expression and neutrophil chemotaxis. The incubation of CSE exposed cells with carbocysteine and beclomethasone counteracted the effects of cigarette smoke on HDAC3 and N-CoR but not on p300/CBP. The increased deacetylation processes due to carbocysteine and beclomethasone dipropionate incubation is associated to reduced p-CREB, IL-1 m-RNA expression, neutrophil chemotaxis. These findings suggest a new role of combination therapy with carbocysteine and beclomethasone dipropionate in restoring deacetylation processes compromised by cigarette smoke exposure. J. Cell. Physiol. 232: 2851-2859, 2017. © 2016 Wiley Periodicals, Inc.

Loading of Beclomethasone in Liposomes and Hyalurosomes Improved with Mucin as Effective Approach to Counteract the Oxidative Stress Generated by Cigarette Smoke Extract

“…The biocompatibility of beclomethasone dipropionate-loaded vesicles against bronchial epithelial cells was around 100%, irrespective of the used concentrations and components, as previously reported for phospholipid vesicles [47]. The efficacy of the formulations was evaluated using beclomethasone dipropionate at a concentration of 10 −9 M, because, on preliminary dose-response experiments and in a previous study, at this concentration it was more effective [33]. The loading of beclomethasone in the phospholipid vesicles and the composition of the vesicles are key parameters capable of inhibiting the ROS production induced by cigarette smoke.…”

“…response experiments (data not shown) and of a previous study [33]. The bronchial epithelial cells unstressed with cigarette smoke extract expressed a basal value of ROS ⁓47%, due the presence of endogenous species.…”

“…The efficacy of the different formulations in inhibiting the production of ROS induced by stressing bronchial epithelial cells with cigarette smoke extract has been assessed (Figure 4). Beclomethasone dipropionate was used at a concentration of 10 −9 M because it was more effective on the basis of preliminary dose-response experiments (data not shown) and of a previous study [33]. The bronchial epithelial cells unstressed with cigarette smoke extract expressed a basal value of ROS~47%, due the presence of endogenous species.…”

The role of cigarette smoke-induced epigenetic alterations in inflammation

“…In addition to its effect on HDACs, CS also alters the expression of HATs. In CS-treated bronchial epithelial cells, the expression of an HAT, cAMP-response element-binding protein ( CBP / p300 ), was demonstrated to be increased and to induce a multitude of acetylating processes [50]. In short, decreased HDAC action and increased HAT action may account for CS-induced hyperacetylation.…”

Association of Smoking, Alcohol Use, and Betel Quid Chewing with Epigenetic Aberrations in Cancers

“…Inhalation and metabolic activation of these carcinogens during exposure to tobacco smoke often causes changes in DNA sequences, such as formation of DNA adducts [ 48 ], induction of double-stranded DNA (dsDNA) breaks [ 49 ], and development of point mutations [ 50 , 51 ]. Furthermore, tobacco smoke also commonly induces changes in the activity of chromatin-modifying enzymes, such as DNMTs [ 28 , 52 ], HATs [ 53 ], HMTs [ 44 ], histone kinases, and ubiquitinases [ 54 ], that result in epigenetic changes and abnormal cell physiology.…”