2016
DOI: 10.1016/j.toxlet.2015.10.009
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The tobacco smoke component acrolein induces glucocorticoid resistant gene expression via inhibition of histone deacetylase

Abstract: Chronic obstructive pulmonary disease (COPD) is the leading cause of cigarette smoke-related death worldwide. Acrolein, a crucial reactive electrophile found in cigarette smoke mimics many of the toxic effects of cigarette smoke-exposure in the lung. In macrophages, cigarette smoke is known to hinder histone deacetylases (HDACs), glucocorticoid-regulated enzymes that play an important role in the pathogenesis of glucocorticoid resistant inflammation, a common feature of COPD. Thus, we hypothesize that acrolein… Show more

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Cited by 18 publications
(5 citation statements)
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References 46 publications
(62 reference statements)
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“…MMP-9 enhanced expression correlated with an increase of H 4 acetylation, which reflects a higher level of chromatin accessibility in these drug-resistant cells. Then, our results were in line with previous studies demonstrating that alterations of epigenetic mechanisms in glucocorticoid-resistant cells, were directly associated with increased expression of proinflammatory or metastasis genes (18,20,38). However, in our glucocorticoid-resistant cells the hyperacetylation was not bound to a decreased HDAC expression and activity, and especially not to HDAC2, a class I histone deacetylase shown to switch off inflammatory genes upon steroids treatment in asthma and chronic obstructive pulmonary disease or lung cancer (17,19,39).…”
Section: Discussionsupporting
confidence: 92%
“…MMP-9 enhanced expression correlated with an increase of H 4 acetylation, which reflects a higher level of chromatin accessibility in these drug-resistant cells. Then, our results were in line with previous studies demonstrating that alterations of epigenetic mechanisms in glucocorticoid-resistant cells, were directly associated with increased expression of proinflammatory or metastasis genes (18,20,38). However, in our glucocorticoid-resistant cells the hyperacetylation was not bound to a decreased HDAC expression and activity, and especially not to HDAC2, a class I histone deacetylase shown to switch off inflammatory genes upon steroids treatment in asthma and chronic obstructive pulmonary disease or lung cancer (17,19,39).…”
Section: Discussionsupporting
confidence: 92%
“…Similarly, impaired GR nuclear translocation has been observed in both immune and airway structural cells from patients with asthma and COPD [ 159 , 160 , 161 ]. Oxidative stress reduces GRα expression and impairs GR DNA binding activity in airway epithelial and smooth muscle cells, in vitro [ 162 , 163 , 164 ]. These studies highlight the negative impact of oxidative stress on GR signaling through a reduction in GRα expression.…”
Section: Oxidative Stress Promotes Corticosteroid Insensitivitymentioning
confidence: 99%
“…Oxidative stress plays a key role in driving COPD-related inflammation and may lead to the activation of proinflammatory transcription factor NF-κ B, impaired antiprotease defense, DNA damage, cell senescence, autoantibody production, and corticosteroid resistance (inactivation through HDAC2) (13). Acrolein in cigarette smoke affects nuclear deacetylase activity by inhibiting HDAC2, thereby promoting glucocorticoid resistance (24). In this study, we have explored the role of monocytes/macrophages in corticosteroid insensitivity using COPD PBMCs and CSE-exposed human U937 monocytic cells, and confirmed the effectiveness of Sal in improving corticosteroid sensitivity in COPD accompanied by restoration of the Nrf2, HO-1 and HDAC2 levels in mononuclear cells.…”
Section: Discussionmentioning
confidence: 99%