Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients

Malhotra, Deepti; Thimmulappa, Rajesh K.; Mercado, Nicolas; Ito, Kazuhiro; Kombairaju, Ponvijay; Kumar, Sarvesh; Ma, Jinfang; Feller‐Kopman, David; Wise, Robert A.; Barnes, Peter J.; Biswal, Shyam

doi:10.1172/jci45144

Cited by 123 publications

(81 citation statements)

References 62 publications

(93 reference statements)

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“…Exogenous GSH treatment of macrophages from individuals with COPD restores HDAC-2 activity and induces a concomitant decrease in S-nitrosylation of HDAC2 (Malhotra et al 2011).…”

Section: Discussionmentioning

confidence: 98%

“…Immunoprecipitation and HDAC-2 activity HDAC-2 activity was assessed as previously described (Malhotra et al 2011). HDAC2 was immunoprecipitated from cell lysates (100 μg) by overnight incubation with anti-HDAC-2 at 4°C and then incubated with protein G-agarose beads.…”

Section: Western Blotmentioning

confidence: 99%

“…Effects of FP and CARB on Nrf2 and HDAC-2 nuclear expression in bronchial epithelial cells Since CSE affects Nrf2 nuclear translocation and reduces the expression of HDAC-2 (Malhotra et al 2011), the effects of carbocysteine and FP on nuclear Nrf2 and HDAC-2 expression in CSE-stimulated bronchial epithelial cells were explored. CSE increased nuclear Nrf2 expression in bronchial epithelial cells.…”

Section: Effects Of Fp and Carb On Ho-1 Expression In Bronchial Epithmentioning

confidence: 99%

“…The inflammatory events present in COPD are largely resistant to corticosteroids (Adcock et al 2010). Oxidative stress contributes to the low response to corticosteroids through the downregulation of histone deacetylase (HDAC) activity, a crucial event in the trans-repression activities of corticosteroids (Barnes and Adcock 2009;Malhotra et al 2011;Barnes 2011). HDACs, deacetylating histones which bind to inflammatory gene promoters, limit the access of the transcriptional machinery to these genes, thus repressing their transcription (Barnes 2011).…”

Section: Introductionmentioning

confidence: 99%

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Comparative cytoprotective effects of carbocysteine and fluticasone propionate in cigarette smoke extract-stimulated bronchial epithelial cells

Pace

Ferraro

Vincenzo

et al. 2013

Cell Stress and Chaperones

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Cigarette smoke extracts (CSE) induce oxidative stress, an important feature in chronic obstructive pulmonary disease (COPD), and oxidative stress contributes to the poor clinical efficacy of corticosteroids in COPD patients. Carbocysteine, an antioxidant and mucolytic agent, is effective in reducing the severity and the rate of exacerbations in COPD patients. The effects of carbocysteine on CSE-induced oxidative stress in bronchial epithelial cells as well as the comparison of these antioxidant effects of carbocysteine with those of fluticasone propionate are unknown. The present study was aimed to assess the effects of carbocysteine (10 −4 M) in cell survival and intracellular reactive oxygen species (ROS) production (by flow cytometry) as well as total glutathione (GSH), heme oxygenase-1 (HO-1), nuclearrelated factor 2 (Nrf2) expression and histone deacetylase 2 (HDAC-2) expression/activation in CSE-stimulated bronchial epithelial cells (16-HBE) and to compare these effects with those of fluticasone propionate (10 −8 M). CSE, carbocysteine or fluticasone propionate did not induce cell necrosis (propidium positive cells) or cell apoptosis (annexin Vpositive/propidium-negative cells) in 16-HBE. CSE increased ROS production, nuclear Nrf2 and HO-1 in 16-HBE. Fluticasone propionate did not modify intracellular ROS production, GSH and HDCA-2 but reduced Nrf2 and HO-1 in CSE-stimulated 16-HBE. Carbocysteine reduced ROS production and increased GSH, HO-1, Nrf2 and HDAC-2 nuclear expression/activity in CSE-stimulated cells and was more effective than fluticasone propionate in modulating the CSEmediated effects. In conclusion, the present study provides compelling evidences that the use of carbocysteine may be considered a promising strategy in diseases associated with corticosteroid resistance.

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“…Exogenous GSH treatment of macrophages from individuals with COPD restores HDAC-2 activity and induces a concomitant decrease in S-nitrosylation of HDAC2 (Malhotra et al 2011).…”

Section: Discussionmentioning

confidence: 98%

Section: Western Blotmentioning

confidence: 99%

Section: Effects Of Fp and Carb On Ho-1 Expression In Bronchial Epithmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Comparative cytoprotective effects of carbocysteine and fluticasone propionate in cigarette smoke extract-stimulated bronchial epithelial cells

Pace

Ferraro

Vincenzo

et al. 2013

Cell Stress and Chaperones

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“…By inducing the scavenger receptor MARCO, Nrf2 enhances the capacity of alveolar macrophages to phagocytize bacterial pathogens that episodically exacerbate the clinical course of COPD patients [61]. Via its antioxidant effects, Nrf2 helps to preserve the expression and activity of the deacetylase HDAC2; [62,63]. This enzyme, whose activity is characteristically low in smokers most notably in those with COPD [64,65] is essential to the trans-repression activity of the activated glucocorticoid receptor, whereby this receptor binds to NF-kappaB transcriptional complexes and inhibits expression of proinflammatory cytokines and metalloproteinases [66].…”

Section: Adjuvant Strategies Targeting Nrf2mentioning

confidence: 99%

DHA May Have a Profoundly Protective Impact on the Lungs of Smokers

Mf¹

2016

J Nutr Food Sci

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Evidence has accumulated over the last twenty years that smokers who frequently ingest fish are at lower risk for both chronic obstructive pulmonary disease (COPD) and lung cancer. Plasma phospholipid levels of DHA, but not EPA, have been reported to correlate inversely with risk for COPD in smokers, suggesting that DHA may be primarily responsible for the apparent protection afforded to lungs of smokers by fish consumption. Meanwhile, evidence is emerging that certain metabolites of DHA -including 4 -hydroxy hexenal (4-HHE), 17 -oxo -DHA, and resolvin D1 -can activate Nrf2 -mediated transcription of heme oxygenase -1 and other antioxidant / cytoprotective enzymes. Since the oxidant stress imposed by cigarette smoke exposure could be expected to promote peroxidation of membrane DHA and hence boost production of 4 -HHE, DHA in lung membranes may in effect up-regulate the protective feedback mechanism whereby oxidative stress provokes Nrf2 -mediated induction of cytoprotective enzymes. DHA can also give rise to the autacoid resolvin D1, which, via activation of a receptor, suppresses NFkappaB activation and the consequent production of pro-inflammatory cytokines. Resolvin D1 can also inhibit macrophage NADPH oxidase and promote an anti-inflammatory M2 phenotype in lung macrophages. Not surprisingly, inhalation of resolvin D1 has a marked anti-inflammatory impact on the lungs of mice exposed to tobacco smoke. These considerations help to rationalize the epidemiology linking fish consumption to lung health, and suggest that smokers who can't or won't quit their habit would be well advised to consume fish or DHA supplements regularly. Higher intakes of fruits and vegetables -likely in part because many of these contain Nrf2 -activating phytochemicals -likewise are associated with lower risk for COPD, and can be recommended for smokers.Keywords: COPD; Lung cancer; Fish; Docosahexaenoic acid (DHA); 4 -hydroxy hexenal; Nrf2; Resolvin D1 Fish Consumption May Protect Smokers from COPDLimited but nonetheless compelling epidemiology has linked heavy dietary consumption of fresh fish to marked decreases in risk for lung cancer and chronic obstructive pulmonary disease (COPD) among smokers. The first key evidence in this regard emerged in 1994. Shahar et al.[1] studied subjects enrolled in the prospective Atherosclerosis Risk in Communities (ARIC) study, who had received a dietary assessment and a physical exam including lung spirometry, and had been questioned regarding lung symptoms [1]. COPD was defined by three separate criteria: self -reported symptoms of chronic bronchitis, physician diagnosis of emphysema, and via spirometry (FEV1 < 65% of predicted value). When risk for COPD was compared between the first and fourth quartiles of estimated daily intake of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), relative risk for COPD in the fourth quartile (mean omega-3 intake 480 mg) after appropriate multivariate adjustments was found to be 0.66 (95% CI 0.52 -0.85), 0.31 (CI 0.18 -0.52), and 0.50 (CI 0.32...

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

Pace

Vincenzo

Ferraro

et al. 2017

Journal Cellular Physiology

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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.

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Denitrosylation of HDAC2 by targeting Nrf2 restores glucocorticosteroid sensitivity in macrophages from COPD patients

Abstract: A r t i c l e A m e n d m e n t s5 5 2 1

Cited by 123 publications

References 62 publications

Comparative cytoprotective effects of carbocysteine and fluticasone propionate in cigarette smoke extract-stimulated bronchial epithelial cells

Comparative cytoprotective effects of carbocysteine and fluticasone propionate in cigarette smoke extract-stimulated bronchial epithelial cells

DHA May Have a Profoundly Protective Impact on the Lungs of Smokers

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

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