Low-dose theophylline restores corticosteroid responsiveness in rats with smoke-induced airway inflammation

Sun, Xianwen; Li, Qingyun; Gong, Yi; Ren, Lei; Wan, Huanying; Deng, Weiwei

doi:10.1139/y2012-079

Cited by 20 publications

(22 citation statements)

References 40 publications

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“…Reversal of corticosteroid resistance in COPD patients by restoring HDAC2 levels has proved to be effective. In this regard, it has been reported that theophylline and phosphoinositide-3 kinase inhibitors could reverse steroid resistance by increasing HDAC2 expression 16,17. Consistent with previous reports,18,19 the present study demonstrated that cigarette smoke inhibited HDAC2 expression.…”

Section: Discussionsupporting

confidence: 92%

Curcumin modulates the effect of histone modification on the expression of chemokines by type II alveolar epithelial cells in a rat COPD model

Gan¹,

Li²,

Wang³

et al. 2016

COPD

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BackgroundStudies have suggested that histone modification has a positive impact on various aspects associated with the progression of COPD. Histone deacetylase 2 (HDAC2) suppresses proinflammatory gene expression through deacetylation of core histones.ObjectiveTo investigate the effect of histone modification on the expression of chemokines in type II alveolar epithelial cells (AEC II) in a rat COPD model and regulation of HDAC2 expression by curcumin in comparison with corticosteroid.Materials and methodsThe rat COPD model was established by cigarette smoke exposure and confirmed by histology and pathophysioloy. AEC II were isolated and cultured in vitro from the COPD models and control animals. The cells were treated with curcumin, corticosteroid, or trichostatin A, and messenger RNA (mRNA) expression of interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2α (MIP-2α) was assessed by quantitative real-time polymerase chain reaction (RT-PCR). The expression of HDAC2 was measured by Western blot. Chromatin immunoprecipitation was used to detect H3/H4 acetylation and H3K9 methylation in the promoter region of three kinds of chemokine genes (IL-8, MCP-1, and MIP-2α).ResultsCompared to the control group, the mRNAs of MCP-1, IL-8, and MIP-2α were upregulated 4.48-fold, 3.14-fold, and 2.83-fold, respectively, in the AEC II from COPD model. The protein expression of HDAC2 in the AEC II from COPD model was significantly lower than from the control group (P<0.05). The decreased expression of HDAC2 was negatively correlated with the increased expression of IL-8, MCP-1, and MIP-2α mRNAs (all P<0.05). The level of H3/H4 acetylation was higher but H3K9 methylation in the promoter region of chemokine genes was lower in the cells from COPD model than from the control group (all P<0.05). Curcumin downregulated the expression of MCP-1, IL-8, and MIP-2α, and the expression was further enhanced in the presence of corticosteroid. Moreover, curcumin restored HDAC2 expression, decreased the levels of H3/H4 acetylation, and increased H3K9 methylation in the promoter region of chemokine in the presence or absence of dexamethasone (all P<0.05).ConclusionCurcumin may suppress chemokines and restore corticosteroid resistance in COPD through modulating HDAC2 expression and its effect on histone modification.

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Section: Discussionsupporting

confidence: 92%

Curcumin modulates the effect of histone modification on the expression of chemokines by type II alveolar epithelial cells in a rat COPD model

Gan¹,

Li²,

Wang³

et al. 2016

COPD

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“…Nortriptyline, a tricyclic antidepressant, has been shown to restore corticosteroid sensitivity induced by cigarette smokemediated oxidative stress, which is associated with increased HDAC activity (81). Low concentration of theophylline restores corticosteroid responsiveness in rats with smoke-induced airway inflammation and increases HDAC2 activity in alveolar macrophages from patients with COPD (23,114). A recent clinical trial has demonstrated that a combination therapy with an inhaled corticosteroid and low-dose of theophylline attenuated airway inflammation in patients with COPD (32).…”

Section: Hdac2 In Inflammation and Steroid Resistancementioning

confidence: 99%

Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD

Yao

Rahman

2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress.

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“…Furthermore, the expression of IL-8 and TNF-α in the lung tissue was negatively correlated with HDAC2 expression, suggesting that HDAC2 is involved in the modulation of inflammatory cytokine release in the context of airway inflammation. Since HDAC dysfunction may be associated with corticosteroid resistance in COPD (8,9,11,12), in the present study, the synergetic effect of the TCHM and glucocorticoid on the expression of HDAC2 as well as inflammatory mediators (IL-8 and TNF-α) in the lungs of the COPD rat model was further explored. The TCHM plus budesonide significantly blocked the suppression of HDAC2 expression in the lungs in response to the intratracheal instillation of LPS plus cigarette smoke exposure, while budesonide treatment alone did not.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of corticosteroid resistance may involve the imbalance of histone acetylation/deacetylation, oxidative stress and genetic or epigenetic alterations (9,10). In this study, histone deacetylase 2 (HDAC2) dysfunction is thought to play an important role in the development of corticosteroid resistance in COPD (8,9,11,12). Thus, increasing HDAC2 activity may be a promising strategy to overcome corticosteroid resistance in COPD.…”

Section: Introductionmentioning

confidence: 95%

Jinwei Tang modulates HDAC2 expression in a rat model of COPD

Wu¹,

Yang³

et al. 2018

Exp Ther Med

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Abstract. The aim of the present study was to investigate the effect of a Traditional Chinese Herbal Medicine (TCHM), named Jinwei Tang on histone deacetylase 2 (HDAC2) and its role in the regulation of corticosteroid resistance in a rat model of chronic obstructive pulmonary disease (COPD). Male Wistar rats were divided into five groups (each n=10): COPD group, established by the intratracheal instillation of lipopolysaccharide and passive smoke exposure, and control, budesonide, theophylline + budesonide and Jinwei Tang + budesonide groups. Lung function was measured, lung tissue histopathology was examined and HDAC2 expression in the lung was assessed by immunohistochemistry. In addition, protein levels of interleukin-8 (IL-8), tumor necrosis factor (TNF)-α and HDAC2 in lung homogenate were quantified by ELISA. The rat COPD model exhibited alterations of the ratio of forced expiratory volume in 0.2 sec (FEV 0.2 ) to the forced vital capacity, FEV 0.2 , dynamic compliance and airway resistance. HDAC2 expression was markedly reduced in the lung tissue of the COPD group compared with the control group, and treatment with Jinwei Tang + budesonide or theophylline + budesonide resulted in significant attenuation of the reduction of HDAC2 expression in the lungs (P<0.05). However, treatment with budesonide alone did not significantly alter HDAC2 expression. In the Jinwei Tang + budesonide and theophylline + budesonide groups, IL-8 and TNF-α expression was significantly decreased (P<0.05) and the HDAC2 level increased (P<0.05) compared with that in the COPD group.In conclusion, Jinwei Tang modulates airway inflammation and may enhance the anti-inflammatory effect of glucocorticoid through the upregulation of HADC2 expression in a rat model of COPD.

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Low-dose theophylline restores corticosteroid responsiveness in rats with smoke-induced airway inflammation

Cited by 20 publications

References 40 publications

Curcumin modulates the effect of histone modification on the expression of chemokines by type II alveolar epithelial cells in a rat COPD model

Curcumin modulates the effect of histone modification on the expression of chemokines by type II alveolar epithelial cells in a rat COPD model

Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD

Jinwei Tang modulates HDAC2 expression in a rat model of COPD

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