pathway is insensitive to glucocorticoid in airway
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GILZ expression is induced by glucocorticoids (GCs) and is involved in the mechanism of airway epithelial cell repair in patients with asthma. The present study aimed to investigate the role of miR-222-3p/GILZ pathway in treatment of airway epithelial cell repair by GCs. 9HTE cells were treated by 10 µmol/L dexamethasone (Dex) for 6, 12, and 24 hours (h). MiR-222-3p mimic and GILZ were used for cell transfection. Cell vitality, migration, and invasion were detected by methyl-thiazolyl tetrazolium (MTT), wound healing, and Transwell. The targeting relationship between miR-222-3p and GILZ was predicted by TargetScan and further confirmed by dual-luciferase reporter assay. The expressions of relative mRNAs or proteins were detected by Western blot and quantitative polymerase chain reaction (qPCR). The results showed that Dex treatment up-regulated the GILZ expression level but inhibited the levels of p-Raf1, p-MEK1/2, p-ERK1/2, and miR-222-3p of the cells, moreover, it also inhibited cell activity, migration, and invasion in a time-dependent manner. MiR-222-3p specifically targeted GILZ. MiR-222-3p mimic ameliorated the cell viability, migration, and invasion reduced by Dex treatment, increased the expression levels of p-Raf1 and p-MEK1/2, p-ERK1/2, and partially reversed the effects of GILZ overexpression on the above indexes. Moreover, GILZ showed the opposite effects to miR-222-3p. MiR-222-3p activated MAPK signaling pathway through inhibiting the GILZ expression, thus promoting the cell viability, migration, and invasion previously reduced by Dex.
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The long noncoding RNA (lncRNA) GAS5 has been found to act as a decoy for the glucocorticoid receptor (GR), thus implicating GAS5 as a potential regulator of glucocorticoid sensitivity and resistance. Airway smooth muscle (ASM) cells and airway epithelial cells (AEC) play an important role in the pathogenesis and persistence of asthma and other chronic airways diseases. These airway structural cell types are also important cellular targets of the anti-inflammatory actions of glucocorticoids. In this study, we sought to examine the relevance of GAS5 to glucocorticoid sensitivity and resistance in ASM and AEC. We provide the first evidence that pro-inflammatory mediators up-regulate GAS5 levels in both airway epithelial and smooth muscle cells, and that decreasing GAS5 levels can enhance glucocorticoid action in AEC.
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Glucocorticoid Receptor alpha Mediates Roflumilast’s Ability to Restore Dexamethasone Sensitivity in COPD Aravind T Reddy, 1, 2 Sowmya P Lakshmi, 1, 2 Asoka Banno, 1 Raju C Reddy 1, 2 1Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; 2Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15240, USACorrespondence: Raju C ReddyDepartment of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213, USATel +1 412 360-6823Fax +1 412 360-1919Email reddyrc@upmc.eduBackground: Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties in severe COPD patients who have a history of exacerbations. Roflumilast has a suggested ability to mitigate glucocorticoid resistance, but the mechanism is unknown.Methods: To understand the mechanism that mediates roflumilast-induced restoration of glucocorticoid sensitivity in COPD, we tested the role of glucocorticoid receptor α (GRα). Roflumilast’s effects on GRα expression and transcriptional activity were assessed in bronchial epithelial cells from COPD patients.Results: We found that both GRα expression and activity are downregulated in bronchial epithelial cells from COPD patients and that roflumilast stimulates both GRα mRNA synthesis and GRα’s transcriptional activity in COPD bronchial epithelial cells. We also demonstrate that roflumilast enhances dexamethasone’s ability to suppress pro-inflammatory mediator production, in a GRα-dependent manner.Discussion: Our findings highlight the significance of roflumilast-induced GRα upregulation for COPD therapeutic strategies by revealing that roflumilast restores glucocorticoid sensitivity by sustaining GRα expression.Keywords: nuclear hormone receptor, glucocorticoid resistance, phosphodiesterase-4 inhibitor; PDE4 inhibitor, airway inflammation, NF-κB, cAMP response element binding protein; CREB
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Second messenger system
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Overexpression of the epithelial Na + channel βsubunit (gene Scnn1b ) in mouse airways results in airway surface dehydration, neonatal mortality, mucous cell metaplasia and airway inflammation. Crossbreeding Scnn1b‐Tg mice with gene‐deficient mice enables quick and efficient determination of specific pathways relevant to the development of lung pathology. We bred Scnn1b‐Tg mice with mice deficient in: 1) IL‐4 receptor alpha chain (IL‐4Rα), shared by IL‐4 and IL‐13 receptors; 2) TNFα; 3) TNFα receptor 1 (TNFαR1), and evaluated inflammatory infiltrate, cytokine profile, lung pathology, and airway bioelectrics. In Scnn1b‐Tg mice, absence of IL‐4Rα improved neonatal survival and was associated with decreased mucous cells and eosinophilic infiltrate at day 10. However, absence of IL‐4Rα did not affect the chronic inflammatory infiltrate and lung pathology in adult Scnn1b‐Tg mice. Although TNFα was increased in Scnn1b airways, absence of TNFα or TNFαR1 did not ameliorate the lung phenotype of Scnn1b‐Tg mice nor modify airways bioelectrics. To assess the contribution of IL‐1β and TLR pathways, we are currently breeding the Scnn1b‐Tg mice with mice deficient in the adaptor molecule MyD88. These results indicate that multiple pathways contribute to airway inflammation and remodeling in the setting of surface dehydration and mucus stasis. Funded by CFF grants LIVRAG04I0 and RANDEL07P0, and NIH P50 HL060280 to R.C.B
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Vitamin A could regulate bronchial asthma(asthma)related signaling pathway of phosphatidylinositol-3 kinase/effector molecules Akt to prevent airway smooth muscle cell migration,inhibite airway hyperresponsiveness and improve the airway remodeling.Inhibition on airway inflammation is through the nuclear factor κB signal transduetion pathway.The balance of Th1/Th2 cells is influenced through the tyrosine kinase activator of transcription signal transduction pathways.To study the role of vitamin A in asthma will not only be able to set out a more systematic nature of asthma through the levels of signal transduction pathway,but also contribute to open up new ways of treatment of asthma.
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Vitamin A; Asthma; Signal transduction
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Corticosteroids are one of the most effective anti-inflammatory drugs for the treatment of inflammatory pulmonary diseases. However, in some patients of chronic obstructive pulmonary disease and severe asthma, corticosteroid responsiveness is attenuated, causing difficulty in controlling of these diseases. Recently, TNF-α is reported to involved in the reduction of corticosteroid responsiveness in vivo and in vitro. Thus, the objective of this study is to reverse corticosteroid insensitive airway inflammation by the neutralization of TNF-α with anti-TNF-α antibody.
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