Abstract:
RATIONALE:Patients with severe asthma (SA) are less responsive to the beneficial effects of corticosteroid (CS) therapy, and relative CS insensitivity has been shown in airway smooth muscle cells (ASMC) from patients with SA. OBJECTIVES:We investigated whether there was a defect in the actions of the glucocorticoid receptor (GR) underlying the ability of CS to suppress the inflammatory response in ASMC of patients with SA. ASMC from healthy subjects (n = 10) and subjects with severe (n = 8) and nonsevere asthma (N-SA; n = 8) were cultured from endobronchial biopsies. MEASUREMENTS AND MAIN RESULTS:GR expression in ASMC from SA and N-SA was reduced compared with that from healthy subjects by 49% (P < 0.01). Although baseline levels of nuclear GR were similar, GR nuclear translocation induced by dexamethasone (10(-7) M) in SA was 60% of that measured in either healthy subjects or subjects with N-SA. Tumor necrosis factor (TNF)-α induced greater nuclear factor (NF)-κB (p65) mRNA expression in ASMC from subjects with SA (5.6- vs. 2.0-fold; P < 0.01), whereas baseline and TNF-α-induced nuclear translocation and dexamethasone-mediated suppression of p65 expression were similar between groups. Dexamethasone, although not modulating TNF-α-induced p65 nuclear translocation, attenuated p65 recruitment to the CCL11 promoter in the healthy and N-SA groups, but this suppressive effect was impaired in subjects with SA. CONCLUSIONS:Decreased GR expression with impaired nuclear translocation in ASMC, associated with reduced dexamethasone-mediated attenuation of p65 recruitment to NF-κB-dependent gene promoters, may underlie CS insensitivity of severe asthma.
journal_name
Am J Respir Crit Care Medauthors
Chang PJ,Michaeloudes C,Zhu J,Shaikh N,Baker J,Chung KF,Bhavsar PKdoi
10.1164/rccm.201402-0314OCsubject
Has Abstractpub_date
2015-01-01 00:00:00pages
54-62issue
1eissn
1073-449Xissn
1535-4970journal_volume
191pub_type
杂志文章abstract::To elucidate the apparent contradictions in vascular remodeling in the lungs of patients with idiopathic pulmonary fibrosis, we evaluated alveolar vascularity in relation to the various degrees of fibrosis in surgically biopsied lungs of usual interstitial pneumonia. Alveolar capillary endothelial cells were intensely...
journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
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abstract:RATIONALE:The contribution of interferon-gamma release assays (IGRAs) to appropriate risk stratification of active tuberculosis suspects has not been studied. OBJECTIVES:To determine whether the addition of quantitative IGRA results to a prediction model incorporating clinical criteria improves risk stratification of ...
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journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:American journal of respiratory and critical care medicine
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:American journal of respiratory and critical care medicine
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journal_title:American journal of respiratory and critical care medicine
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更新日期:1998-11-01 00:00:00
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pub_type: 临床试验,杂志文章
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journal_title:American journal of respiratory and critical care medicine
pub_type: 杂志文章
doi:10.1164/ajrccm.158.6.9709003
更新日期:1998-12-01 00:00:00
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