哮喘联盟

   摘要
   基本原理：重症哮喘（severe asthma, SA）患者对糖皮质激素（corticosteroid, CS）治疗的有效性反应更差。已有研究表明重症哮喘患者气道平滑肌细胞（airway smooth muscle cells, ASMC）对糖皮质激素相对不敏感。
   目的：探索在重症哮喘患者气道平滑肌细胞中，糖皮质激素对炎症反应的抑制作用方面是否存在潜在的糖皮质激素受体（glucocorticoid receptor, GR）作用缺陷。气道平滑肌细胞来源于健康受试者（n=10）、重症哮喘患者（n=8）和非重症哮喘患者（non-severe asthma, N-SA; n=8）支气管内组织活检，并进行细胞培养。
   测量和主要结果：与正常受试者比较，重症哮喘与非重症哮喘患者气道平滑肌细胞中糖皮质激素受体的表达减少了49%（P < 0.01）。尽管基线水平三组间糖皮质激素核受体水平相同，但SA组地塞米松（10-7M）诱导的糖皮质激素受体核移位仅为健康受试者或N-SA组核移位的60%。在SA组气道平滑肌细胞中，肿瘤坏死因子(Tumor necrosis factor, TNF)-α诱导产生核因子(nuclear factor, NF)-κB（p65）mRNA表达更多(5.6-vs.2.0倍；P < 0.01)，然而，基线核移位、TNF-α诱导的核移位以及地塞米松介导的p65表达抑制在三组间情况近似。在健康受试者组与N-SA组中，地塞米松虽然不能调节TNF-α诱导的p65核移位，但是可衰减p65与CCL11启动子结合，然而SA组这种衰减作用受损。
   结论：气道平滑肌细胞核移位受损导致糖皮质激素受体表达降低，以及地塞米松介导p65与NF-κB依赖基因启动子结合的衰减作用减弱，可能是重症哮喘患者激素不敏感的原因。
   关键词：气道平滑肌细胞；哮喘；糖皮质激素不敏感；糖皮质激素受体；核移位

 

(张丽 张红萍 王刚  四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（Am J Respir Crit Care Med. 2015; 191: 54–62.）


 

Impaired Nuclear Translocation of the Glucocorticoid Receptor in Corticosteroid-Insensitive Airway Smooth Muscle in Severe Asthma
 

Chang PJ, Michaeloudes C, Zhu J, Shaikh N, Baker J, Chung KF, and Bhavsar PK.
 

Am J Respir Crit Care Med. 2015; 191: 54–62.
 

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 non-severe 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) 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 mediate 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.
KEYWORDS: airway smooth muscle; asthma; corticosteroid insensitivity; glucocorticoid receptor; nuclear translocation