Airway Disease, National Heart and Lung Institute, Imperial College London, and the Biomedical Research Unit, Royal Brompton NHS Foundation Trust, London, United Kingdom.
J Allergy Clin Immunol. 2012 Oct;130(4):877-85.e5. doi: 10.1016/j.jaci.2012.07.017. Epub 2012 Sep 1.
Patients with severe asthma are less responsive to the beneficial effects of corticosteroid therapy.
We investigated whether corticosteroid insensitivity was present in airway smooth muscle cells (ASMCs) of patients with severe asthma.
ASMCs cultured from bronchial biopsy specimens of nonasthmatic control subjects (n = 12) and patients with nonsevere (n = 10) or severe (n = 10) asthma were compared for the effect of dexamethasone on suppression of TNF-α- and IFN-γ-induced CCL11 (eotaxin), CXCL8 (IL-8), and CX3CL1 (fractalkine) expression. The mechanisms of corticosteroid insensitivity are also determined.
CCL11 release was higher in ASMCs of patients with nonsevere but not severe asthma and nonasthmatic control subjects; CXCL8 and CX3CL1 release were similar in all groups. In patients with severe asthma, dexamethasone caused less suppression of CCL11 and CXCL8 release induced by TNF-α. Dexamethasone potentiated TNF-α- and IFN-γ-induced CX3CL1 release equally in all 3 groups. TNF-α-induced phosphorylated p38 mitogen-activated protein kinase levels were increased in ASMCs from patients with severe asthma compared with those from patients with nonsevere asthma and nonasthmatic subjects, whereas TNF-α-induced phosphorylated c-Jun N-terminal kinase and phosphorylated extracellular signal-related kinase levels were increased in all asthmatic groups. A p38 inhibitor increased the inhibitory effect of dexamethasone.
ASMCs of patients with severe asthma are corticosteroid insensitive; this might be secondary to heightened p38 mitogen-activated protein kinase levels.
严重哮喘患者对皮质类固醇治疗的有益效果反应较差。
我们研究了严重哮喘患者气道平滑肌细胞（ASMC）是否存在皮质类固醇不敏感。
比较了支气管活检标本中培养的非哮喘对照者（n=12）、非严重哮喘患者（n=10）和严重哮喘患者（n=10）的 ASMC 对地塞米松抑制 TNF-α和 IFN-γ诱导的 CCL11（嗜酸性粒细胞趋化蛋白）、CXCL8（IL-8）和 CX3CL1（ fractalkine）表达的影响。还确定了皮质类固醇不敏感的机制。
非严重哮喘患者和非哮喘对照者的 ASMC 释放的 CCL11 较高，但严重哮喘患者则没有；所有组的 CXCL8 和 CX3CL1 释放相似。在严重哮喘患者中，地塞米松对 TNF-α 诱导的 CCL11 和 CXCL8 释放的抑制作用较小。地塞米松在所有 3 组中均同等增强 TNF-α和 IFN-γ诱导的 CX3CL1 释放。与非严重哮喘患者和非哮喘患者相比，严重哮喘患者的 ASMC 中 TNF-α诱导的磷酸化 p38 丝裂原活化蛋白激酶水平升高，而所有哮喘组中 TNF-α诱导的磷酸化 c-Jun N-末端激酶和磷酸化细胞外信号调节激酶水平升高。p38 抑制剂增加了地塞米松的抑制作用。
严重哮喘患者的 ASMC 对皮质类固醇不敏感；这可能是由于 p38 丝裂原活化蛋白激酶水平升高所致。
