Department of Pharmacology, Faculty of Medicine, Jaume I University, Valencia, Spain.
Pharmacy Unit, University General Hospital Consortium, Valencia, Spain.
Allergy. 2019 Jan;74(1):111-121. doi: 10.1111/all.13546. Epub 2018 Oct 2.
The loss of corticosteroid efficacy is an important issue in severe asthma management and may lead to poor asthma control and deterioration of airflow. Recent data indicate that Mucin 1 (MUC1) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis, but the role of MUC1 in uncontrolled severe asthma is unknown. The objective was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in asthma.
Mucin 1 expression was evaluated by real-time PCR in human bronchial epithelial cells (HBEC) and blood neutrophils from uncontrolled severe asthma (n = 27), controlled mild asthma (n = 16), and healthy subjects (n = 13). IL-8, MMP9, and GM-CSF were measured by ELISA in HBEC and neutrophils. An asthma model of ovalbumin (OVA) was used in MUC1 KO and WT C57BL/6 mice according to ARRIVE guidelines.
Mucin 1-CT expression was downregulated in bronchial epithelial cells and peripheral blood neutrophils from severe asthma patients compared with mild asthma and healthy subjects (P < 0.05). Daily dose of inhaled corticosteroids (ICS) inversely correlated with MUC1 expression in neutrophils from mild and severe asthma (ρ = -0.71; P < 0.0001). Dexamethasone showed lower anti-inflammatory effects in severe asthma peripheral blood neutrophils and HBECs stimulated with lipopolysaccharide (LPS) than in cells from mild asthma. Glucocorticoid receptor (GR)-α phosphorylated at serine 226 was increased in cells from severe asthma, and the MUC1-CT/GRα complex was downregulated in severe asthma cells. OVA asthma model in MUC1 KO mice was resistant to the anti-inflammatory effects of dexamethasone.
Mucin 1-CT modulates corticosteroid efficacy in vitro and in vivo asthma models.
皮质类固醇疗效丧失是严重哮喘管理中的一个重要问题，可能导致哮喘控制不佳和气流恶化。最近的数据表明，粘蛋白 1（MUC1）膜粘蛋白可介导慢性鼻-鼻窦炎中皮质类固醇的疗效，但 MUC1 在未控制的严重哮喘中的作用尚不清楚。目的是分析 MUC1 对哮喘中皮质类固醇疗效的先前未探索的作用。
通过实时 PCR 评估未控制的严重哮喘（n=27）、控制的轻度哮喘（n=16）和健康受试者（n=13）的人支气管上皮细胞（HBEC）和血液中性粒细胞中的 Mucin 1 表达。通过 ELISA 测量 HBEC 和中性粒细胞中的 IL-8、MMP9 和 GM-CSF。根据 ARRIVE 指南，在 MUC1 KO 和 WT C57BL/6 小鼠中使用卵清蛋白（OVA）哮喘模型。
与轻度哮喘和健康受试者相比，严重哮喘患者的支气管上皮细胞和外周血中性粒细胞中的粘蛋白 1-CT 表达下调（P<0.05）。轻度和重度哮喘患者中性粒细胞中每日吸入皮质类固醇（ICS）剂量与 MUC1 表达呈负相关（ρ=-0.71；P<0.0001）。地塞米松在严重哮喘患者外周血中性粒细胞和 LPS 刺激的 HBEC 中的抗炎作用低于轻度哮喘细胞。严重哮喘细胞中 GR-α 丝氨酸 226 磷酸化增加，严重哮喘细胞中 MUC1-CT/GRα 复合物下调。MUC1 KO 小鼠的 OVA 哮喘模型对地塞米松的抗炎作用具有抗性。
粘蛋白 1-CT 调节体外和体内哮喘模型中的皮质类固醇疗效。
