Department of Pharmacology, Faculty of Medicine, Jaume I University, Castellón de la Plana, Spain.
Pharmacy Unit, University General Hospital Consortium, Valencia, Spain.
Respir Res. 2018 Nov 20;19(1):226. doi: 10.1186/s12931-018-0927-4.
Lung inflammation in COPD is poorly controlled by inhaled corticosteroids (ICS). Strategies to improve ICS efficacy or the search of biomarkers who may select those patients candidates to receive ICS in COPD are needed. Recent data indicate that MUC1 cytoplasmic tail (CT) membrane mucin can mediate corticosteroid efficacy in chronic rhinosinusitis. The objective of this work was to analyze the previously unexplored role of MUC1 on corticosteroid efficacy in COPD in vitro and in vivo models.
MUC1-CT expression was measured by real time PCR, western blot, immunohistochemistry and immunofluorescence. The inflammatory mediators IL-8, MMP9, GM-CSF and MIP3α were measured by ELISA. The effect of MUC1 on inflammation and corticosteroid anti-inflammatory effects was measured using cell siRNA in vitro and Muc1-KO in vivo animal models.
MUC1-CT expression was downregulated in lung tissue, bronchial epithelial cells and lung neutrophils from smokers (n = 11) and COPD (n = 11) patients compared with healthy subjects (n = 10). MUC1 was correlated with FEV1% (ρ = 0.7479; p < 0.0001) in smokers and COPD patients. Cigarette smoke extract (CSE) decreased the expression of MUC1 and induced corticosteroid resistance in human primary bronchial epithelial cells and human neutrophils. MUC1 Gene silencing using siRNA-MUC1 impaired the anti-inflammatory effects of dexamethasone and reduced glucocorticoid response element activation. Dexamethasone promoted glucocorticoid receptor alpha (GRα) and MUC1-CT nuclear translocation and co-localization that was inhibited by CSE. Lung function decline and inflammation induced by lipopolysaccharide and cigarette smoke in Muc1 KO mice was resistant to dexamethasone.
These results confirm a role for MUC1-CT mediating corticosteroid efficacy in COPD.
慢性阻塞性肺疾病（COPD）患者的肺部炎症对吸入性皮质类固醇（ICS）的治疗反应不佳。因此，需要探索提高 ICS 疗效的策略，或者寻找可能选择 COPD 患者接受 ICS 治疗的生物标志物。最近的数据表明，MUC1 细胞质尾（CT）膜粘蛋白可介导慢性鼻-鼻窦炎患者皮质类固醇的疗效。本研究的目的是分析 MUC1 在 COPD 体外和体内模型中对皮质类固醇疗效的先前未知作用。
通过实时 PCR、western blot、免疫组化和免疫荧光测定 MUC1-CT 的表达。通过 ELISA 测定炎症介质 IL-8、MMP9、GM-CSF 和 MIP3α。使用细胞 siRNA 在体外和 Muc1-KO 动物模型中测量 MUC1 对炎症和皮质类固醇抗炎作用的影响。
与健康受试者（n=10）相比，吸烟者（n=11）和 COPD 患者（n=11）的肺组织、支气管上皮细胞和肺中性粒细胞中的 MUC1-CT 表达下调。MUC1 与吸烟者和 COPD 患者的 FEV1%相关（ρ=0.7479；p<0.0001）。香烟烟雾提取物（CSE）降低了人原代支气管上皮细胞和人中性粒细胞中 MUC1 的表达，并诱导皮质类固醇耐药。使用 siRNA-MUC1 进行 MUC1 基因沉默会损害地塞米松的抗炎作用，并减少糖皮质激素反应元件的激活。地塞米松促进糖皮质激素受体α（GRα）和 MUC1-CT 核易位，并被 CSE 抑制。Muc1 KO 小鼠的脂多糖和香烟烟雾引起的肺功能下降和炎症对地塞米松耐药。
这些结果证实了 MUC1-CT 在 COPD 中调节皮质类固醇疗效的作用。
