Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, 210046, Nanjing, China.
School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 211198, Nanjing, China.
Mucosal Immunol. 2021 Jan;14(1):125-134. doi: 10.1038/s41385-020-0272-z. Epub 2020 Mar 4.
Claudin1 plays a critical role in maintaining the epithelial barrier, and mucus hypersecretion induced by epidermal growth factor receptor (EGFR) activation is a pivotal pathological feature of asthma. The relationship between claudin1 expression and mucus hypersecretion and EGFR activation is still poorly understood. In this report, we showed that claudin1 expression correlated with asthma stage, in both patients with asthma and in the house dust mite (HDM)-induced mouse asthma model. Claudin1 knockdown induced MUC5AC overexpression both in 16HBE cells and in mouse airways. In addition, claudin1 expression negatively correlated with asthma severity as demonstrated by significantly higher MUC5AC expression, more severe airway inflammation, and increased airway hyperreactivity in mouse lungs with claudin1 knockdown following HDM challenge. EGFR activation reduced claudin1 expression and increased MUC5AC expression, both in vitro and in vivo. Erlotinib alleviated murine allergic airway inflammation, restored claudin1 expression and decreased MUC5AC expression. These results suggest that EGFR activation-induced decreases in claudin1 promote goblet-cell metaplasia, and restoring claudin1 to maintain barrier integrity by EGFR antagonism may provide a novel therapeutic strategy for asthma.
Claudin1 在维持上皮屏障方面起着关键作用，表皮生长因子受体 (EGFR) 激活诱导的黏液过度分泌是哮喘的一个重要病理特征。Claudin1 表达与黏液过度分泌和 EGFR 激活之间的关系仍知之甚少。在本报告中，我们表明 Claudin1 表达与哮喘阶段相关，无论是在哮喘患者中还是在屋尘螨 (HDM) 诱导的小鼠哮喘模型中。Claudin1 敲低在 16HBE 细胞和小鼠气道中均诱导 MUC5AC 过表达。此外，Claudin1 表达与哮喘严重程度呈负相关，表现在 Claudin1 敲低的小鼠肺部在 HDM 挑战后，MUC5AC 表达更高、气道炎症更严重和气道高反应性增加。EGFR 激活在体外和体内均降低 Claudin1 表达并增加 MUC5AC 表达。厄洛替尼减轻了小鼠过敏性气道炎症，恢复了 Claudin1 表达并降低了 MUC5AC 表达。这些结果表明，EGFR 激活诱导的 Claudin1 减少促进杯状细胞化生，通过 EGFR 拮抗作用恢复 Claudin1 以维持屏障完整性可能为哮喘提供一种新的治疗策略。
