KMID : 1225720230150050614
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Allergy, Asthma & Immunology Research : AAIR 2023 Volume.15 No. 5 p.614 ~ p.635
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Estrogen Receptor-¥á Exacerbates EGF-Inducing Airway Remodeling and Mucus Production in Bronchial Epithelium of Asthmatics
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Lu Qin
Junqing Yue Mingzhou Guo Cong Zhang Xiaoyu Fang Shengding Zhang Wenxue Bai Xiansheng Liu Min Xie
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Abstract
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Purpose : Although estrogen receptors (ERs) signal pathways are involved in the pathogenesis and development of asthma, their expressions and effects remain controversial. This study aimed to investigate the expressions of ER¥á and ER¥â as well as their mechanisms in airway remodeling and mucus production in asthma.
Methods : The expressions of ER¥á and ER¥â in the airway epithelial cells of bronchial biopsies and induced sputum cells were examined by immunohistochemistry. The associations of ERs expressions with airway inflammation and remodeling were evaluated in asthmatic patients. In vitro, the regulations of ERs expressions in human bronchial epithelial cell lines were examined using western blot analysis. The epidermal growth factor (EGF)-mediated ligand-independent activation of ER¥á and its effect on epithelial-mesenchymal transitions (EMTs) were investigated in asthmatic epithelial cells by western blot, immunofluorescent staining, and quantitative real-time polymerase chain reaction.
Results : ER¥á and ER¥â were expressed on both bronchial epithelial cells and induced sputum cells, and the expressions showed no sex difference. Compared to controls, male asthmatic patients had higher levels of ER¥á on the bronchial epithelium, and there were cell-specific expressions of ER¥á and ER¥â in induced sputum. The expression of ER¥á in the airway epithelium was inversely correlated to forced expiratory volume in 1 second (FEV1) % and FEV1/forced vital capacity. Severe asthmatic patients had significantly greater levels of ER¥á in the airway epithelium than mild-moderate patients. ER¥á level was positively correlated with the thickness of the subepithelial basement membrane and airway epithelium. In vitro, co-stimulation of interleukin (IL)-4 and EGF increased the expression of ER¥á and promoted its nuclear translocation. EGF activated the phosphorylation of ER¥á via extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways. ER¥á knockdown alleviated EGF-mediated EMTs and mucus production in airway epithelial cells of asthma.
Conclusions : ER¥á contributes to asthmatic airway remodeling and mucus production through the EGF-mediated ligand-independent pathway.
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KEYWORD
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Asthma, estrogen receptors, epithelial-mesenchymal transition, airway remodeling, epidermal growth factor, mucus
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