Glucocorticoid dexamethasone regulates the differentiation of mouse conducting airway epithelial progenitor cells
Glucocorticoid dexamethasone regulates the differentiation of mouse conducting airway epithelial progenitor cells
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DOI：
10.1016/j.steroids.2013.12.001
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发表时间：
2014-02-01
期刊：
影响因子：
2.7
通讯作者：
Wu, Qi
中科院分区：
文献类型：
--
作者：
Chen, Huaiyong;Sun, Xin;Wu, Qi
吸入性糖皮质激素地塞米松是目前治疗哮喘最有效的药物。上皮损伤和脱落是哮喘病理学的明确表现。然而，地塞米松是否调节负责上皮修复的气道祖细胞的功能仍然是未知的。在本研究中，分泌球蛋白1a 1（Scgb 1a 1）谱系示踪小鼠腹腔注射他莫昔芬诱导绿色荧光蛋白（GFP）的表达Scgb 1a 1表达传导气道祖细胞。通过流式细胞分选从Scgb1a1谱系示踪小鼠的肺中分离Scgb1a1表达祖细胞。体外三维基质胶培养结果显示，地塞米松对气道上皮祖细胞殖民地形成能力影响不大，但对祖细胞的分化有显著影响。与未治疗组相比，地塞米松治疗组抑制了叉头盒J1（FoxJ1）和粘蛋白A和C亚型（Muc5Ac）的表达，但促进了钙激活氯离子通道3（Clca3）和囊性纤维化跨膜传导调节因子（Cftr）的表达。地塞米松对FoxJ1、Muc5Ac和Clca3表达的影响在糖皮质激素受体拮抗剂RU486存在下被消除甚至逆转，表明糖皮质激素受体在地塞米松对气道上皮祖细胞的调节中起作用。这些数据表明，尽管地塞米松治疗能有效减轻气道炎症，但在哮喘患者的治疗中，地塞米松单独治疗不能完全恢复粘膜纤毛清除功能。(C)2013爱思唯尔有限公司保留所有权利。
Inhaled glucocorticoid dexamethasone is the most effective treatment of asthma currently available. Epithelial damage and shedding represents a clear manifestation of asthmatic pathologies. However it remains unknown if dexamethasone regulates functions of airway progenitor cells that are responsible for epithelial repair. In present study Secretoglob1a1 (Scgb1a1) lineage tracing mice were injected intraperitoneally with tamoxifen to induce the expression of green fluorescence protein (GFP) in Scgb1a1-expressing conducting airway progenitor cells. Scgb1a1-expressing progenitor cells were isolated from lungs of Scgb1a1 lineage tracing mice via flow activated cell sorting. In vitro three-dimensional matrigel culture of these progenitor cells revealed that dexamethasone has little effect on the colony forming ability of airway epithelial progenitor cells, but exhibits significant effects on the differentiation of the progenitor cells. Compared to the untreated group, dexamethasone treatment inhibited the expression of forkhead box J1 (FoxJ1) and mucin subtype A & C (Muc5Ac), but promoted the expression of calcium activated chloride channel 3 (Clca3) and cystic fibrosis transmembrane conductance regulator (Cftr). Dexamethasone-induced effects on the expression of FoxJ1, Muc5Ac and Clca3 were abolished or even reversed in the presence of RU486, an antagonist of glucocorticoid receptor, indicating that glucocorticoid receptor plays a role in the regulation of airway epithelial progenitor cells by dexamethasone. These data suggested that, though effective to reduce airway inflammation, dexamethasone treatment alone fails to fully restore the mucociliary clearance function in the treatment of asthma patients. (C) 2013 Elsevier Ltd. All rights reserved.