Park Kwon-Sik, Korfhagen Thomas R, Bruno Michael D, Kitzmiller Joseph A, Wan Huajing, Wert Susan E, Khurana Hershey Gurjit K, Chen Gang, Whitsett Jeffrey A
Division of Pulmonary Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
J Clin Invest. 2007 Apr;117(4):978-88. doi: 10.1172/JCI29176. Epub 2007 Mar 8.
Goblet cell hyperplasia and mucous hypersecretion contribute to the pathogenesis of chronic pulmonary diseases including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In the present work, mouse SAM pointed domain-containing ETS transcription factor (SPDEF) mRNA and protein were detected in subsets of epithelial cells lining the trachea, bronchi, and tracheal glands. SPDEF interacted with the C-terminal domain of thyroid transcription factor 1, activating transcription of genes expressed selectively in airway epithelial cells, including Sftpa, Scgb1a1, Foxj1, and Sox17. Expression of Spdef in the respiratory epithelium of adult transgenic mice caused goblet cell hyperplasia, inducing both acidic and neutral mucins in vivo, and stainined for both acidic and neutral mucins in vivo. SPDEF expression was increased at sites of goblet cell hyperplasia caused by IL-13 and dust mite allergen in a process that was dependent upon STAT-6. SPDEF was induced following intratracheal allergen exposure and after Th2 cytokine stimulation and was sufficient to cause goblet cell differentiation of Clara cells in vivo.
杯状细胞增生和黏液分泌过多参与了包括囊性纤维化、哮喘和慢性阻塞性肺疾病在内的慢性肺部疾病的发病机制。在本研究中，在气管、支气管和气管腺内衬的上皮细胞亚群中检测到了小鼠含SAM结构域的ETS转录因子（SPDEF）的mRNA和蛋白。SPDEF与甲状腺转录因子1的C末端结构域相互作用，激活在气道上皮细胞中选择性表达的基因的转录，包括Sftpa、Scgb1a1、Foxj1和Sox17。成年转基因小鼠呼吸道上皮中Spdef的表达导致杯状细胞增生，在体内诱导酸性和中性黏蛋白，并在体内对酸性和中性黏蛋白进行染色。在由IL-13和尘螨变应原引起的杯状细胞增生部位，SPDEF表达增加，这一过程依赖于STAT-6。气管内变应原暴露后以及Th2细胞因子刺激后诱导SPDEF表达，并且其足以在体内引起克拉拉细胞向杯状细胞分化。
