CTGF公司
纤维化
医学
癌症研究
细胞外基质
肺纤维化
结缔组织
成纤维细胞
小干扰RNA
生长因子
病理
内分泌学
免疫学
内科学
生物
细胞生物学
受体
细胞培养
遗传学
转染
作者
Jing Yun Chen,Wun Hao Cheng,Kang Yun Lee,Han Pin Kuo,Kian Fan Chung,Chien‐Chin Chen,Bing Chang Chen,Chien Huang Lin
标识
DOI:10.1016/j.biopha.2021.111701
摘要
Patients with chronic obstructive asthma (COA) develop airflow obstruction caused by subepithelial fibrosis. Although a disintegrin and metalloproteinase 17 (ADAM17) has been implicated in lung inflammation and tissue fibrosis, its role in airway fibrosis in COA has not been explored. Here, we found marked overexpression of ADAM17, phosphorylated ADAM17, and connective tissue growth factor (CTGF) in human airway fibroblasts from COA patients, compared with those of normal subjects. Similarly, levels of ADAM17, CTGF, α-smooth muscle actin (α-SMA), and collagen were increased in endobronchial biopsies from COA patients, but not in controls. In an ovalbumin-challenge asthma model, airway fibrosis was inhibited in ADAM17f/f/Cre+ mice compared to control mice. TGF-β- and thrombin-induced fibrotic protein expression was reduced by ADAM17 small interfering (si)RNA, TAPI-0 (an ADAM17 inhibitor), and EGFR siRNA. In addition, exogenous HB-EGF reversed fibrotic response in ADAM17 knockdown human lung fibroblasts. ADAM17 causes subepithelial fibrosis through regulation of enhanced extracellular matrix production and fibroblast differentiation and is the common pathway for airway fibrosis mediated by TGF-β and thrombin through an aberrant ADAM17/EGFR signalling pathway.
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