Keratin 15 protects against cigarette smoke-induced epithelial mesenchymal transformation by MMP-9

作者：Wensi Zhu, Linxiao Han, Yuanyuan Wu, Lin Tong, Ludan He, Qin Wang, Yu Yan, Ting Pan, Jie Shen, Yuanlin Song, Yao Shen, Qiaoliang Zhu, Jian Zhou · 发表于：Respiratory Research · 年份：2023 · DOI：10.1186/s12931-023-02598-w · 被引用次数：14 · 研究领域：Skin and Cellular Biology Research、Proteoglycans and glycosaminoglycans research、Wnt/β-catenin signaling in development and cancer

Abstract Background Chronic obstructive pulmonary disease (COPD), a chronic inflammatory lung disease, is a leading cause of morbidity and mortality worldwide. Prolonged cigarette smoking (CS) that causes irreversible airway remodeling and significantly reduces lung function is a major risk factor for COPD. Keratin15 + (Krt15 + ) cells with the potential of self-renewal and differentiation properties have been implicated in the maintenance, proliferation, and differentiation of airway basal cells; however, the role of Krt15 in COPD is not clear. Methods Krt15 knockout (Krt15 −/− ) and wild-type (WT) mice of C57BL/6 background were exposed to CS for six months to establish COPD models. Krt15-CrePGR;Rosa26-LSL-tdTomato mice were used to trace the fate of the Krt15 + cells. Hematoxylin and eosin (H&E) and Masson stainings were performed to assess histopathology and fibrosis, respectively. Furthermore, lentivirus-delivered short hairpin RNA (shRNA) was used to knock down KRT15 in human bronchial epithelial (HBE) cells stimulated with cigarette smoke extract (CSE). The protein expression was assessed using western blot, immunohistochemistry, and enzyme-linked immunosorbent assay. Results Krt15 −/− CS mice developed severe inflammatory cell infiltration, airway remodeling, and emphysema. Moreover, Krt15 knockout aggravated CS-induced secretion of matrix metalloproteinase-9 (MMP-9) and epithelial–mesenchymal transformation (EMT), which was reversed by SB-3CT, an MMP-9 inhibitor....