文章基本信息

标题：Enhanced Notch3 signaling contributes to pulmonary emphysema in a Murine Model of Marfan syndrome
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作者：Kathryn Jespersen ; Zhibo Liu ; Chenxin Li 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2020
卷号：10
期号：1
页码：1-11
DOI：10.1038/s41598-020-67941-3
出版社：Springer Nature
摘要：Marfan syndrome (MFS) is a heritable disorder of connective tissue, caused by mutations in the fibrillin-1 gene. Pulmonary functional abnormalities, such as emphysema and restrictive lung diseases, are frequently observed in patients with MFS. However, the pathogenesis and molecular mechanism of pulmonary involvement in MFS patients are underexplored. Notch signaling is essential for lung development and the airway epithelium regeneration and repair. Therefore, we investigated whether Notch3 signaling plays a role in pulmonary emphysema in MFS. By using a murine model of MFS, fibrillin-1 hypomorphic mgR mice, we found pulmonary emphysematous-appearing alveolar patterns in the lungs of mgR mice. The septation in terminal alveoli of lungs in mgR mice was reduced compared to wild type controls in the early lung development. These changes were associated with increased Notch3 activation. To confirm that the increased Notch3 signaling in mgR mice was responsible for structure alterations in the lungs, mice were treated with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglucine t-butyl ester (DAPT), a $$\gamma$$ -secretase inhibitor, which inhibits Notch signaling. DAPT treatment reduced lung cell apoptosis and attenuated pulmonary alteration in mice with MFS. This study indicates that Notch3 signaling contributes to pulmonary emphysema in mgR mice. Our results may have the potential to lead to novel strategies to prevent and treat pulmonary manifestations in patients with MFS.