Abstract
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.
Highlights
Marfan syndrome (MFS) is a heritable disorder of connective tissue, caused by mutations in the fibrillin-1 gene
Previous studies of mouse models of Marfan syndrome (Fbn1mgΔ/mgΔ and Fbn1mgR/mgR) have shown that Fbn1mgΔ/mgΔ and Fbn1mgR/mgR mice developed pulmonary emphysema as early as postnatal day (PD)[1] and PD14, respectively[10]. Because they are severely affected, Fbn1mgΔ/mgΔ mice have a short lifespan, 2–3 weeks, which makes it hard to study the pathogenesis of emphysema and test pharmacologic agents
Compared to their wild type (WT) littermates, lungs of mgR mice had enlarged distal airspaces at PD7 and PD56 (Fig. 1B, D) which is consistent with previous findings[10]
Summary
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. MgR represents a hypomorphic mutation of FBN1, and homozygous mgR mice express approximately 20% of normal fibrillin-1 These mice develop all the characteristic phenotypes in the skeletal, vascular, and pulmonary systems observed in classical MFS p atients[13]. Notch signaling in the epithelium is responsible for a host of processes involved in development of the distal lung[19] It prevents epithelial club cells from differentiating into goblet cells and plays a critical role in recovery of the airway epithelium following injury[20,21,22]. We found that inhibition of Notch signaling rescued development of the distal alveoli in MFS mice
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