Targeting of cathepsin S reduces cystic fibrosis-like lung disease
Cathepsin S (CatS) is upregulated in the lungs of patients with cystic fibrosis (CF). However, its role in CF lung disease pathogenesis remains unclear. - In this study, β-epithelial Na+ channel-overexpressing transgenic (βENaC-Tg) mice, a model of CF-like lung disease, were crossed with CatS null (...
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| Hauptverfasser: | , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
March 28, 2019
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| In: |
The European respiratory journal
Year: 2019, Jahrgang: 53, Heft: 3 |
| ISSN: | 1399-3003 |
| DOI: | 10.1183/13993003.01523-2018 |
| Online-Zugang: | Verlag, Pay-per-use, Volltext: https://doi.org/10.1183/13993003.01523-2018 Verlag, Pay-per-use: https://erj.ersjournals.com/content/53/3/1801523 
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| Verfasserangaben: | Donna M. Small, Ryan R. Brown, Declan F. Doherty, Anthony Abladey, Zhe Zhou-Suckow, Rebecca J. Delaney, Lauren Kerrigan, Caoifa M. Dougan, Keren S. Borensztajn, Leslie Holsinger, Robert Booth, Christopher J. Scott, Guillermo López-Campos, J. Stuart Elborn, Marcus A. Mall, Sinéad Weldon and Clifford C. Taggart |
MARC
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| 520 | |a Cathepsin S (CatS) is upregulated in the lungs of patients with cystic fibrosis (CF). However, its role in CF lung disease pathogenesis remains unclear. - In this study, β-epithelial Na+ channel-overexpressing transgenic (βENaC-Tg) mice, a model of CF-like lung disease, were crossed with CatS null (CatS−/−) mice or treated with the CatS inhibitor VBY-999. - Levels of active CatS were elevated in the lungs of βENaC-Tg mice compared with wild-type (WT) littermates. CatS−/−βENaC-Tg mice exhibited decreased pulmonary inflammation, mucus obstruction and structural lung damage compared with βENaC-Tg mice. Pharmacological inhibition of CatS resulted in a significant decrease in pulmonary inflammation, lung damage and mucus plugging in the lungs of βENaC-Tg mice. In addition, instillation of CatS into the lungs of WT mice resulted in inflammation, lung remodelling and upregulation of mucin expression. Inhibition of the CatS target, protease-activated receptor 2 (PAR2), in βENaC-Tg mice resulted in a reduction in airway inflammation and mucin expression, indicating a role for this receptor in CatS-induced lung pathology. - Our data indicate an important role for CatS in the pathogenesis of CF-like lung disease mediated in part by PAR2 and highlight CatS as a therapeutic target. - Tweetable abstract ERSpublications - click to tweetCathepsin S is involved in inflammation, mucus production and lung tissue damage in a model of CF-like lung disease http://ow.ly/tHcm30nhlcX | ||
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