| First Author | Small DM | Year | 2019 |
| Journal | Eur Respir J | Volume | 53 |
| Issue | 3 | PubMed ID | 30655278 |
| Mgi Jnum | J:296742 | Mgi Id | MGI:6469767 |
| Doi | 10.1183/13993003.01523-2018 | Citation | Small DM, et al. (2019) Targeting of cathepsin S reduces cystic fibrosis-like lung disease. Eur Respir J 53(3) |
| abstractText | 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, beta-epithelial Na(+) channel-overexpressing transgenic (betaENaC-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 betaENaC-Tg mice compared with wild-type (WT) littermates. CatS(-/-)betaENaC-Tg mice exhibited decreased pulmonary inflammation, mucus obstruction and structural lung damage compared with betaENaC-Tg mice. Pharmacological inhibition of CatS resulted in a significant decrease in pulmonary inflammation, lung damage and mucus plugging in the lungs of betaENaC-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 betaENaC-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. |
