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.
- Small, D. M.
- Brown, R. R.
- Doherty, D. F.
- Abladey, A.
- Zhou-Suckow, Z.
- Delaney, R. J.
- Kerrigan, L.
- Dougan, C. M.
- Borensztajn, K. S.
- Holsinger, L.
- Booth, R.
- Scott, C. J.
- Lopez-Campos, G.
- Elborn, J. S.
- Mall, M. A.
- Weldon, S.
- Taggart, C. C.
