Targeting of cathepsin S reduces cystic fibrosis-like lung disease. Issue 3 (28th March 2019)

• Record Type: Journal Article
• Authors: Small, Donna M.; Brown, Ryan R.; Doherty, Declan F.; Abladey, Anthony; Zhou-Suckow, Zhe; Delaney, Rebecca J.; Kerrigan, Lauren; Dougan, Caoifa M.; Borensztajn, Keren S.; Holsinger, Leslie; Booth, Robert; Scott, Christopher J.; López-Campos, Guillermo; Elborn, J. Stuart; Mall, Marcus A.; Weldon, Sinéad; Taggart, Clifford C.
• Is Part Of: European respiratory journal. Volume 53:Issue 3(2019)
• Publication Date: 2019-03-28
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.01523-2018
• Languages: English
• ISSNs: 0903-1936

Abstract

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. Cathepsin S is involved in inflammation, mucus production and lung tissue damage in a model of CF-like lung disease http://ow.ly/tHcm30nhlcX