Details

Autor(en) / Beteiligte

• 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

Titel

Targeting of cathepsin S reduces cystic fibrosis-like lung disease

Ist Teil von

• The European respiratory journal, 2019-03, Vol.53 (3), p.1801523

Ort / Verlag

England

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.