PT  - JOURNAL ARTICLE
AU  - Donna M. Small
AU  - Ryan R. Brown
AU  - Declan F. Doherty
AU  - Anthony Abladey
AU  - Zhe Zhou-Suckow
AU  - Rebecca J. Delaney
AU  - Lauren Kerrigan
AU  - Caoifa M. Dougan
AU  - Keren S. Borensztajn
AU  - Leslie Holsinger
AU  - Robert Booth
AU  - Christopher J. Scott
AU  - Guillermo López-Campos
AU  - J. Stuart Elborn
AU  - Marcus A. Mall
AU  - Sinéad Weldon
AU  - Clifford C. Taggart
TI  - Targeting of cathepsin S reduces cystic fibrosis-like lung disease
AID  - 10.1183/13993003.01523-2018
DP  - 2019 Mar 01
TA  - European Respiratory Journal
PG  - 1801523
VI  - 53
IP  - 3
4099  - http://erj.ersjournals.com/content/53/3/1801523.short
4100  - http://erj.ersjournals.com/content/53/3/1801523.full
SO  - Eur Respir J2019 Mar 01; 53
AB  - 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