Targeting of Cathepsin S Reduces Cystic Fibrosis-like Lung Disease

Donna M. Small, Ryan R. Brown, Declan F. Doherty, Anthony Abladey, Zhe Zhou- Suckow, Rebecca J. Delaney, Lauren Kerrigan, Caoifa M. Dougan, Keren S. Borensztajn, Leslie Holsinger, Robert Booth, Christopher J. Scott, Guillermo Lopez Campos, J. Stuart Elborn, Marcus A Mall, Sinead Weldon, Clifford C. Taggart

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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 cathepsin S 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 to wild-type (WT) littermates. CatS-/-βENaC-Tg mice exhibited decreased pulmonary inflammation, mucus obstruction and structural lung damage compared to 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 (PAR-2), 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 PAR-2 and highlights CatS as a therapeutic target.
Original languageEnglish
Article number1801523
JournalEuropean Respiratory Journal
Issue number3
Early online date17 Jan 2019
Publication statusPublished - 28 Mar 2019


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