Targeting of cathepsin S reduces cystic fibrosis-like lung disease.

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.

• Authors: 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 López-Campos, J Stuart Elborn, Marcus A Mall, Sinéad Weldon, Clifford C Taggart
• Journal: The European respiratory journal (Eur Respir J) Vol. 53 Issue 3 (03 2019) ISSN: 1399-3003 [Electronic] England
• PMID: 30655278 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2019.

Chemical References

• Epithelial Sodium Channels
• F2rl1 protein, mouse
• Receptor, PAR-2
• Cathepsins
• cathepsin S

Topics

• Airway Obstruction (metabolism)
• Animals
• Cathepsins (genetics, metabolism)
• Cystic Fibrosis (metabolism)
• Disease Models, Animal
• Epithelial Sodium Channels (genetics)
• Lung (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mucus (metabolism)
• Pneumonia (etiology, metabolism)
• Receptor, PAR-2 (metabolism)