Targeting of cathepsin S reduces cystic fibrosis-like lung disease

Eur Respir J. 2019 Mar 28;53(3):1801523. doi: 10.1183/13993003.01523-2018. Print 2019 Mar.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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