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 López-Campos; J. Stuart Elborn; Marcus A. Mall; Sinéad Weldon; Clifford C. Taggart

doi:10.1183/13993003.01523-2018

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 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.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Small has nothing to disclose.

Conflict of interest: Dr. Brown has nothing to disclose.

Conflict of interest: Dr. Doherty has nothing to disclose.

Conflict of interest: Dr. Abladey has nothing to disclose.

Conflict of interest: Dr. Delaney has nothing to disclose.

Conflict of interest: Dr. Kerrigan has nothing to disclose.

Conflict of interest: Dr. Dougan has nothing to disclose.

Conflict of interest: Dr. Borensztajn has nothing to disclose.

Conflict of interest: Dr. Holsinger reports other from Virobay, during the conduct of the study; other from Virobay, outside the submitted work.

Conflict of interest: Dr. Booth has a patent US 7,547,701 issued.

Conflict of interest: Dr. Scott reports other from Fusion Antibodies PLC, outside the submitted work; In addition, Dr. Scott has a patent Patents on antibodies for Cathepsin S licensed to Fusion Antibodies PLC.

Conflict of interest: Dr. López-Campos has nothing to disclose.

Conflict of interest: Dr. Elborn reports personal fees from Bayer, grants and personal fees from Horizion, during the conduct of the study; personal fees from Cheisi, personal fees from Polyfor, from null, outside the submitted work.

Conflict of interest: Dr. Mall reports grants from German Federal Ministry of Education and Research , during the conduct of the study; personal fees from Spyryx Biosciences, personal fees from Boehringer Ingelheim, personal fees from ProQR, personal fees from PTC Pharmaceuticals, personal fees from Arrowhead, personal fees from Pro Axis, personal fees from Bayer, personal fees from Polyphor, personal fees from Enterprise Therapeutics, personal fees from Sterna Biologicals, personal fees from Vertex Pharmaceuticals, outside the submitted work; In addition, Dr. Mall has a patent Patent on the Scnn1b-transgenic mouse with royalties paid.

Conflict of interest: Dr. Weldon reports grants from Randox, grants from Pfizer UK, outside the submitted work.

Conflict of interest: Dr. Taggart reports personal fees from Albumedix, grants from Randox, grants from Pfizer UK, outside the submitted work.

Conflict of interest: Dr. Zhou-Sukow has nothing to disclose.

View Full Text

INDIVIDUALS

LIBRARY USERS

Log in through your institution

If your library has a subscription, you may already be logged in via your IP address. Otherwise you may be able to log in via one of the following routes.

If you think you should have access, please contact your librarian or email journals@ersnet.org