Targeting of cathepsin S reduces cystic fibrosis-like lung disease

• Verfasst von: Small, Donna M. [VerfasserIn]
• Verfasst von: Brown, Ryan [VerfasserIn]
• Verfasst von: Zhou-Suckow, Zhe [VerfasserIn]
• Verfasst von: Mall, Marcus A. [VerfasserIn]
• Titel: Targeting of cathepsin S reduces cystic fibrosis-like lung disease
• Verf.angabe: 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 and Clifford C. Taggart
• E-Jahr: 2019
• Jahr: March 28, 2019
• Umfang: 11 S.
• Fussnoten: Gesehen am 15.11.2019 ; Donna M. Small and Ryan R. Brown contributed equally to this work
• Titel Quelle: Enthalten in: European respiratory journal
• Ort Quelle: Lausanne : ERS, 1988
• Jahr Quelle: 2019
• Band/Heft Quelle: 53(2019,3) Artikel-Nummer 1801523, 11 Seiten
• ISSN Quelle: 1399-3003
• DOI: doi:10.1183/13993003.01523-2018
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1681975947

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. - Tweetable abstract @ERSpublications - click to tweetCathepsin S is involved in inflammation, mucus production and lung tissue damage in a model of CF-like lung disease http://ow.ly/tHcm30nhlcX