Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice. (20th March 2021)

• Record Type: Journal Article
• Authors: Brown, Ryan; Small, Donna M.; Doherty, Declan F.; Holsinger, Leslie; Booth, Robert; Williams, Richard; Ingram, Rebecca J.; Elborn, J. Stuart; Mall, Marcus A.; Taggart, Clifford C.; Weldon, Sinéad
• Other Names: Martins Joilson O. Academic Editor.
• Is Part Of: Mediators of inflammation. Volume 2021(2021)
• Publication Date: 2021-03-20
• Subjects: Inflammation -- Mediators -- Periodicals; Biological response modifiers -- Periodicals; Inflammation (Pathologie) -- Médiateurs; Immunomodulateurs; Biological response modifiers; Inflammation -- Mediators; Immunology; Autacoids; Immunologic Factors; Cell Adhesion Molecules; Cell Communication; Cytokines; Inflammation; Periodicals; Electronic journals; 616.0473
• DOI: 10.1155/2021/6682657
• Languages: English
• ISSNs: 0962-9351

Abstract

Abstract : Background . Elevated levels of the cysteine protease cathepsin S (CatS) are associated with chronic mucoobstructive lung diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). We have previously demonstrated that prophylactic treatment with a CatS inhibitor from birth reduces inflammation, mucus plugging, and lung tissue damage in juvenile β -epithelial Na+ channel-overexpressing transgenic ( β ENaC-Tg) mice with chronic inflammatory mucoobstructive lung disease. In this study, we build upon this work to examine the effects of therapeutic intervention with a CatS inhibitor in adult β ENaC-Tg mice with established disease. Methods . β ENaC-Tg mice and wild-type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS -/- β ENaC-Tg mice were analysed at 6 weeks of age. Bronchoalveolar lavage (BAL) fluid inflammatory cell counts were quantified, and lung tissue destruction and mucus obstruction were analysed histologically. Results . At 6 weeks of age, β ENaC-Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS -/- β ENaC-Tg mice and β ENaC-Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS -/- β ENaC-Tg mice, therapeutic inhibition of CatS in β ENaC-Tg mice had no effect on established emphysema-like lung tissue damage. Conclusions . These results suggest that while early CatS targeting may be required to prevent the onset and progression of lung tissue damage, therapeutic CatS targeting effectively inhibited airway inflammation and mucus obstruction. These results indicate the important role CatS may play in the pathogenesis and progression of mucoobstructive lung disease.