Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice
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 birt...
Main Authors: | , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Hindawi Limited
2021-01-01
|
Series: | Mediators of Inflammation |
Online Access: | http://dx.doi.org/10.1155/2021/6682657 |
id |
doaj-7f801294803e401ab88bd8dd4b1176eb |
---|---|
record_format |
Article |
spelling |
doaj-7f801294803e401ab88bd8dd4b1176eb2021-03-29T00:08:44ZengHindawi LimitedMediators of Inflammation1466-18612021-01-01202110.1155/2021/6682657Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg MiceRyan Brown0Donna M. Small1Declan F. Doherty2Leslie Holsinger3Robert Booth4Richard Williams5Rebecca J. Ingram6J. Stuart Elborn7Marcus A. Mall8Clifford C. Taggart9Sinéad Weldon10Airway Innate Immunity Research (AiiR) GroupAirway Innate Immunity Research (AiiR) GroupAirway Innate Immunity Research (AiiR) GroupViroBay Inc.ViroBay Inc.Patrick G Johnston Centre for Cancer ResearchWellcome-Wolfson Institute for Experimental MedicineWellcome-Wolfson Institute for Experimental MedicineDepartment of Translational PulmonologyAirway Innate Immunity Research (AiiR) GroupAirway Innate Immunity Research (AiiR) GroupBackground. 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 (βENaC-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 βENaC-Tg mice with established disease. Methods. βENaC-Tg mice and wild-type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS-/-βENaC-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, βENaC-Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS-/-βENaC-Tg mice and βENaC-Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS-/-βENaC-Tg mice, therapeutic inhibition of CatS in βENaC-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.http://dx.doi.org/10.1155/2021/6682657 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ryan Brown Donna M. Small Declan F. Doherty Leslie Holsinger Robert Booth Richard Williams Rebecca J. Ingram J. Stuart Elborn Marcus A. Mall Clifford C. Taggart Sinéad Weldon |
spellingShingle |
Ryan Brown Donna M. Small Declan F. Doherty Leslie Holsinger Robert Booth Richard Williams Rebecca J. Ingram J. Stuart Elborn Marcus A. Mall Clifford C. Taggart Sinéad Weldon Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice Mediators of Inflammation |
author_facet |
Ryan Brown Donna M. Small Declan F. Doherty Leslie Holsinger Robert Booth Richard Williams Rebecca J. Ingram J. Stuart Elborn Marcus A. Mall Clifford C. Taggart Sinéad Weldon |
author_sort |
Ryan Brown |
title |
Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice |
title_short |
Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice |
title_full |
Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice |
title_fullStr |
Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice |
title_full_unstemmed |
Therapeutic Inhibition of Cathepsin S Reduces Inflammation and Mucus Plugging in Adult βENaC-Tg Mice |
title_sort |
therapeutic inhibition of cathepsin s reduces inflammation and mucus plugging in adult βenac-tg mice |
publisher |
Hindawi Limited |
series |
Mediators of Inflammation |
issn |
1466-1861 |
publishDate |
2021-01-01 |
description |
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 (βENaC-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 βENaC-Tg mice with established disease. Methods. βENaC-Tg mice and wild-type (WT) littermates were treated with a CatS inhibitor from 4 to 6 weeks of age, and CatS-/-βENaC-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, βENaC-Tg mice developed significant airway inflammation, lung tissue damage, and mucus plugging when compared to WT mice. CatS-/-βENaC-Tg mice and βENaC-Tg mice receiving inhibitor had significantly reduced airway mononuclear and polymorphonuclear (PMN) cell counts as well as mucus plugging. However, in contrast to CatS-/-βENaC-Tg mice, therapeutic inhibition of CatS in βENaC-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. |
url |
http://dx.doi.org/10.1155/2021/6682657 |
work_keys_str_mv |
AT ryanbrown therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT donnamsmall therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT declanfdoherty therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT leslieholsinger therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT robertbooth therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT richardwilliams therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT rebeccajingram therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT jstuartelborn therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT marcusamall therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT cliffordctaggart therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice AT sineadweldon therapeuticinhibitionofcathepsinsreducesinflammationandmucusplugginginadultbenactgmice |
_version_ |
1714761236409745408 |