학술논문
Adverse roles of mast cell chymase-1 in COPD.
Document Type
Academic Journal
Author
Liu G; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Jarnicki AG; Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.; Paudel KR; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Lu W; Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, Australia.; Wadhwa R; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Philp AM; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; St Vincent's Medical School, University of New South Wales Medicine, University of New South Wales, Sydney, Australia.; Van Eeckhoutte H; Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.; Marshall JE; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Malyla V; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Katsifis A; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Fricker M; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.; Hansbro NG; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Dua K; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, Australia.; Kermani NZ; Data Science Institute, Department of Computing, Imperial College London, London, UK.; Eapen MS; Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, Australia.; Tiotiu A; National Heart and Lung Institute, Imperial College London, London, UK.; Department of Pulmonology, University Hospital of Nancy, Nancy, France.; Chung KF; National Heart and Lung Institute, Imperial College London, London, UK.; Caramori G; UOC di Pneumologia, Dipartimento di Scienze Biomediche, Odontoiatriche e delle Immagini Morfologiche e Funzionali (BIOMORF), Università di Messina, Messina, Italy.; Bracke K; Laboratory for Translational Research in Obstructive Pulmonary Diseases, Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.; Adcock IM; National Heart and Lung Institute, Imperial College London, London, UK.; Sohal SS; Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, University of Tasmania, Launceston, Australia.; Wark PA; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.; Oliver BG; Woolcock Institute and School of Life Science, Faculty of Science Life Science, University of Technology Sydney, Sydney, Australia.; Hansbro PM; Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia philip.hansbro@uts.edu.au.; Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, University of Newcastle, Callaghan, Australia.
Source
Publisher: European Respiratory Society Country of Publication: England NLM ID: 8803460 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1399-3003 (Electronic) Linking ISSN: 09031936 NLM ISO Abbreviation: Eur Respir J Subsets: MEDLINE
Subject
Language
English
Abstract
Background: COPD is the third leading cause of death worldwide. Cigarette smoke (CS)-induced chronic inflammation inducing airway remodelling, emphysema and impaired lung function is the primary cause. Effective therapies are urgently needed. Human chymase (hCMA)1 and its orthologue mCMA1/mouse mast cell protease (mMCP)5 are exocytosed from activated mast cells and have adverse roles in numerous disorders, but their role in COPD is unknown.
Methods: We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5 -deficient (-/- ) mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used ex vivo/in vitro studies to define mechanisms.
Results: The levels of hCMA1 mRNA and CMA1+ mast cells were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated mast cell numbers and mMCP5 protein were increased in lung tissues of wild-type mice with experimental COPD. mmcp5 -/- mice were protected against CS-induced inflammation and macrophage accumulation, airway remodelling, emphysema and impaired lung function in experimental COPD. CS extract challenge of co-cultures of mast cells from wild-type, but not mmcp5 -/- mice with wild-type lung macrophages increased in tumour necrosis factor (TNF)-α release. It also caused the release of CMA1 from human mast cells, and recombinant hCMA-1 induced TNF-α release from human macrophages. Treatment with CMA1 inhibitor potently suppressed these hallmark features of experimental COPD.
Conclusion: CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.
Competing Interests: Conflict of interest: M. Fricker reports grants from GlaxoSmithKline, outside the submitted work. P.M. Hansbro reports grants from National Health and Medical Research Council, grants from Australian Research Council, during the conduct of the study. The remaining authors disclose no potential conflicts of interest.
(Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)
Methods: We evaluated hCMA1 levels in lung tissues of COPD patients. We used mmcp5 -deficient (
Results: The levels of hCMA1 mRNA and CMA1
Conclusion: CMA1/mMCP5 promotes the pathogenesis of COPD, in part, by inducing TNF-α expression and release from lung macrophages. Inhibiting hCMA1 may be a novel treatment for COPD.
Competing Interests: Conflict of interest: M. Fricker reports grants from GlaxoSmithKline, outside the submitted work. P.M. Hansbro reports grants from National Health and Medical Research Council, grants from Australian Research Council, during the conduct of the study. The remaining authors disclose no potential conflicts of interest.
(Copyright ©The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org.)