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Adverse roles of mast cell chymase-1 in chronic obstructive pulmonary disease

Citation

Liu, G and Jarnicki, AG and Paudel, KR and Lu, W and Wadhwa, R and Philp, AM and Van Eeckhoutte, H and Marshall, JE and Malyla, V and Katsifis, A and Fricker, M and Hansbro, NG and Dua, K and Kermani, NZ and Eapen, MS and Tiotiu, A and Chung, KF and Caramori, G and Bracke, K and Adcock, IM and Sohal, SS and Wark, PA and Oliver, BG and Hansbro, PM, Adverse roles of mast cell chymase-1 in chronic obstructive pulmonary disease, The European Respiratory Journal, 60, (5) ISSN 0903-1936 (2022) [Refereed Article]

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The authors 2022. For reproduction rights and permissions contact permissions@ersnet.org

DOI: doi:10.1183/13993003.01431-2021

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-1 (hCMA1) and it's ortholog mCMA1/mouse mast cell (MC) protease-5 (mMCP5) are exocytosed from activated MCs 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 proteases' role and potential for therapeutic targeting in CS-induced experimental COPD. We also used ex vivo/in vitro studies to define mechanisms.

Results: The levels of hCMA1 mRNA and CMA1+ MCs were increased in lung tissues from severe compared to early/mild COPD patients, non-COPD smokers and healthy controls. Degranulated MC numbers and mMCP5 protein were increased in lung tissues of wild-type (WT) 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 MCs from WT but not mmcp5 -/- mice with WT lung macrophages increased in TNF-α release. It also caused the release of CMA1 from human MCs, 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.

Item Details

Item Type:Refereed Article
Keywords:COPD, asthma, mast cells, inflammation, Smoking
Research Division:Biomedical and Clinical Sciences
Research Group:Cardiovascular medicine and haematology
Research Field:Cardiology (incl. cardiovascular diseases)
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Lu, W (Dr Monica Lu)
UTAS Author:Eapen, MS (Dr Mathew Eapen)
UTAS Author:Sohal, SS (Dr Sukhwinder Sohal)
ID Code:153594
Year Published:2022
Deposited By:Health Sciences
Deposited On:2022-09-27
Last Modified:2022-11-15
Downloads:0

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