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

Liu, G; Jarnicki, AG; Paudel, KR; Lu, W; Wadhwa, R; Philp, AM; Van Eeckhoutte, H; Marshall, JE; Malyla, V; Katsifis, A; Fricker, M; Hansbro, NG; Dua, K; Kermani, NZ; Eapen, MS; Tiotiu, A; Chung, KF; Caramori, G; Bracke, K; Adcock, IM; Sohal, SS; Wark, PA; Oliver, BG; Hansbro, PM

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

Jarnicki, AG Paudel, KR Lu, W Wadhwa, R Philp, AM Van Eeckhoutte, H Marshall, JE Malyla, V Katsifis, A Fricker, M Hansbro, NG Dua, K

Kermani, NZ Eapen, MS Tiotiu, A Chung, KF Caramori, G Bracke, K Adcock, IM Sohal, SS Wark, PA Oliver, BG Hansbro, PM

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Publisher:: European Respiratory Society (ERS)
Publication Type:: Journal Article
Citation:: Eur Respir J, 2022, pp. 2101431
Issue Date:: 2022-07-01

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Field	Value	Language
dc.contributor.author	Liu, G https://orcid.org/0000-0002-0489-2638
dc.contributor.author	Jarnicki, AG
dc.contributor.author	Paudel, KR
dc.contributor.author	Lu, W
dc.contributor.author	Wadhwa, R
dc.contributor.author	Philp, AM
dc.contributor.author	Van Eeckhoutte, H
dc.contributor.author	Marshall, JE
dc.contributor.author	Malyla, V
dc.contributor.author	Katsifis, A
dc.contributor.author	Fricker, M
dc.contributor.author	Hansbro, NG
dc.contributor.author	Dua, K https://orcid.org/0000-0002-7507-1159
dc.contributor.author	Kermani, NZ
dc.contributor.author	Eapen, MS
dc.contributor.author	Tiotiu, A
dc.contributor.author	Chung, KF
dc.contributor.author	Caramori, G
dc.contributor.author	Bracke, K
dc.contributor.author	Adcock, IM
dc.contributor.author	Sohal, SS
dc.contributor.author	Wark, PA
dc.contributor.author	Oliver, BG
dc.contributor.author	Hansbro, PM
dc.date.accessioned	2022-08-17T01:53:40Z
dc.date.available	2022-06-08
dc.date.available	2022-08-17T01:53:40Z
dc.date.issued	2022-07-01
dc.identifier.citation	Eur Respir J, 2022, pp. 2101431
dc.identifier.issn	0903-1936
dc.identifier.issn	1399-3003
dc.identifier.uri	http://hdl.handle.net/10453/160407
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	European Respiratory Society (ERS)
dc.relation.ispartof	Eur Respir J
dc.relation.isbasedon	10.1183/13993003.01431-2021
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.subject	11 Medical and Health Sciences, 1116 Medical Physiology
dc.subject.classification	Respiratory System
dc.title	Adverse roles of mast cell chymase-1 in chronic obstructive pulmonary disease.
dc.type	Journal Article
utslib.location.activity	England
utslib.for	11 Medical and Health Sciences
utslib.for	1116 Medical Physiology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/Graduate School of Health/GSH.Pharmacy
utslib.copyright.status	open_access	*
utslib.copyright.embargo	2023-07-01T00:00:00+1000Z
dc.date.updated	2022-08-17T01:53:39Z
pubs.publication-status	Published online

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.

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http://hdl.handle.net/10453/160407