- Title
- Adverse roles of mast cell chymase-1 in chronic obstructive pulmonary disease
- Creator
- Liu, Gang; Jarnicki, Andrew G.; Paudel, Keshav R.; Lu, Wenying; Wadhwa, Ridhima; Philp, Ashleigh M.; Van Eeckhoutte, Hannelore; Marshall, Jacqueline E.; Malyla, Vamshikrishna; Katsifis, Angelica; Fricker, Michael; Hansbro, Nicole G.; Dua, Kamal; Kermani, Nazanin Z.; Eapen, Mathew S.; Tiotiu, Angelica; Chung, K. Fan; Caramori, Gaetano; Bracke, Ken; Adcock, Ian M.; Wark, Peter A.; Hansbro, Philip M.
- Relation
- European Respiratory Journal Vol. Early view
- Publisher Link
- http://dx.doi.org/10.1183/13993003.01431-2021
- Publisher
- European Respiratory Society
- Resource Type
- journal article
- Date
- 2022
- Description
- 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.
- Subject
- chronic obstructive pulmonary disease (COPD); patients; therapies; human chymase-1 (hCMA1)
- Identifier
- http://hdl.handle.net/1959.13/1448488
- Identifier
- uon:43418
- Identifier
- ISSN:0903-1936
- Language
- eng
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