- Title
- Adverse roles of mast cell chymase-1 in COPD
- Creator
- Liu, Gang; Jarnicki, Andrew G.; 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.; Paudel, Keshav R.; Sohal, Sukhwinder S.; Wark, Peter A.; Oliver, Brian G.; Hansbro, Philip M.; Lu, Wenying; Wadhwa, Ridhima; Philp, Ashleigh M.; Van Eeckhoutte, Hannelore; Marshall, Jacqueline E.; Malyla, Vamshikrishna; Katsifis, Angelica
- Relation
- ARC.DP150102153 http://purl.org/au-research/grants/arc/DP150102153 & NHMRC 1079187 http://purl.org/au-research/grants/nhmrc/1079187
- Relation
- European Respiratory Journal Vol. 60, Issue 6, no. 2101431
- 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 (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.
- Subject
- chronic obstructive pulmonary disease (COPD); mast cell; chymase-1; mMCP5; TNF-a; SDG 3; Sustainable Development Goals
- Identifier
- http://hdl.handle.net/1959.13/1495026
- Identifier
- uon:53957
- Identifier
- ISSN:0903-1936
- Language
- eng
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