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

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