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

journal contribution
posted on 2023-05-21, 13:54 authored by Liu, G, Jarnicki, AG, Paudel, KR, Wenying LuWenying Lu, Wadhwa, R, Philp, AM, Van Eeckhoutte, H, Marshall, JE, Malyla, V, Katsifis, A, Fricker, M, Hansbro, NG, Dua, K, Kermani, NZ, Mathew Eapen, Tiotiu, A, Chung, KF, Caramori, G, Bracke, K, Adcock, IM, Sukhwinder SohalSukhwinder Sohal, Wark, PA, Oliver, BG, Hansbro, PM

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.


Clifford Craig Foundation


Publication title

The European Respiratory Journal








School of Health Sciences


European Respiratory Soc Journals Ltd

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146 West St, Ste 2.4, Huttons Bldg, Sheffield, England, S1 4Es

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Diagnosis of human diseases and conditions

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