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.

Adverse roles of mast cell chymase-1 in COPD / Liu, G.; Jarnicki, A. G.; Paudel, K. R.; Lu, W.; Wadhwa, R.; Philp, A. M.; Van Eeckhoutte, H.; Marshall, J. E.; Malyla, V.; Katsifis, A.; Fricker, M.; Hansbro, N. G.; Dua, K.; Kermani, N. Z.; Eapen, M. S.; Tiotiu, A.; Chung, K. F.; Caramori, G.; Bracke, K.; Adcock, I. M.; Sohal, S. S.; Wark, P. A.; Oliver, B. G.; Hansbro, P. M.. - In: EUROPEAN RESPIRATORY JOURNAL. - ISSN 0903-1936. - 60:6(2022), pp. 2101431.1-2101431.16. [10.1183/13993003.01431-2021]

Adverse roles of mast cell chymase-1 in COPD

Caramori G.
Membro del Collaboration Group
;
2022-01-01

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 (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.
2022
Adverse roles of mast cell chymase-1 in COPD / Liu, G.; Jarnicki, A. G.; Paudel, K. R.; Lu, W.; Wadhwa, R.; Philp, A. M.; Van Eeckhoutte, H.; Marshall, J. E.; Malyla, V.; Katsifis, A.; Fricker, M.; Hansbro, N. G.; Dua, K.; Kermani, N. Z.; Eapen, M. S.; Tiotiu, A.; Chung, K. F.; Caramori, G.; Bracke, K.; Adcock, I. M.; Sohal, S. S.; Wark, P. A.; Oliver, B. G.; Hansbro, P. M.. - In: EUROPEAN RESPIRATORY JOURNAL. - ISSN 0903-1936. - 60:6(2022), pp. 2101431.1-2101431.16. [10.1183/13993003.01431-2021]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2982634
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