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.
Abstract
hCMA1 released from mast cells induces macrophages to release TNF-α in the lung and promotes the pathogenesis of COPD. hCMA1 may be a novel therapeutic target in COPD. https://bit.ly/3b3OkKT
Footnotes
Author contributions: G. Liu performed most of the in vitro and in vivo experiments. K.R. Paudel, A.M. Philp, A.G. Jarnicki, M. Fricker and K. Dua performed in vivo experiments. W. Lu, M.S. Eapen and S.S. Sohal performed human immunohistochemistry. R. Wadhwa and V. Malyla assisted in vitro experiments. H. Van Eeckhoutte and K. Bracke performed qPCR in human samples. J.E. Marshall assisted immunoblot. A. Katsifis assisted qPCR in mice. N.Z. Kermani and I.M. Adcock performed sc-RNA-seq analysis. K.F. Chung, G. Caramori, A. Tiotiu and I.M. Adcock assisted in dataset analysis. G. Liu and P.M. Hansbro designed the experiments. P.M. Hansbro, P.A. Wark and B.G. Oliver revised the manuscript. P.M. Hansbro funded the experiments. All authors read and approved the manuscript.
This article has an editorial commentary: https://doi.org/10.1183/13993003.01356-2022
Conflict of interest: M. Fricker reports grants from GlaxoSmithKline, outside the submitted work. P.M. Hansbro reports grants from National Health and Medical Research Council, grants from Australian Research Council, during the conduct of the study. The remaining authors disclose no potential conflicts of interest.
Support statement: P.M. Hansbro is supported by a fellowship and grants from the National Health and Medical Research Council of Australia (NHMRC #1079187, #1175134), Australian Research Council (#150102153), and the University of Technology Sydney. G. Liu is supported by CREATE Hope Scientific Fellowship and grants from Lung Foundation Australia. S.S. Sohal is supported by grants from Clifford Craig Foundation Launceston General Hospital.
- Received May 20, 2021.
- Accepted June 8, 2022.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org