Centre for Inflammation, Centenary Institute and University of Technology Sydney, School of Life Sciences, Faculty of Science, Sydney, Australia.
Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Australia.
Eur Respir J. 2022 Dec 8;60(6). doi: 10.1183/13993003.01431-2021. Print 2022 Dec.
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.
We evaluated hCMA1 levels in lung tissues of COPD patients. We used -deficient () mice to evaluate this protease's role and potential for therapeutic targeting in CS-induced experimental COPD. In addition, we used studies to define mechanisms.
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. 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 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.
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.
慢性阻塞性肺疾病（COPD）是全球第三大致死原因。香烟烟雾（CS）引起的慢性炎症导致气道重塑、肺气肿和肺功能受损，是其主要病因。目前迫切需要有效的治疗方法。人组织蛋白酶 M（hCMA）1 及其同源物 mCMA1/小鼠肥大细胞蛋白酶（mMCP）5 从激活的肥大细胞中出胞，在许多疾病中发挥不良作用，但在 COPD 中的作用尚不清楚。
我们评估了 COPD 患者肺组织中的 hCMA1 水平。我们使用 CMA1 缺陷（）小鼠来评估该蛋白酶在 CS 诱导的实验性 COPD 中的作用及其潜在的治疗靶向作用。此外，我们使用 研究来定义其机制。
与早期/轻度 COPD 患者、非 COPD 吸烟者和健康对照者相比，严重 COPD 患者的肺组织中 hCMA1mRNA 和 CMA1 肥大细胞的水平增加。实验性 COPD 野生型小鼠的肺组织中脱颗粒肥大细胞数量和 mMCP5 蛋白增加。CMA1 缺陷（）小鼠在 CS 诱导的实验性 COPD 中受到保护，免受炎症和巨噬细胞积聚、气道重塑、肺气肿和肺功能受损的影响。CS 提取物对野生型而非 小鼠的肥大细胞与野生型肺巨噬细胞共培养物的刺激增加了肿瘤坏死因子（TNF）-α 的释放。它还导致 CMA1 从人肥大细胞中释放，重组 hCMA-1 诱导人巨噬细胞释放 TNF-α。CMA1 抑制剂的治疗强力抑制了实验性 COPD 的这些标志性特征。
CMA1/mMCP5 通过诱导肺巨噬细胞中 TNF-α 的表达和释放，促进 COPD 的发病机制。抑制 hCMA1 可能是治疗 COPD 的一种新方法。
