针对支气管扩张症的中性粒细胞丝氨酸蛋白酶。

IF 16.6 1区 医学 Q1 RESPIRATORY SYSTEM
James D Chalmers, Marcus A Mall, Sanjay H Chotirmall, Anne E O'Donnell, Patrick A Flume, Naoki Hasegawa, Felix C Ringshausen, Henrik Watz, Jin-Fu Xu, Michal Shteinberg, Pamela J McShane
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引用次数: 0

摘要

持续的中性粒细胞炎症是支气管扩张症(BE)发病和恶化的核心特征。中性粒细胞释放中性粒细胞丝氨酸蛋白酶(NSP),如中性粒细胞弹性蛋白酶、酪蛋白酶 G 和蛋白酶 3。当长期高水平的游离 NSP 活性超过保护性抗蛋白酶的活性时,就会出现肺部结构性破坏、粘膜相关缺陷、更易感染以及临床结果恶化。尽管长期高水平的 NSPs 在 BE 中的作用已经明确,但目前还没有获得治疗 BE 的控制中性粒细胞炎症的药物许可。以往抑制中性粒细胞炎症的方法(如直接抑制中性粒细胞弹性蛋白酶)并不成功;然而,一种旨在解决中性粒细胞介导的病理学问题的新兴疗法,即抑制半胱氨酸蛋白酶Cathepsin C(CatC,又称二肽基肽酶1),是一种很有希望改善中性粒细胞炎症的方法,因为这可能会降低与BE发病机制有关的所有NSP的活性,而不仅仅是中性粒细胞弹性蛋白酶。目前的数据表明,CatC抑制剂可有效恢复BE中蛋白酶-抗蛋白酶的平衡,从而改善疾病预后。CatC抑制剂在BE中的临床试验报告了积极的III期结果。在这篇叙述性综述中,我们将讨论高 NSP 活性在 BE 中的作用,以及这一特征如何导致 BE 的相关发病率和死亡率。本综述讨论了旨在治疗 BE 肺部中性粒细胞炎症的治疗方法,总结了临床试验结果,并强调需要更多有效解决 BE 中慢性中性粒细胞炎症的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting neutrophil serine proteases in bronchiectasis.

Persistent neutrophilic inflammation is a central feature in both the pathogenesis and progression of bronchiectasis (BE). Neutrophils release neutrophil serine proteases (NSPs), such as neutrophil elastase, cathepsin G and proteinase 3. When chronically high levels of free NSP activity exceed those of protective antiproteases, structural lung destruction, mucosal-related defects, further susceptibility to infection and worsening of clinical outcomes can occur. Despite the defined role of prolonged, high levels of NSPs in BE, no drug that controls neutrophilic inflammation is licensed for the treatment of BE. Previous methods of suppressing neutrophilic inflammation (such as direct inhibition of neutrophil elastase) have not been successful; however, an emerging therapy designed to address neutrophil-mediated pathology, inhibition of the cysteine protease cathepsin C (CatC, also known as dipeptidyl peptidase 1), is a promising approach to ameliorate neutrophilic inflammation, since this may reduce the activity of all NSPs implicated in BE pathogenesis, and not just neutrophil elastase. Current data suggest that CatC inhibition may effectively restore the protease-antiprotease balance in BE and improve disease outcomes as a result. Clinical trials for CatC inhibitors in BE have reported positive Phase III results. In this narrative review, we discuss the role of high NSP activity in BE, and how this feature drives the associated morbidity and mortality seen in BE. This review discusses therapeutic approaches aimed at treating neutrophilic inflammation in the BE lung, summarising clinical trial outcomes, and highlighting the need for more treatment strategies that effectively address chronic neutrophilic inflammation in BE.

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来源期刊
European Respiratory Journal
European Respiratory Journal 医学-呼吸系统
CiteScore
27.50
自引率
3.30%
发文量
345
审稿时长
2-4 weeks
期刊介绍: The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.
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