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.

中文翻译：

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靶向支气管扩张症中的中性粒细胞丝氨酸蛋白酶。


持续的中性粒细胞炎症是支气管扩张症 （BE） 发病机制和进展的核心特征。中性粒细胞释放中性粒细胞丝氨酸蛋白酶 （NSP），例如中性粒细胞弹性蛋白酶、组织蛋白酶 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、结构性肺破坏、粘膜相关缺陷时，可能会发生对感染的进一步易感性和临床结果恶化。尽管长期、高水平的 NSP 在 BE 中的作用明确，但没有控制中性粒细胞炎症的药物被批准用于治疗 BE。以前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）尚未成功;然而，一种旨在解决中性粒细胞介导的病理学的新兴疗法，抑制半胱氨酸蛋白酶组织蛋白酶 C（CatC，也称为二肽基肽酶 1），是一种很有前途的改善中性粒细胞炎症的方法，因为这可能会降低所有与 BE 发病机制有关的 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 抑制可能会有效恢复 BE 中的蛋白酶-抗蛋白酶平衡，从而改善疾病预后。BE 中 CatC 抑制剂的临床试验报告了积极的 III 期结果。在这篇叙述性综述中，我们讨论了高 NSP 活性在 BE 中的作用，以及该特征如何驱动 BE 中相关的发病率和死亡率。本综述讨论了旨在治疗 BE 肺中性粒细胞炎症的治疗方法，总结了临床试验结果，并强调了需要更多有效解决 BE 慢性中性粒细胞炎症的治疗策略。