Johnson Emma, Gilmour Amy, Chalmers James D
Division of Respiratory Medicine and Gastroenterology, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
Division of Respiratory Medicine and Gastroenterology, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK
Eur Respir Rev. 2025 Jun 18;34(176). doi: 10.1183/16000617.0257-2024. Print 2025 Apr.
Dipeptidyl peptidase (DPP)-1 (also known as cathepsin C) inhibitors are the first disease-specific therapy shown to be effective in bronchiectasis. The mechanism of action of DPP-1 inhibitors is suppression of activity of neutrophil serine proteases (NSPs) by preventing them from being activated during neutrophil maturation in the bone marrow. NSPs exert multiple directly damaging effects and contribute to ongoing dysregulated airway inflammation. High airway levels of NSPs are linked to bronchiectasis disease severity. Several phase 2 and one phase 3 trial have now confirmed that DPP-1 inhibitors reduce activity of the NSPs in the airways and have clinical benefits in bronchiectasis including reducing exacerbations and improving other clinical end-points such as quality of life and slowing lung function decline. DPP-1 inhibition may also be a promising treatment avenue in other diseases where neutrophilic inflammation is implicated. Future directions include establishing direct and downstream effects of DPP-1 inhibitors in humans and seeking biomarkers to guide clinical application.
二肽基肽酶（DPP）-1（也称为组织蛋白酶C）抑制剂是首个被证明对支气管扩张有效的疾病特异性疗法。DPP-1抑制剂的作用机制是通过阻止中性粒细胞丝氨酸蛋白酶（NSPs）在骨髓中中性粒细胞成熟过程中被激活，从而抑制其活性。NSPs会产生多种直接损害作用，并导致持续的气道炎症失调。气道中高水平的NSPs与支气管扩张疾病的严重程度相关。现在，多项2期试验和一项3期试验已证实，DPP-1抑制剂可降低气道中NSPs的活性，并对支气管扩张具有临床益处，包括减少病情加重次数、改善生活质量和减缓肺功能下降等其他临床终点。在其他涉及嗜中性粒细胞炎症的疾病中，DPP-1抑制也可能是一种有前景的治疗途径。未来的方向包括确定DPP-1抑制剂在人体中的直接和下游效应，并寻找生物标志物以指导临床应用。
