Department of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom.
Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Front Immunol. 2023 Dec 14;14:1239151. doi: 10.3389/fimmu.2023.1239151. eCollection 2023.
Neutrophils have a critical role in the innate immune response to infection and the control of inflammation. A key component of this process is the release of neutrophil serine proteases (NSPs), primarily neutrophil elastase, proteinase 3, cathepsin G, and NSP4, which have essential functions in immune modulation and tissue repair following injury. Normally, NSP activity is controlled and modulated by endogenous antiproteases. However, disruption of this homeostatic relationship can cause diseases in which neutrophilic inflammation is central to the pathology, such as chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, bronchiectasis, and cystic fibrosis, as well as many non-pulmonary pathologies. Although the pathobiology of these diseases varies, evidence indicates that excessive NSP activity is common and a principal mediator of tissue damage and clinical decline. NSPs are synthesized as inactive zymogens and activated primarily by the ubiquitous enzyme dipeptidyl peptidase 1, also known as cathepsin C. Preclinical data confirm that inactivation of this protease reduces activation of NSPs. Thus, pharmacological inhibition of dipeptidyl peptidase 1 potentially reduces the contribution of aberrant NSP activity to the severity and/or progression of multiple inflammatory diseases. Initial clinical data support this view. Ongoing research continues to explore the role of NSP activation by dipeptidyl peptidase 1 in different disease states and the potential clinical benefits of dipeptidyl peptidase 1 inhibition.
中性粒细胞在感染的先天免疫反应和炎症控制中起着关键作用。这个过程的一个关键组成部分是中性粒细胞丝氨酸蛋白酶 (NSPs) 的释放，主要是中性粒细胞弹性蛋白酶、蛋白酶 3、组织蛋白酶 G 和 NSP4，它们在损伤后的免疫调节和组织修复中具有重要功能。正常情况下，NSP 活性受内源性抗蛋白酶的控制和调节。然而，这种动态平衡关系的破坏会导致以中性粒细胞炎症为中心的病理学疾病，如慢性阻塞性肺疾病 (COPD)、α-1 抗胰蛋白酶缺乏症、支气管扩张和囊性纤维化，以及许多非肺部病理学疾病。尽管这些疾病的病理生物学有所不同，但有证据表明，过度的 NSP 活性很常见，是组织损伤和临床恶化的主要介质。NSPs 作为无活性的酶原合成，并主要被广泛存在的酶二肽基肽酶 1（也称为组织蛋白酶 C）激活。临床前数据证实，这种蛋白酶的失活可减少 NSP 的激活。因此，二肽基肽酶 1 的药理学抑制可能会降低异常 NSP 活性对多种炎症性疾病的严重程度和/或进展的贡献。初步的临床数据支持这一观点。正在进行的研究继续探索二肽基肽酶 1 对不同疾病状态下 NSP 激活的作用以及二肽基肽酶 1 抑制的潜在临床益处。
