Cathepsin S inhibition as a treatment for lung inflammation and lung damage in Chronic Lung Disease

组织蛋白酶 S 抑制可治疗慢性肺病中的肺部炎症和肺损伤

• 批准号: MR/X001504/1
• 负责人: Clifford Taggart
• 金额: $ 90.1万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001504%2F1
• 关键词: Cathepsin; inhibition; treatment; lung; inflammation

The cells lining the upper part of the respiratory tract, called bronchial epithelial cells, play an important role in defending the lung against any foreign particles landing on this surface including bacteria, viruses and smoke particles. However, over time, particularly in individuals who have smoked cigarettes for a long period of their life, constant exposure of bronchial epithelial cells to the particles in cigarette smoke can alter the function of these cells. The cells can start dying more rapidly and can also produce chemicals called cytokines that can cause tissue damage to the airways, a process called inflammation. This can lead to a condition called chronic obstructive pulmonary disease (COPD) which is thought to affect many people worldwide (including the UK) and is now the 3rd leading cause of death worldwide. We have found a way to reduce cells from dying and producing cytokines by inhibiting a protein produced by epithelial cells called cathepsin S (CTSS). The identification of CTSS in this role has been uncovered by the use of specific inhibitors of CTSS. We now wish to learn more about how CTSS can make the lung more inflammatory and lead to increased cell death by looking at the activation of another group of proteins called protease activated receptors (PARs) and chemokines which are known to be activated by CTSS and can increase inflammation. We will also test how well these CTSS inhibitors work in a mouse model of COPD. If we see improvements in mouse lung function, reduced inflammation and a reduction in lung damage in this model this will bode well for taking these CTSS inhibitors forward into future clinical trials in individuals with COPD. The very clear application of this study is in the targeting of CTSS to improve bronchial cell function and reduce the progression of COPD, although there is a potential role for this CTSS-mediated pathway in other disease processes including gastrointestinal and dermatological disorders. In future studies, we will test CTSS inhibitors in clinical trials for COPD, which is a very real possibility as we are set-up in Queen's to carry out such studies in Queen's Belfast as part of the NIHR Respiratory Translational Research Collaboration group.

呼吸道上部的细胞称为支气管上皮细胞，在保护肺部免受任何外来颗粒（包括细菌，病毒和烟雾颗粒）的影响方面发挥着重要作用。然而，随着时间的推移，特别是在长期吸烟的个体中，支气管上皮细胞持续暴露于香烟烟雾中的颗粒会改变这些细胞的功能。这些细胞可以开始更快地死亡，也可以产生称为细胞因子的化学物质，这些化学物质可以导致气道组织损伤，这一过程称为炎症。这可能导致一种称为慢性阻塞性肺疾病（COPD）的疾病，这种疾病被认为会影响全球许多人（包括英国），现在是全球第三大死亡原因。我们已经找到了一种方法，通过抑制上皮细胞产生的一种称为组织蛋白酶S（CTSS）的蛋白质来减少细胞死亡和产生细胞因子。通过使用CTSS的特异性抑制剂，已经发现了CTSS在这一作用中的鉴定。我们现在希望了解更多关于CTSS如何使肺部更具炎症性并导致细胞死亡增加，方法是观察另一组称为蛋白酶激活受体（PAR）和趋化因子的蛋白质的激活，已知这些蛋白质被CTSS激活并可增加炎症。我们还将测试这些CTSS抑制剂在COPD小鼠模型中的作用。如果我们在这个模型中看到小鼠肺功能的改善，炎症的减少和肺损伤的减少，这将预示着将这些CTSS抑制剂用于未来COPD患者的临床试验。这项研究的非常明确的应用是靶向CTSS，以改善支气管细胞功能并减少COPD的进展，尽管这种CTSS介导的途径在其他疾病过程中（包括胃肠道和皮肤病）有潜在的作用。在未来的研究中，我们将在COPD的临床试验中测试CTSS抑制剂，这是一个非常真实的可能性，因为我们在皇后学院设立，作为NIHR呼吸转化研究协作组的一部分，在皇后学院贝尔法斯特开展此类研究。