The role of Cathepsin S in PAR-1 mediated lung inflammation - a new paradigm for neutrophilic inflammation

在感染期间，身体通常会产生免疫反应。这通常涉及到白细胞的招募，白细胞在清除入侵的生物体中发挥作用。一种被称为中性粒细胞的特殊白细胞在清除感染部位（包括肺部）的细菌过程中起着关键作用。在某些病例中，中性粒细胞大量到达肺和其他器官部位，不是感染的结果，而是一种定义不清的炎症过程的结果。当它们到达肺部时，这些中性粒细胞就会对肺组织造成损害。我们发现了中性粒细胞迁移到肺部的新途径，其中涉及一种名为组织蛋白酶S （CTSS）的蛋白质的作用。通过使用特定的CTSS抑制剂，已经发现了CTSS在这一作用中的作用，但我们现在希望进一步确认CTSS在中性粒细胞募集中的作用，使用新的基因生成模型，其中关键的CTSS靶点-称为蛋白酶激活受体（PARs）将被消融，从而使我们能够确认CTSS在中性粒细胞募集中的作用。我们还将扩展该项目，超越简单的小鼠模型，以确认CTSS在独特的猪和人体外肺灌注（EVLP）模型中中性粒细胞募集中的作用。这项研究的一个非常明确的应用是靶向CTSS来调节疾病中的中性粒细胞募集，特别是肺部疾病，尽管CTSS介导的途径在其他疾病过程中也有潜在的作用，包括胃肠道和皮肤疾病。为此，我们与包括Virobay在内的参与CTSS抑制剂设计和临床测试的公司进行了非常积极的合作。事实上，我们为该项目生成的许多初步数据包括使用Virobay CTSS抑制剂。与Virobay（或其他开发临床CTSS抑制剂的制药公司）合作进行CTSS抑制剂在肺部疾病的临床评估的未来研究是非常有可能的，因为我们将在贝尔法斯特女王大学开展此类研究，作为英国呼吸转化研究伙伴关系的一部分。

During an infection the body normally responds by mounting an immune response. This generally involves the recruitment of white blood cells that play a role in removing the invading organism. A specific white blood cell, called the neutrophil, is pivotally involved in the process of removing bacteria from sites of infection including the lung. In some cases of disease, neutrophils arrive in significant numbers to the lung, and other organ sites, not as result of infection but as a result of a poorly-defined inflammatory process. When they arrive at the lung these neutrophils become involved in causing damage to the lung tissue. We have uncovered a new pathway by which neutrophils migrate to the lung involving the role of a protein called cathepsin S (CTSS). The identification of CTSS in this role has been uncovered by the use of specific inhibitors of CTSS but we now wish to confirm further the role of CTSS in neutrophil recruitment using novel genetically generated models in which key CTSS targets - called protease activated receptors (PARs) will be ablated thus allowing us to confirm the role of CTSS in neutrophil recruitment. We will also expand this project beyond simple mouse models to confirm a role for CTSS in neutrophil recruitment in unique porcine and human ex vivo lung perfusion (EVLP) models. The very clear application of this study is in the targeting of CTSS to regulate neutrophil recruitment in disease, particularly lung disease, although there is a potential role for this CTSS-mediated pathway in other disease processes including gastrointestinal and dermatological disorders. To this end, we have a very active collaboration with companies that are involved in the design and clinical testing of CTSS inhibitors including Virobay. Indeed, a lot of the preliminary data that we have generated for this project includes the use of the Virobay CTSS inhibitor. Future studies looking at the clinical evaluation of CTSS inhibitors in lung disease in collaboration with Virobay (or other Pharma developing clinical CTSS inhibitors) is a very real possibility as we are set-up to carry out such studies in Queen's Belfast as part of the UK Respiratory Translational Research Partnership.