The Role of the Extracellular Immunoproteasome in Acute Respiratory Distress Syndrome

在感染期间，身体通常会产生免疫反应。这通常涉及白色血细胞的募集，这些血细胞在清除入侵生物体中发挥作用。在某些疾病的情况下，过量的细胞大量到达肺部和其他器官部位，不是由于感染，而是由于定义不清的炎症过程。当它们到达肺部时，这些细胞参与对肺组织造成损害。我们已经发现了一种最近描述的蛋白质，细胞外免疫蛋白酶体，它可能在将这些炎症细胞的破坏水平带到或吸引到肺部中发挥作用。此外，我们提出，肺中的细胞外免疫蛋白酶体可能通过激活肺中另一组称为蛋白酶激活受体（PAR）的蛋白质将这些炎症细胞带到肺中。我们将通过使用模型的组合来证实我们的提议，以确认细胞外免疫蛋白酶体在炎症细胞募集中的作用。这项研究的非常明确的应用是靶向细胞外免疫蛋白酶体以调节疾病中的肺损伤和肺损伤，尽管这种细胞外免疫蛋白酶体介导的途径在包括炎性疾病在内的其他疾病过程中具有潜在作用。为此，我们开发了一种非常特异的细胞外免疫蛋白酶体抑制剂，其对免疫蛋白酶体的特异性比其他治疗性蛋白酶体抑制剂高得多。未来的研究着眼于细胞外免疫蛋白酶体抑制剂在肺部疾病中的临床评价是一个非常真实的可能性，因为我们将在女王贝尔法斯特开展此类研究，作为英国呼吸转化研究合作伙伴关系的一部分。

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. In some cases of disease, excess numbers of cells 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 cells become involved in causing damage to the lung tissue. We have uncovered a recently described protein, the Extracellular Immunoproteasome, which may play role in bringing, or attracting, damaging levels of these inflammatory cells to the lung. In addition, we propose that the Extracellular Immunoproteasome in the lung may bring these inflammatory cells to the lung by activating another group of proteins, called protease activated receptors (PARs), in the lung. We will confirm our proposal by using a combination of models to confirm a role for Extracellular Immunoproteasome in inflammatory cell recruitment. The very clear application of this study is in the targeting of Extracellular Immunoproteasome to regulate lung damage and lung injury in disease, although there is a potential role for this Extracellular Immunoproteasome -mediated pathway in other disease processes including inflammatory disorders. To this end, we have a developed a very specific inhibitor of the Extracellular Immunoproteasome which is much more specific for the immunoproteasome than other therapeutic proteasome inhibitors. Future studies looking at the clinical evaluation of Extracellular Immunoproteasome inhibitors in lung disease 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.