The Role of the Extracellular Immunoproteasome in Acute Respiratory Distress Syndrome

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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.