The Role of the Extracellular Immunoproteasome in Acute Respiratory Distress Syndrome

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.

Inflammatory cell recruitment to sites of infection is a common and necessary process to remove bacteria in 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. In the case of acute lung inflammation, excessive inflammatory cell recruitment can lead to damage, which is mediated, in part, by the neutrophil. 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. We now wish to confirm further the role of Extracellular Immunoproteasome in inflammatory cell recruitment and lung injury using a novel Immunoproteasome inhibitor, QUB1034, in models of acute lung inflammation. We will also confirm a role for protease activated receptors (PARs) as a target for Extracellular Immunoproteasome-mediated inflammatory cell recruitment and injury using specific PAR antagonists. The very clear application of this study is in the targeting of Extracellular Immunoproteasome to regulate inflammatory and injury in disease, particularly lung disease, although there is a potential role for this Extracellular Immunoproteasome-mediated pathway in other inflammatory disease processes. Future studies looking at the evaluation of the Extracellular Immunoproteasome QUB1034 inhibitor in lung disease in collaboration 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.

Who Will Benefit from this Research?

The findings from this study will benefit the life science community especially those working in the area of innate host defense and regulation of inflammation. In addition, the findings may be of therapeutic value given that proteasome is a therapeutic target in other processes and disease including cancer. For example, proteasome inhibitors are either in use such as bortezomib, developed by Takeda Oncology and carfilzomib, developed by Onyx Pharmaceuticals. Although these drugs are beneficial for the treatment of some cancers, they are not specific for immunoproteasome. Clearly, charities linked to inflammatory diseases including the British Thoracic Society and the British Lung Foundation will also be interested in new data and potential targets for the treatment of inflammatory lung diseases such as ARDS. Such societies/charities generally have excellent links with local and national governments who would also be interested in the development of new therapies, especially therapeutics that could reduce healthcare costs and improve quality of life as well as being of use in the treatment of other acute (and chronic) lung diseases with an inflammation/infection component which may be potentially related to increased Extracellular Immunoroteasome activity including most significantly chronic obstructive pulmonary disease (COPD).

How will they benefit from this research?

We would be keen to pursue pre-clinical studies in collaboration with relevant respiratory CROs including Domainex by securing future funding from MRC perhaps via the MICA or DPFS funding stream. Subsequent studies could lead to a phase 1 clinical trial that could be carried out in conjunction with clinical colleagues in Queen's. We have an excellent pre-clinical and clinical trials programme at QUB led by Professor Danny McAuley (one of the co-PIs on this application) and there are clear pathways to development of Extracellular Immunoproteasome inhibitors initially in the human LPS model and, if successful, ARDS patients. Such studies could be funded by NIHR/EME programmes. The development of Extracellular Immunoproteasome inhibitors for treatment of lung disease patients could improve the lifestyle of these patients as well as increase their lifespan. There could also be spin-offs from our research leading to investigation of Extracellular Immunoproteasome in other diseases such as COPD which represents a large patient cohort worldwide with significant impact on patient treatment as well as representing a large market for pharma companies developing Extracellular Immunoproteasome inhibitors.