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

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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. 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.