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

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.

Neutrophil 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 neutrophil recruitment can lead to damage which is mediated, in part, by the neutrophil. We have uncovered a new pathway by which neutrophils migrate to the lung involving the role of the protease, cathepsin S (CTSS). The identification of CTSS in this role has been uncovered by the use of specific inhibitors of CTSS. We now wish to confirm further the role of CTSS in neutrophil recruitment using novel new genetically generated models in which a new target for CTSS activity - protease activated receptor 1 (PAR-1) is genetically ablated thus allowing us to confirm the role of CTSS in neutrophil recruitment via PAR-1. 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) acute inflammation models and using specific PAR antagonists. 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. Future studies looking at the evaluation of CTSS inhibitors in lung disease in collaboration with Virobay and other pharma 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 CTSS is a therapeutic target in other processes and disease including pain relief and cancer. For example, cathepsin S inhibitors are being developed by various companies including Virobay, Johnson & Johnson, Eli Lilly and Medavir and the opportunity exists to develop some of these CTSS inhibitors for treatment of dysregulated inflammation - CTSS inhibitors are currently being developed for the treatment of autoimmune disease so our findings may expand the disease-relevant targets for these companies. 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 disease. 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 CTSS 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 our contacts in the pharma industry (eg. Leslie Holsinger and Robert Booth at Virobay and other pharma companies developing CTSS inhibitors) 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 CTSS inhibitors initially in the human LPS model and, if successful, ARDS patients. Such studies could be funded by NIHR/EME programmes. The development of CTSS 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 CTSS in other diseases such as COPD and colitis which represents a much larger patient cohort worldwide with greater impact on patient treatment as well as representing a much larger market for pharma companies developing CTSS inhibitors.