Cathepsin S inhibition as a treatment for lung inflammation and lung damage in Chronic Lung Disease

The cells lining the upper part of the respiratory tract, called bronchial epithelial cells, play an important role in defending the lung against any foreign particles landing on this surface including bacteria, viruses and smoke particles. However, over time, particularly in individuals who have smoked cigarettes for a long period of their life, constant exposure of bronchial epithelial cells to the particles in cigarette smoke can alter the function of these cells. The cells can start dying more rapidly and can also produce chemicals called cytokines that can cause tissue damage to the airways, a process called inflammation. This can lead to a condition called chronic obstructive pulmonary disease (COPD) which is thought to affect many people worldwide (including the UK) and is now the 3rd leading cause of death worldwide. We have found a way to reduce cells from dying and producing cytokines by inhibiting a protein produced by epithelial cells called 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 learn more about how CTSS can make the lung more inflammatory and lead to increased cell death by looking at the activation of another group of proteins called protease activated receptors (PARs) and chemokines which are known to be activated by CTSS and can increase inflammation. We will also test how well these CTSS inhibitors work in a mouse model of COPD. If we see improvements in mouse lung function, reduced inflammation and a reduction in lung damage in this model this will bode well for taking these CTSS inhibitors forward into future clinical trials in individuals with COPD. The very clear application of this study is in the targeting of CTSS to improve bronchial cell function and reduce the progression of COPD, although there is a potential role for this CTSS-mediated pathway in other disease processes including gastrointestinal and dermatological disorders. In future studies, we will test CTSS inhibitors in clinical trials for COPD, which is a very real possibility as we are set-up in Queen's to carry out such studies in Queen's Belfast as part of the NIHR Respiratory Translational Research Collaboration group.

Chronic inflammation, lung damage and infection are characteristic features of chronic lung diseases such as Chronic Obstructive Pulmonary Disease (COPD). Bronchial epithelial cells play a vital role in protecting the lungs against infectious and other noxious stimuli by mounting a potent innate antimicrobial and inflammatory response on the respiratory tract. However, cigarette smoke is thought to alter bronchial epithelial function following a prolonged period of exposure resulting in an elevated inflammatory response, increased cell death, cell sloughing and reduced capacity to deal with infection. We have shown in preliminary experiments that inhibition of the protease, cathepsin S (CTSS), can reduce the inflammatory response by COPD primary bronchial epithelial cells (PBECs) and reduce cell death/cell shedding in these cells. 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 COPD and identify how CTSS may alter PBEC function by focusing on activation of protease activated receptors and neutrophil chemokine activation. We will also confirm these effects in a model of chronic smoke exposure in which we have previously demonstrated elevated CTSS activity (Doherty D et al, Am J Respir Crit Care Med. 2019, 200:51-62). Novel CTSS inhibitors will be synthesised in this study that can be delivered directly to the lungs of these mice and will be compared to CTSS inhibitors that are systemically delivered. We will assess effects of CTSS inhibition on lung neutrophilic inflammation, lung function and lung damage in these mice in the laboratory of our other co-investigator, Dr Geraghty. The very clear application of this study is in the targeting of CTSS to ameliorate lung inflammation and damage associated with COPD which will be taken forward into further pre-clinical testing with a view to evaluation in clinical trials for COPD.