Evaluation of protease activated receptor 2 (PAR2) as a novel therapeutic target for chronic obstructive pulmonary disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a progressive and highly debilitating lung condition now reported as being the third leading cause of death worldwide.The disease has no cure and is characterised by the presence of chronic bronchitis and emphysema.
Protease activated receptor 2 (PAR2) is a G-protein coupled receptor which has been shown to have a role in inflammatory disease pathology. The receptor has a unique mode of activation involving the cleavage of the N-terminal by specific serine proteases to reveal a tethered ligand which binds to extracellular loop two of the receptor causing cell signalling. Once activated, PAR2 will regulate the secretion of pro-inflammatory mediators, such as interleukin 6 (IL-6) and IL-8. While the role of PAR2 in COPD pathogenesis has been relatively underexplored, preliminary studies from our group have shown the receptor to be expressed in human bronchial epithelial cells (HBEC) from normal and COPD (or diseased) lung (DHBEC). The COPD lung is a rich source of proteases, with many of the serine proteases present, such as mast cell tryptase, neutrophil elastase and matriptase able to cleave PAR2, potentially driving inflammation. Using normal HBEC and the PAR2 activating protease, matriptase, we have generated an in vitro model reflective of the COPD lung environment. We have shown increased secretion of the inflammatory cytokines, IL-6 and IL-8, with increasing concentrations of matriptase (Figure 1), suggesting a role for PAR2 in this process. In addition to driving inflammation, PAR2 has also been reported as being able to ‘crosstalk’ with innate pathogen sensing receptors, namely toll-like receptor (TLR) 2, 3 and 4. COPD patients are susceptible to both viral and bacterial infection, with non-typeable Haemophilus Influenzae and Streptococcus pneumoniae most commonly reported and sensed via TLR2/3 and TLR4 respectively (expressed on lung epithelial cells). We hypothesise that a novel molecular axis linking PAR2 / inflammation and infection exists in bronchial epithelial cells and that PAR2 targeted treatment may be an attractive therapeutic approach in reducing COPD inflammation linked to proteases and infection

Chronic obstructive pulmonary disease (COPD) is a debilitating and life limiting lung condition, characterised by the presence of emphysema (destruction of the small air sacs within the lung involved in absorbing oxygen) and chronic bronchitis (inflammation of the bronchi). Our group has recently found that a protein called proteinase activated receptor 2 (PAR2), is expressed by human bronchial epithelial (lining) cells (HBEC). This receptor can be activated by specialised proteins called 'proteases', many of which are found in the COPD lung. Interestingly, PAR2 can also interact with other receptors known as toll-like receptors (TLRs), which are involved in the sensing of infection and drive inflammation. Together this suggests a role for PAR2 in inflammation and infection driven exacerbations in the COPD lung. The aim of this study is to evaluate PAR2 as a potential therapeutic target for the treatment of COPD. HBECs will be stimulated with a range of PAR2 activating proteases (found in the COPD lung environment) or TLR activators (to mimic infection), in the presence or absence of PAR2 activity (using chemical inhibitors or gene disruption). The impact on downstream parameters associated with COPD lung pathology will be investigated. This work will improve our current understanding of PAR2 in COPD inflammation, with the potential to inform future targeted therapy.