TRPV4 has emerged as a novel therapeutic target in chronic respiratory disease. TRPV4-induced ATP release through Pannexin-1 channels and subsequent activation of P2X receptors has been implicated in chronic lung disease. We have recently demonstrated that TRPV4 deficiency or pharmacologic inhibition of TRPV4 abolished the development of allergic airway inflammation (AAI), airway hyper-responsiveness (AHR) or late asthmatic response (LAR) in rodent models of allergic airway disease (AAD). The aim of this thesis was to elucidate TRPV4 signalling cascade in AAD and identify key cells driving the cascade together with upstream and downstream targets.
Using a murine house dust mite (HDM) model of AAD, CD4+ T cells and dendritic cells were identified as the initiators of immune responses to HDM and proposed as drivers of TRPV4 axis due to their Trpv4 and Panx-1 expression. Those cells expressed P2rx1, P2rx4 and P2rx7 which were dysregulated upon HDM challenge, suggesting their role downstream of TRPV4. P2X7 but not P2X4 or P2X1 deficiency ameliorated AAI upon HDM challenge, however none of the receptors modulated HDM-induced AHR. PAR2 was investigated as a potential mechanism of TRPV4 activation as HDM challenge was associated with dysregulated PAR2 ligand activity and immune cell Par2 expression. While PAR2 deficiency ameliorated HDM-induced AAI, but not AHR, a PAR2 blocking antibody MEDI2344 offered no protection against HDM-induced AAD. Lastly, to confirm the preliminary observations, selective TRPV4 antagonists were tested in rodent models of AAD and were associated with a trend towards reduced AAI, but were inefficacious in AHR or LAR, respectively.
In conclusion, this thesis demonstrated a lack of role of TRPV4 in responses evoked by allergen challenge but rather implicated PAR2/TRPV4 signalling in allergen sensitisation. However, further work is needed to elucidate the role of TRPV4-ATP-P2X axis in other asthma phenotypes and associated symptoms such as cough.