The TRPV4 channel is a member of the Transient Receptor Potential family of ion channels and is known to be expressed on airway smooth muscle, macrophages and epithelial cells within the lung. Whilst it has been reported that TRPV4 is present on sensory nerves, its role in modulating the function of airway sensory nerves and the cough reflex remains unexplored. The aim of this thesis was therefore to determine a role for TRPV4 in sensory nerve activity and the cough reflex.
Using an in vitro model of vagal sensory nerve activation and an in vivo guinea pig cough model, it was established that activation of TRPV4 by selective ligands activates airway sensory nerves and cause cough. Calcium imaging of isolated neurons and airway single fibre recordings determined that this was through activation of a different population of nerve fibres than those activated by TRPV1 and TRPA1 ligands, which are both known to activate sensory nerves and cause cough.
Calcium flux and fibre firing demonstrated a delay prior to activation by a TRPV4 agonist, suggesting an indirect mechanism of action. Activation of TRPV4 has been linked to ATP release in several cell types, and therefore it was hypothesised that activation of TRPV4 on the nerves leads to ATP release and subsequently activation of airway sensory nerves. The purine receptor P2X3, which is activated by ATP, is expressed on airway sensory nerves, and a selective P2X1/3 agonist caused depolarisation of the vagus nerve and firing of Aδ single fibres in vivo. Further, TRPV4 induced activation of sensory nerves in vitro and cough in vivo was inhibited following the administration of a selective P2X3 antagonist.
This data would suggest that the activation of airway sensory nerves by TRPV4 ligands causes ATP release which then activates P2X3 possibly present on the same subset of sensory nerves, to cause cough. The work within my thesis has therefore uncovered TRPV4 as a modulator of airway sensory nerves and associated functions such as cough, which exerts its actions via a novel mechanism of action and as such is a good candidate for possible anti-tussive therapies.