The role of the ion channel TRPV4 in the Late Asthmatic Response

Abstract

In some patients, asthma is thought to be an atopic disease whereby exposure to allergens provokes symptoms. In fact, allergen inhalation can lead to a prolonged episode of airway narrowing named the late asthmatic response (LAR). Although it is a relevant clinical endpoint, the mechanisms driving it remain unclear. Evidence suggests that nerves could be involved, with allergen challenge resulting in the activation of airway sensory nerves within the vagus nerve and a subsequent reflex bronchospasm. This thesis investigated if the TRPV4 ion channel, a known activator of sensory nerves, could be a driver of the LAR. The ability of TRPV4 to stimulate airway sensory nerves was studied in Brown Norway rats. A TRPV4 agonist depolarised rat vagal nerves and this was inhibited by TRPV4 and P2X3-P2X2/3 antagonists, suggesting that TRPV4 signalling induces the release of ATP which stimulates P2X3-P2X2/3 receptors on the neurons. Therefore, further studies interrogated whether this TRPV4-P2X3 nerve axis could be driving the LAR. Accordingly, both TRPV4 and P2X3-P2X2/3 antagonists inhibited the LAR induced by ovalbumin (OVA) in Brown Norway rats, suggesting a role for the TRPV4-P2X3 axis in experimental LAR. Seeing these results, the mechanism leading to TRPV4 activation was investigated. PAR2 receptors, which are activated by proteases released upon allergen challenge, were considered as promising TRPV4 activators. Indeed, a PAR2 agonist depolarised rat vagal nerves and this was blocked by PAR2, TRPV4 and P2X3-P2X2/3 antagonists. However, two PAR2 antagonists did not reduce the LAR in the rat OVA model, suggesting that PAR2 receptors may not be involved in this model. Overall, these data suggest that the TRPV4-P2X3 axis could play a role in the LAR by activating airway sensory nerves. This thesis highlights that investigating receptors on airway sensory nerves could help to develop asthma therapies targeting alternative mechanisms than immune pathways.Open Acces