Central role for the TRPV4-ATP-P2X3 axis in sensory nerve activation and the late asthmatic response

Abstract

The late asthmatic response (LAR) is a defining symptom of asthma and is regularly used as a model for proof of concept clinical trials with new therapeutic agents, yet the mechanism driving LAR is not fully understood. Recently we have shown using a preclinical model that the LAR involves the following processes: allergen challenge triggering airway sensory nerves which initiate a central reflex event leading to a parasympathetic cholinergic constrictor response (Raemdonck K. et al .Thorax.2012:67:19). We have also shown that activation of the TRPV4-ATP-P2X3 axis can trigger a response in airway Aδ afferent fibres and it is known that ATP levels are increased in the asthmatic airway (Bonvini S.J. et al. JACI.2016). We hypothesised that this axis could be the trigger that engages neuronal reflexes and the subsequent LAR. In a rat model of allergic asthma, antigen challenge triggered a LAR response that was inhibited by two structurally distinct Long Acting Muscarinic Antagonists (LAMA, tiotropium and glycopyrrolate). In naive rats, an inhaled TRPV4 agonist (GSK1016790a) caused a “LAR-like” response which was attenuated by a TRPV4 inhibitor (GSK2193874), a P2X3 inhibitor (AF-353) and a LAMA (glycopyrrolate), suggesting that stimulation of the axis could replicate the LAR. To confirm the role we showed that blockade of TRPV4 or P2X3 attenuated the LAR (74.9% and 88.3%, respectively) in the asthma model. These data suggest that airway sensory nerves can be triggered via a TRPV4-ATP-P2X3 axis to cause the parasympathetic reflex to drive the LAR. Targeting this axis could be a novel and effective treatment for this key feature of asthma and in patients with an allergic asthma phenotype.