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A7411 - Oestradiol Triggers Airway Sensory Nerve Activation Via The TRPM3 - P2X2/3 Ion Channel Axis
Author Block: S. J. Bonvini, M. A. Wortley, J. J. Adcock, E. Dubuis, J. Bolaji, S. D'Sa, J. Ma, M. A. Birrell, M. G. Belvisi; Respiratory Pharmacology, Imperial College, London, United Kingdom.
Rationale: There is a growing body of evidence to suggest that women are consistently over represented in chronic cough clinics1. Furthermore, healthy females and those with atopic and non-atopic asthma exhibit an exaggerated capsaicin-evoked cough, indicative of neuronal dysfunction, compared to males in equivalent groups2. Based on these observations, we hypothesised that a hormonal mechanism could be involved, so our aim was to investigate if, and how, oestradiol (the primary sex hormone and main oestrogen found in women) could activate airway sensory nerves. Methods: We utilised in vitro sensory nerve (vagus) tissue and primary airway neurons harvested from guinea pigs (and for key experiments, vagal tissue from human donor lungs) alongside in vivo electrophysiology and cough recordings. Results: In vivo, β-oestradiol evoked cough in conscious unrestrained guinea-pigs and caused action potential firing in both C and Aδ fibres which was inhibited by the non-selective oestrogen receptor antagonist ICI 182780. In vitro, β-oestradiol caused a concentration dependent depolarisation (indicative of sensory nerve activation) of the isolated guinea pig vagus which was significantly inhibited (92.7±4.5%) by ICI 182780 and also by the selective G-Protein Coupled Estrogen Receptor (GPER) antagonist G36 (63.3±3.1%). Furthermore, single cell RT-PCR analysis of airway specific ganglia neurons indicated that GPER was expressed on airway specific nodose and jugular ganglia. To determine the mechanism of action a pharmacological approach was adopted utilising a number of ion channel antagonists and the isolated vagus nerve assay. The data indicated that the response initiated by β-oestradiol involved the TRPM3-P2X2/3 axis3. Key translational data was obtained using human vagal tissue. Additionally, we showed that GPER was co-expressed with TRPM3 and P2X2/3 ion channels on airway specific neurons. Conclusions: These data may help to explain the increased cough reflex sensitivity seen in females compared to males which was most pronounced in non-atopic asthmatic females compared to atopic females and healthy volunteers2. These observations highlight a role for hormonal mechanisms in neuronal dysfunction and, in particular, the TRPM3-P2X2/3 pathway in the β-oestradiol evoked activation of airway sensory nerves following the activation of ER receptors. Whilst further investigation is required, this data may help to explain the higher number of females attending chronic cough clinics and possible interventional strategies which could be employed in susceptible patient groups. 1. Kelsall et al Thorax 2009 393-8 2. Satia et al JACI 2017 771-779 3. Bonvini et al AJRCCM 2017 A7047