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P4 Establishing A Role For Trpv1 On Sensory Nerves In Copd Associated Chronic Cough
  1. MA Wortley1,
  2. SA Maher1,
  3. SJ Bonvini1,
  4. ED Dubuis1,
  5. J Nasra1,
  6. K Holt2,
  7. R Dockry2,
  8. S Sen2,
  9. D Singh2,
  10. JA Smith2,
  11. P Round3,
  12. S Gilbert3,
  13. V Marchant3,
  14. J Ford3,
  15. MA Birrell1,
  16. MG Belvisi1
  1. 1National Heart and Lung Institute, Imperial College, London, UK
  2. 2University of Manchester, University Hospital of South Manchester, Manchester, UK
  3. 3Ario Pharma Limited, Cambridge, UK

Abstract

Background An increase in cough reflex sensitivity to capsaicin in COPD has been described in some studies, suggesting a role for TRPV1 in the disease phenotype. We utilised a guinea-pig cigarette-smoke (CS) exposure COPD model to investigate an enhanced cough phenotype, and evaluate the role of TRPV1 using a novel clinical-ready inhibitor, XEN-D0501.1 Furthermore, we confirmed enhanced cough responses in COPD patients using a dose-response capsaicin challenge to determine EMax.

Methods Guinea-pigs were exposed to air/cigarette smoke (CS) for 1 h, twice daily, for 8 days. Coughs evoked by aerosolised capsaicin (30 μM), depolarisation of isolated vagus nerve tissue induced by capsaicin (1 μM), or increases in intracellular calcium [Ca2+]i to capsaicin (1 μM) in airway-terminating (i.n. DiI stained) jugular and nodose neurons were evaluated. Vagus nerve was obtained from human non-smoker/smoker subjects for similar assessment. Coughs evoked by capsaicin (4 inhalations, 0.49–1000 µM) were recorded in COPD and compared with healthy controls.

Results Capsaicin-evoked cough was increased in COPD patients (Fig.1A) and in CS-exposed guinea-pigs (Fig.1B) compared to controls. Capsaicin induced greater depolarisation in nerve tissue from CS-exposed guinea-pigs, and in human vagus nerves from smokers, compared to controls. Capsaicin also induced greater [Ca2+]i increases in airway-terminating jugular and nodose (which are normally capsaicin-unresponsive) neurons from CS-exposed guinea-pigs. XEN-D0501 (i.p. 1 h before cough recording) almost completely inhibited the cough response to capsaicin in both air- and CS-exposed guinea-pigs (Fig.1B).

Conclusions CS-exposure evoked increased cough to capsaicin in guinea-pigs, mimicking the enhanced cough phenotype observed in COPD patients. This was paralleled by enhanced capsaicin responses in isolated vagus nerves and airway neurons from CS-exposed guinea-pigs and in human vagus from smokers suggesting the enhanced cough phenotype is due to increased TRPV1-mediated sensory nerve responsiveness. Inhibition of the CS-enhanced cough response by XEN-D0501 further implicated a role for TRPV1. This data, together with the finding that TRPV1 KO mice display less inflammation in a similar pre-clinical model of CS-exposure2, indicates the potential utility of TRPV1 antagonists in the treatment of COPD, which is currently being evaluated in an ongoing COPD clinical trial.

References

  1. Round. Br J Clin Pharmacol. 2011;72:921–931

  2. Baxter ATS. 2014;A2079

Abstract P4 Figure 1

(A) Human coughs to capsaicin — healthy controls; n = 15, median age 56 (IQR 39–60) 5 females, mean FEV1 109.5% (±17.0). CDPD patient: n = 15, median age 69 (64–72),5 female, mean FEV1 58% (±11,2), p < 0.001 (General Estimating Equations. (B)Guinea-pig coughs to capsaicin (30 μM);*p < 0.05 compared to Veh control (Kruskal-Wallis with Dunn’s post-test) n = 8.

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