ATS 2021 will feature presentations of original research from accepted abstracts. Mini Symposia and Thematic Poster Sessions are abstract based sessions.
Please use the form below to browse scientific abstracts and case reports accepted for ATS 2021. Abstracts presented at the ATS 2021 will be published in the Online Abstract Issue of the American Journal of Respiratory and Critical Care Medicine, Volume 203, May 3, 2021.
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A Novel Mechanism of Action for the NK1 Receptor in Airway Sensory Nerves
Session Title
TP118 - TP118 AIRWAY HYPERRESPONSIVENESS AND INFLAMMATION IN ASTHMA
Abstract
A4511 - A Novel Mechanism of Action for the NK1 Receptor in Airway Sensory Nerves
Author Block: S. J. Bonvini1, J. H. Miles2, P. Flajolet2, M. A. Wortley2, J. J. Adcock1, J. Smith3, M. A. Birrell1, M. G. Belvisi4; 1Bioscience Cough and In Vivo Research and Early Development, AstraZeneca, Gothenburg, Sweden, 2National Heart and Lung Institute, Imperial College London, London, United Kingdom, 3University of Manchester, Manchester, United Kingdom, 4SVP and Head of Research and Early Development, Research and Early Development, Respiratory and Immu, AstraZeneca, Gothenburg, Sweden.
Rationale: Cough is a defensive reflex driven by activation of peripheral airway sensory nerves housed within the vagus nerve. In disease, this response can become excessive, leading to chronic cough where novel, safe and effective therapies are urgently required. A recent study has highlighted that NK1 antagonists may reduce cough frequencies in patients with lung cancer. However, an effect on peripheral nerves has not been fully investigated. Methods: An in vitro grease gap recording system was utilised with vagus nerve tissue from mice, rats guinea pigs and donor human tissue, alongside in vivo afferent fibre firing recording in guinea pigs (GPs). Results: The effect of substance P, as the primary endogenous agonist of the NK1 receptor, was investigated in GP, rat and human vagal nerves where it was shown to cause a concentration dependent increase in depolarisation. Three structurally different, selective NK1 antagonists; CP99994 (300nM), aprepitant (10µM) and RP67580 (1µM) all inhibited the depolarisation induced by a submaximal concentration of substance P, with an NK2 antagonist having no effect. To determine the mechanism by which activation of the NK1 receptor triggers the sensory nerves we used a range of relevant ion channel blockers (Transient Receptor Potential). This data indicated that TRPV1 and TRPA1 ion channels were not involved but the TRPV4 channel plays a key role. This was confirmed using tissue harvested from TRPV4 KO mice and the use of a P2X3 channel blocker (AF-353) (Fig. 1)In vivo in the guinea pig, substance P was shown to activate single afferent Aδ fibres, similarly to the TRPV4 agonist GSK1016790A. Conclusion: These data suggest that the NK1 receptor can play a role in peripheral sensory nerve activation and that this involves the TRPV4/P2X3 axis. Previous studies have indicated that different neuronal phenotypes exist and may contribute to symptoms across chronic lung diseases. These data could suggest a peripheral role for substance P and the NK1 receptor in activating sensory nerves which could be relevant for patients with lung cancer cough but may not be for patients with chronic idiopathic cough where NK1 antagonists have not been shown to inhibit objective cough counts.
Author Block: S. J. Bonvini1, J. H. Miles2, P. Flajolet2, M. A. Wortley2, J. J. Adcock1, J. Smith3, M. A. Birrell1, M. G. Belvisi4; 1Bioscience Cough and In Vivo Research and Early Development, AstraZeneca, Gothenburg, Sweden, 2National Heart and Lung Institute, Imperial College London, London, United Kingdom, 3University of Manchester, Manchester, United Kingdom, 4SVP and Head of Research and Early Development, Research and Early Development, Respiratory and Immu, AstraZeneca, Gothenburg, Sweden.
Rationale: Cough is a defensive reflex driven by activation of peripheral airway sensory nerves housed within the vagus nerve. In disease, this response can become excessive, leading to chronic cough where novel, safe and effective therapies are urgently required. A recent study has highlighted that NK1 antagonists may reduce cough frequencies in patients with lung cancer. However, an effect on peripheral nerves has not been fully investigated. Methods: An in vitro grease gap recording system was utilised with vagus nerve tissue from mice, rats guinea pigs and donor human tissue, alongside in vivo afferent fibre firing recording in guinea pigs (GPs). Results: The effect of substance P, as the primary endogenous agonist of the NK1 receptor, was investigated in GP, rat and human vagal nerves where it was shown to cause a concentration dependent increase in depolarisation. Three structurally different, selective NK1 antagonists; CP99994 (300nM), aprepitant (10µM) and RP67580 (1µM) all inhibited the depolarisation induced by a submaximal concentration of substance P, with an NK2 antagonist having no effect. To determine the mechanism by which activation of the NK1 receptor triggers the sensory nerves we used a range of relevant ion channel blockers (Transient Receptor Potential). This data indicated that TRPV1 and TRPA1 ion channels were not involved but the TRPV4 channel plays a key role. This was confirmed using tissue harvested from TRPV4 KO mice and the use of a P2X3 channel blocker (AF-353) (Fig. 1)In vivo in the guinea pig, substance P was shown to activate single afferent Aδ fibres, similarly to the TRPV4 agonist GSK1016790A. Conclusion: These data suggest that the NK1 receptor can play a role in peripheral sensory nerve activation and that this involves the TRPV4/P2X3 axis. Previous studies have indicated that different neuronal phenotypes exist and may contribute to symptoms across chronic lung diseases. These data could suggest a peripheral role for substance P and the NK1 receptor in activating sensory nerves which could be relevant for patients with lung cancer cough but may not be for patients with chronic idiopathic cough where NK1 antagonists have not been shown to inhibit objective cough counts.
