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Browse ATS 2021 Abstracts

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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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Activation of GPR35 Inhibits Airway Sensory Nerves and the Late Asthmatic Response in Preclinical Model Systems

Session Title
TP118 - TP118 AIRWAY HYPERRESPONSIVENESS AND INFLAMMATION IN ASTHMA
Abstract
A4513 - Activation of GPR35 Inhibits Airway Sensory Nerves and the Late Asthmatic Response in Preclinical Model Systems
Author Block: X. Chen1, S. J. Bonvini2, J. Adcock2, A. Brown3, M. A. Birrell2, M. G. Belvisi4; 1Respiratory Pharmacology Group, Division of Airway Disease, NHLI, Imperial College London, London, United Kingdom, 2Cough and In Vivo Bioscience, Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden, 3Sosei Heptares, Granta Park, Cambridge, United Kingdom, 4Research and Early Development, Respiratory and Immunology, Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Rationale: The Late Asthmatic Response (LAR) is a characteristic feature of asthma and has been shown to involve the activation of airway sensory nerves in a preclinical model1. In asthmatics, DiSodium Cromoglycate (DSCG) is known to modulate LAR but its use is limited because of its duration of action evidenced by its pharmacokinetic (PK) profile. Previously, our group has demonstrated that DSCG can inhibit LAR in a model of allergic asthma. Data suggests that this impact is due its ability to reduce sensory nerve firing via the activation of GPR352. Aim: The aim of this work was to confirm the inhibitory role of GPR35 in the model system with a selective agonist. Methods: Profiled a range of selective GPR35 agonist (HTL) in an in vitro sensory nerve system. DMPK assessment of active tools to select candidate for in vivo studies. Confirm effectiveness of tool compound in the lung with an in vivo single fibre recording preparation. Finally, profile the agonist in the in vivo asthma model. Results: The GPR35 agonist (HTL) inhibited vagal nerve depolarisation in vitro; the role of GPR35 was confirmed with a GPR35 antagonist. A DMPK analysis suggested that 0.1 mg/kg HTL (dosed intratracheally) would give sufficient levels to activate GPR35. Indeed, this dose attenuated airway sensory nerve firing in the rat lung. Finally, we were able to demonstrate that HTL could modulate the LAR in the rodent asthma model to a similar degree as DSCG treatment (Figure 1).Conclusion: These data show that activation of GPR35 receptors can attenuate the LAR in a rodent model of asthma. This is further evidence towards understanding the mechanisms by which DSCG alleviates asthmatic symptoms. Furthermore, it highlights GPR35 agonist as a potential new therapy for asthma. Reference: 1. Raemdonck, et al. 2011. Thorax 2. Maher et al. 2015. ERJ
Figure 1: Effect of DSCG and HTL on the LAR in the BN Rat