Calcium-sensing receptor antagonists abrogate airways hyperresponsiveness and inflammation in allergic asthma

Yarova, Polina L., Stewart, Alecia L., Sathish, Venkatachalem, Britt, Rodney D. Jnr., Thompson, Michael A., Lowe, Alexander P. P., Freeman, Michelle, Aravamadun, Bharathi, Kita, Hitohito, Brennan, Sarah C. ORCID: https://orcid.org/0000-0002-8719-4367, Schepelmann, Martin ORCID: https://orcid.org/0000-0002-7017-5426, Davies, Thomas, Yung, Sun, Cholisoh, Zakky, Kidd, Emma J. ORCID: https://orcid.org/0000-0001-5507-1170, Ford, William R. ORCID: https://orcid.org/0000-0002-8792-6169, Broadley, Kenneth J. ORCID: https://orcid.org/0000-0002-3339-2050, Rietdorf, Katja, Chang, Wenham, Bin Khayat, Mohamed E., Ward, Donald T., Corrigan, Christopher J., Ward, Jeremy P. T., Kemp, Paul J. ORCID: https://orcid.org/0000-0003-2773-973X, Pabelick, Christina M., Prakash, Y. S. and Riccardi, Daniela ORCID: https://orcid.org/0000-0002-7322-3163 2015. Calcium-sensing receptor antagonists abrogate airways hyperresponsiveness and inflammation in allergic asthma. Science Translational Medicine 7 (284) , 284ra60. 10.1126/scitranslmed.aaa0282

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Abstract

Airways hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma and are accompanied by increases in certain polycations, such as eosinophil cationic protein, whose levels in body fluids correlate with asthma severity. Here we show that polycations, or elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cAMP breakdown and p38 MAPK phosphorylation in airway smooth muscle (ASM) cells, effects prevented by CaSR antagonists, termed calcilytics. Asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than their healthy counterparts. Polycations induced hyperreactivity in mouse bronchi, effect prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is upregulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Calcilytics may represent a novel, effective asthma therapeutics.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Biosciences
Subjects:	Q Science > QR Microbiology R Medicine > RM Therapeutics. Pharmacology
Publisher:	American Association for the Advancement of Science
ISSN:	1946-6234
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	24 February 2015
Last Modified:	07 Nov 2024 21:00
URI:	https://orca.cardiff.ac.uk/id/eprint/71332

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