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

Polina L. Yarova, Alecia L. Stewart, Venkatachalem Sathish, Rodney D. Britt, Michael A. Thompson, Alexander P.P. Lowe, Michelle Freeman, Bharathi Aravamudan, Hirohito Kita, Sarah C. Brennan, Martin Schepelmann, Thomas Davies, Sun Yung, Zakky Cholisoh, Emma J. Kidd, William R. Ford, Kenneth J. Broadley, Katja Rietdorf, Wenhan Chang, Mohd E. Bin KhayatDonald T. Ward, Christopher J. Corrigan, Jeremy P.T. Ward, Paul J. Kemp, Christina M. Pabelick, Y. S. Prakash, Daniela Riccardi

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergensensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyperreactivity in mouse bronchi, and this effect was 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 up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics.

Original languageEnglish (US)
Pages (from-to)284ra58
JournalScience translational medicine
Volume7
Issue number284
DOIs
StatePublished - Apr 22 2015

ASJC Scopus subject areas

  • Medicine(all)

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