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Lookup NU author(s): Dr Polina YarovaORCiD
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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.
Author(s): Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, Lowe APP, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ, Ward JPT, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D
Publication type: Article
Publication status: Published
Journal: Science Translational Medicine
Year: 2015
Volume: 7
Issue: 284
Print publication date: 22/04/2015
Acceptance date: 24/02/2015
ISSN (print): 1946-6234
ISSN (electronic): 1946-6242
Publisher: American Association for the Advancement of Science
URL: https://doi.org/10.1126/scitranslmed.aaa0282
DOI: 10.1126/scitranslmed.aaa0282
PubMed id: 25904744
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