1. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma.
- Author
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Yarova PL, Stewart AL, Sathish V, Britt RD Jr, Thompson MA, P Lowe AP, 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, T Ward JP, Kemp PJ, Pabelick CM, Prakash YS, and Riccardi D more...
- Subjects
- Allergens chemistry, Animals, Asthma metabolism, Biopsy, Bronchi metabolism, Bronchi pathology, Bronchoalveolar Lavage Fluid, Bronchoconstriction, Cations, HEK293 Cells, Homeostasis, Humans, Inflammation pathology, Male, Mice, Mice, Inbred BALB C, Phosphorylation, p38 Mitogen-Activated Protein Kinases metabolism, Asthma pathology, Asthma physiopathology, Bronchial Hyperreactivity metabolism, Hypersensitivity pathology, Receptors, Calcium-Sensing antagonists & inhibitors
- 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 allergen-sensitized 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., (Copyright © 2015, American Association for the Advancement of Science.) more...
- Published
- 2015
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