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

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.

• Authors: Polina L Yarova, Alecia L Stewart, Venkatachalem Sathish, Rodney D Britt Jr, 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 Khayat, Donald T Ward, Christopher J Corrigan, Jeremy P T Ward, Paul J Kemp, Christina M Pabelick, Y S Prakash, Daniela Riccardi
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 284 Pg. 284ra60 (Apr 22 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 25904744 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• Allergens
• Cations
• Receptors, Calcium-Sensing
• p38 Mitogen-Activated Protein Kinases

Topics

• Allergens (chemistry)
• Animals
• Asthma (metabolism, pathology, physiopathology)
• Biopsy
• Bronchi (metabolism, pathology)
• Bronchial Hyperreactivity (metabolism)
• Bronchoalveolar Lavage Fluid
• Bronchoconstriction
• Cations
• HEK293 Cells
• Homeostasis
• Humans
• Hypersensitivity (pathology)
• Inflammation (pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Phosphorylation
• Receptors, Calcium-Sensing (antagonists & inhibitors)
• p38 Mitogen-Activated Protein Kinases (metabolism)