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

Polina L. Yarova, Alecia L. Stewart, Venkatachalem Sathish, Rodney Jr. 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 Khayat & 7 others Donald T. Ward, Christopher J. Corrigan, Jeremy P. T Ward, Paul J. Kemp, Christina M Pabelick, Y.s. Prakash, Daniela Riccardi

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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.

Original languageEnglish (US)
JournalScience Translational Medicine
Volume7
Issue number284
DOIs
StatePublished - Apr 22 2015

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Calcium-Sensing Receptors
Asthma
Inflammation
Allergens
Smooth Muscle
Eosinophil Cationic Protein
Calcium
Body Fluids
p38 Mitogen-Activated Protein Kinases
Bronchi
Cyclic AMP
Smooth Muscle Myocytes
Cations
Phosphorylation
polycations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. / Yarova, Polina L.; Stewart, Alecia L.; Sathish, Venkatachalem; Britt, Rodney Jr.; Thompson, Michael A.; P Lowe, Alexander P.; Freeman, Michelle; Aravamudan, Bharathi; Kita, Hirohito; Brennan, Sarah C.; Schepelmann, Martin; Davies, Thomas; Yung, Sun; Cholisoh, Zakky; Kidd, Emma J.; Ford, William R.; Broadley, Kenneth J.; Rietdorf, Katja; Chang, Wenhan; Bin Khayat, Mohd E.; Ward, Donald T.; Corrigan, Christopher J.; T Ward, Jeremy P.; Kemp, Paul J.; Pabelick, Christina M; Prakash, Y.s.; Riccardi, Daniela.

In: Science Translational Medicine, Vol. 7, No. 284, 22.04.2015.

Research output: Contribution to journalArticle

Yarova, PL, Stewart, AL, Sathish, V, Britt, RJ, 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 & Riccardi, D 2015, 'Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma', Science Translational Medicine, vol. 7, no. 284. https://doi.org/10.1126/scitranslmed.aaa0282
Yarova, Polina L. ; Stewart, Alecia L. ; Sathish, Venkatachalem ; Britt, Rodney Jr. ; Thompson, Michael A. ; P Lowe, Alexander P. ; Freeman, Michelle ; Aravamudan, Bharathi ; Kita, Hirohito ; Brennan, Sarah C. ; Schepelmann, Martin ; Davies, Thomas ; Yung, Sun ; Cholisoh, Zakky ; Kidd, Emma J. ; Ford, William R. ; Broadley, Kenneth J. ; Rietdorf, Katja ; Chang, Wenhan ; Bin Khayat, Mohd E. ; Ward, Donald T. ; Corrigan, Christopher J. ; T Ward, Jeremy P. ; Kemp, Paul J. ; Pabelick, Christina M ; Prakash, Y.s. ; Riccardi, Daniela. / Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. In: Science Translational Medicine. 2015 ; Vol. 7, No. 284.
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AU - Yarova, Polina L.

AU - Stewart, Alecia L.

AU - Sathish, Venkatachalem

AU - Britt, Rodney Jr.

AU - Thompson, Michael A.

AU - P Lowe, Alexander P.

AU - Freeman, Michelle

AU - Aravamudan, Bharathi

AU - Kita, Hirohito

AU - Brennan, Sarah C.

AU - Schepelmann, Martin

AU - Davies, Thomas

AU - Yung, Sun

AU - Cholisoh, Zakky

AU - Kidd, Emma J.

AU - Ford, William R.

AU - Broadley, Kenneth J.

AU - Rietdorf, Katja

AU - Chang, Wenhan

AU - Bin Khayat, Mohd E.

AU - Ward, Donald T.

AU - Corrigan, Christopher J.

AU - T Ward, Jeremy P.

AU - Kemp, Paul J.

AU - Pabelick, Christina M

AU - Prakash, Y.s.

AU - Riccardi, Daniela

PY - 2015/4/22

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N2 - 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.

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