TY - JOUR
T1 - Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma
AU - Yarova, Polina L.
AU - Stewart, Alecia L.
AU - Sathish, Venkatachalem
AU - Britt, Rodney D.
AU - Thompson, Michael A.
AU - Lowe, Alexander P.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 - Ward, Jeremy P.T.
AU - Kemp, Paul J.
AU - Pabelick, Christina M.
AU - Prakash, Y. S.
AU - Riccardi, Daniela
PY - 2015/4/22
Y1 - 2015/4/22
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 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aaa0282
DO - 10.1126/scitranslmed.aaa0282
M3 - Article
C2 - 25904744
AN - SCOPUS:85016649721
SN - 1946-6234
VL - 7
SP - 284ra58
JO - Science translational medicine
JF - Science translational medicine
IS - 284
ER -