TY - JOUR
T1 - Upregulation of airway smooth muscle calcium-sensing receptor by lowmolecular- weight hyaluronan
AU - Lazrak, Ahmed
AU - Yu, Zhihong
AU - Doran, Stephen
AU - Jian, Ming Yuan
AU - Creighton, Judy
AU - Laube, Mandy
AU - Garantziotis, Stavros
AU - Prakash, Y. S.
AU - Matalon, Sadis
N1 - Funding Information:
This work was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Environmental Health Sciences (NIEHS) (Grants 5UO1 ES026458 03, 3UO1 ES026458 03S1, and 5UO1 ES027697 02) to S. Matalon, the National Heart, Lung and Blood Institute (NHLBI) (Grants 2R01 HL056470-18 and 1R01 HL138402-03) to Y. S. Prakash. S. Garantziotis is supported by the Division of Intramural Research (NIEHS Grant ZIA ES102605).
Publisher Copyright:
© 2020 American Physiological Society. All rights reserved.
PY - 2020
Y1 - 2020
N2 - We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization (Vm Air: 62 ± 3 mV; 3 h post Br2:-45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.
AB - We investigated the mechanisms involved in the development of airway hyperresponsiveness (AHR) following exposure of mice to halogens. Male mice (C57BL/6; 20-25 g) exposed to either bromine (Br2) or Cl2 (600 or 400 ppm, respectively, for 30 min) developed AHR 24 h after exposure. Nifedipine (5 mg/kg body wt; an L-type calcium channel blocker), administered subcutaneously after Br2 or Cl2 exposure, produced higher AHR compared with Br2 or Cl2 alone. In contrast, diltiazem (5 mg/kg body wt; a nondihydropyridine L-type calcium channel blocker) decreased AHR to control (air) values. Exposure of immortalized human airway smooth muscle cells (hASMC) to Br2 resulted in membrane potential depolarization (Vm Air: 62 ± 3 mV; 3 h post Br2:-45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca2+]i, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br2 and nifedipine-induced Vm depolarization and [Ca2+]i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br2 reversed the effects of Br2 and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br2, caused Vm depolarization, [Ca2+]i increase, and Ca-SR expression to a similar extent as exposure to Br2 and Cl2. The addition of HMW-HA to cells or mice exposed to Br2, Cl2, or LMW-HA reversed these effects in vitro and improved AHR in vivo. We conclude that detrimental effects of halogen exposure on AHR are mediated via activation of the Ca-SR by LMW-HA.
KW - Airway hyperresponsiveness
KW - Calcium-sensing receptor
KW - Diltiazem
KW - Halogens
KW - Human airway smooth muscle cells
KW - Membrane potential
KW - Nifedipine
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U2 - 10.1152/AJPLUNG.00429.2019
DO - 10.1152/AJPLUNG.00429.2019
M3 - Article
C2 - 31913654
AN - SCOPUS:85080843152
VL - 318
SP - L459-L471
JO - American Journal of Physiology
JF - American Journal of Physiology
SN - 1040-0605
IS - 3
ER -