Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan.
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.
['Lazrak|Ahmed|A|', 'Yu|Zhihong|Z|', 'Doran|Stephen|S|', 'Jian|Ming-Yuan|MY|', 'Creighton|Judy|J|', 'Laube|Mandy|M|', 'Garantziotis|Stavros|S|0000-0003-4007-375X', 'Prakash|Y S|YS|0000-0002-2968-224X', 'Matalon|Sadis|S|']
D000818:Animals D001966:Bromine D002118:Calcium D002121:Calcium Channel Blockers D002478:Cells, Cultured D002712:Chlorides D006801:Humans D006820:Hyaluronic Acid D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D008970:Molecular Weight D009130:Muscle, Smooth D044169:Receptors, Calcium-Sensing D012130:Respiratory Hypersensitivity D055675:Viscosupplements
calcium-sensing receptor airway hyperresponsiveness halogens nifedipine diltiazem human airway smooth muscle cells membrane potential