scholarly journals Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan

2020 ◽  
Vol 318 (3) ◽  
pp. L459-L471 ◽  
Author(s):  
Ahmed Lazrak ◽  
Zhihong Yu ◽  
Stephen Doran ◽  
Ming-Yuan Jian ◽  
Judy Creighton ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Smooth Muscle ◽  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Airway Smooth Muscle ◽  
Channel Blocker ◽  
Airway Smooth Muscle Cells ◽  
Low Molecular Weight ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

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.

MAGNESIUM SULFATE RESEMBLES A CALCIUM CHANNEL BLOCKER IN AIRWAY SMOOTH MUSCLE

1988 ◽  
Vol 69 (3A) ◽  
pp. A699-A699
Author(s):  
K. S. Lindeman ◽  
C. A. Hirshman ◽  
A. N. Freed
Keyword(s):  
Smooth Muscle ◽  
Calcium Channel ◽  
Magnesium Sulfate ◽  
Calcium Channel Blocker ◽  
Airway Smooth Muscle ◽  
Channel Blocker

Dihydropyridine-sensitive single calcium channels in airway smooth muscle cells

1990 ◽  
Vol 259 (6) ◽  
pp. L468-L480 ◽  
Author(s):  
J. F. Worley ◽  
M. I. Kotlikoff
Keyword(s):  
Smooth Muscle ◽  
Calcium Channels ◽  
Smooth Muscle Cells ◽  
Calcium Channel ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Membrane Depolarization ◽  
Airway Smooth Muscle Cells ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

We have identified and characterized single voltage-dependent calcium channels in both acutely dissociated rat bronchial and cultured human tracheobronchial smooth muscle cells using the patch-clamp technique. In both cell types, on-cell membrane patches displayed unitary currents selective for barium ions and exhibited one conductance level (21–26 pS), and the open state probability was increased by membrane depolarization. Unitary barium currents were enhanced by the calcium channel selective agonist, BAY R 5417, and inhibited by the dihydropyridine calcium channel antagonist, nisoldipine (apparent inhibition constant less than 100 nM). Moreover, the degree of nisoldipine inhibition of the rat bronchial smooth muscle channels was increased with membrane depolarization in a manner consistent with the drug interacting with highest affinity to the inactivated channel state. In addition, the sensitivity to BAY R 5417 augmentation and nisoldipine inhibition of depolarization-induced tonic force of intact rat bronchial ring segments was in close agreement to the single channel results. Thus these data suggest that activation of voltage-dependent calcium channels can influence airway contraction and that dihydropyridines may be effective modulators of depolarization-induced increases in bronchial tone. We conclude that both rat and human airway smooth muscle cells have high-conductance voltage-dependent calcium channels that interact in a predictable manner with dihydropyridines and are similar to voltage-dependent calcium channels observed in other smooth muscle cells.

scholarly journals Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury

2015 ◽  
Vol 308 (9) ◽  
pp. L891-L903 ◽  
Author(s):  
Ahmed Lazrak ◽  
Judy Creighton ◽  
Zhihong Yu ◽  
Svetlana Komarova ◽  
Stephen F. Doran ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Smooth Muscle ◽  
Lung Injury ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Lavage Fluid ◽  
Airway Smooth Muscle Cells ◽  
Intratracheal Administration ◽  
Epithelial Lining Fluid ◽  
Intracellular Ca

Chlorine (Cl2) inhalation induces severe oxidative lung injury and airway hyperresponsiveness (AHR) that lead to asthmalike symptoms. When inhaled, Cl2 reacts with epithelial lining fluid, forming by-products that damage hyaluronan, a constituent of the extracellular matrix, causing the release of low-molecular-weight fragments (L-HA, <300 kDa), which initiate a series of proinflammatory events. Cl2 (400 ppm, 30 min) exposure to mice caused an increase of L-HA and its binding partner, inter-α-trypsin-inhibitor (IαI), in the bronchoalveolar lavage fluid. Airway resistance following methacholine challenge was increased 24 h post-Cl2 exposure. Intratracheal administration of high-molecular-weight hyaluronan (H-HA) or an antibody against IαI post-Cl2 exposure decreased AHR. Exposure of human airway smooth muscle (HASM) cells to Cl2 (100 ppm, 10 min) or incubation with Cl2-exposed H-HA (which fragments it to L-HA) increased membrane potential depolarization, intracellular Ca2+, and RhoA activation. Inhibition of RhoA, chelation of intracellular Ca2+, blockade of cation channels, as well as postexposure addition of H-HA, reversed membrane depolarization in HASM cells. We propose a paradigm in which oxidative lung injury generates reactive species and L-HA that activates RhoA and Ca2+ channels of airway smooth muscle cells, increasing their contractility and thus causing AHR.

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