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Male mice (C57BL\/6; 20\u201325 g) exposed to either bromine (Br<jats:sub>2<\/jats:sub>) or Cl<jats:sub>2<\/jats:sub>(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 Br<jats:sub>2<\/jats:sub>or Cl<jats:sub>2<\/jats:sub>exposure, produced higher AHR compared with Br<jats:sub>2<\/jats:sub>or Cl<jats:sub>2<\/jats:sub>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 Br<jats:sub>2<\/jats:sub>resulted in membrane potential depolarization ( V<jats:sub>m<\/jats:sub>Air: 62\u2009\u00b1\u20093 mV; 3 h post Br<jats:sub>2<\/jats:sub>:\u221245\u2009\u00b1\u20095 mV; means\u2009\u00b1\u20091 SE; P &lt; 0.001), increased intracellular [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br<jats:sub>2<\/jats:sub>and nifedipine-induced V<jats:sub>m<\/jats:sub>depolarization and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br<jats:sub>2<\/jats:sub>reversed the effects of Br<jats:sub>2<\/jats:sub>and nifedipine on AHR. Incubation of hASMC with low-molecular-weight hyaluronan (LMW-HA), generated by exposing high-molecular-weight hyaluronan (HMW-HA) to Br<jats:sub>2<\/jats:sub>, caused V<jats:sub>m<\/jats:sub>depolarization, [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>increase, and Ca-SR expression to a similar extent as exposure to Br<jats:sub>2<\/jats:sub>and Cl<jats:sub>2<\/jats:sub>. The addition of HMW-HA to cells or mice exposed to Br<jats:sub>2<\/jats:sub>, Cl<jats:sub>2<\/jats:sub>, 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.<\/jats:p>","DOI":"10.1152\/ajplung.00429.2019","type":"journal-article","created":{"date-parts":[[2020,1,8]],"date-time":"2020-01-08T17:46:08Z","timestamp":1578505568000},"page":"L459-L471","source":"Crossref","is-referenced-by-count":19,"title":["Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan"],"prefix":"10.1152","volume":"318","author":[{"given":"Ahmed","family":"Lazrak","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhihong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Doran","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Yuan","family":"Jian","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judy","family":"Creighton","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, Division of Molecular and Translational Biomedicine & Pulmonary Injury Repair Center, University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mandy","family":"Laube","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Neonatology, Leipzig University, Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-375X","authenticated-orcid":false,"given":"Stavros","family":"Garantziotis","sequence":"additional","affiliation":[{"name":"Matrix Biology Group, Immunity, Inflammation, and Disease Laboratory, National Institutes of Health\/National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2968-224X","authenticated-orcid":false,"given":"Y. 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