{"doi":"10.1152/ajplung.00429.2019","title":"Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan","abstract":"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 (Br 2 ) or Cl 2 (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 2 or Cl 2 exposure, produced higher AHR compared with Br 2 or Cl 2 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 2 resulted in membrane potential depolarization ( V m Air: 62 ± 3 mV; 3 h post Br 2 :−45 ± 5 mV; means ± 1 SE; P < 0.001), increased intracellular [Ca 2+ ] i , and increased expression of the calcium-sensing receptor (Ca-SR) protein. Treatment of hASMC with a siRNA against Ca-SR significantly inhibited the Br 2 and nifedipine-induced V m depolarization and [Ca 2+ ] i increase. Intranasal administration of an antagonist to Ca-SR in mice postexposure to Br 2 reversed the effects of Br 2 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 2 , caused V m depolarization, [Ca 2+ ] i increase, and Ca-SR expression to a similar extent as exposure to Br 2 and Cl 2 . The addition of HMW-HA to cells or mice exposed to Br 2 , Cl 2 , 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.","journal":"American Journal of Physiology-Lung Cellular and Molecular Physiology","year":2020,"id":77736,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9633,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":236993,"name":"Zhihong Yu","orcid":"0000-0001-8304-1833","position":1,"is_corresponding":false},{"id":382560,"name":"Stephen Doran","orcid":"0000-0002-9236-5407","position":2,"is_corresponding":false},{"id":384028,"name":"Ming‐Yuan Jian","orcid":null,"position":3,"is_corresponding":false},{"id":405862,"name":"Judy Creighton","orcid":null,"position":4,"is_corresponding":false},{"id":404776,"name":"Mandy Laube","orcid":"0000-0002-7180-2858","position":5,"is_corresponding":false},{"id":266862,"name":"Stavros Garantziotis","orcid":"0000-0003-4007-375X","position":6,"is_corresponding":false},{"id":245519,"name":"Y. S. Prakash","orcid":"0000-0002-2968-224X","position":7,"is_corresponding":false},{"id":382562,"name":"Sadis Matalon","orcid":"0000-0003-0683-3700","position":8,"is_corresponding":false},{"id":404775,"name":"Ahmed Lazrak","orcid":"0000-0002-4127-1937","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-18T21:49:16.197289Z","pmid":"31913654","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}