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Airway hyperresponsiveness results from enhanced airway smooth muscle (ASM) contraction potentially under the control of an epithelium\u2010derived relaxing factor (EpDRF). However, relatively rare is known about EpDRF. We aimed to elucidate the role of epithelium\u2010derived stanniocalcin\u20101 (STC1) on AHR and ASM contraction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Stanniocalcin\u20101 levels in the serum of asthmatic patients and healthy volunteers and in bronchoalveolar lavage fluid (BALF) from ovalbumin (OVA)\u2010challenged mice were measured by ELISA. The effects of exogenous STC1 on AHR and on inflammation were examined in mice. IL\u201013 modulation of STC1 mRNA and protein levels was studied in human bronchial epithelial cell lines (16HBE). The function of STC1 on Ca<jats:sup>2+<\/jats:sup> influx and ASM contraction was examined <jats:italic>ex vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Serum STC1 was decreased in asthma (<jats:italic>n<\/jats:italic>\u00a0=\u00a093) compared with healthy volunteers (1071\u00a0\u00b1\u00a030.4 vs 1414\u00a0\u00b1\u00a075.1\u00a0pg\/ml, <jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001, <jats:italic>n<\/jats:italic>\u00a0=\u00a023) and correlated with asthma control (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0270), lung function (FEV1, <jats:italic>p<\/jats:italic>\u00a0=\u00a00.0130), and serum IL\u201013 levels (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.0009). Treatment of ten asthmatic subjects with inhaled corticosteroids\/long\u2010acting beta2\u2010agonists (ICS\/LABA) for 1\u00a0year enhanced STC1 expression which correlated with improved asthma control (<jats:italic>p<\/jats:italic>\u00a0=\u00a00.022). STC1 was mainly expressed in bronchial epithelium and intranasal administration of recombinant human STC1 (rhSTC1) reduced AHR and inflammation in mice. IL\u201013 suppressed STC1 release from 16HBE, whereas rhSTC1 blocked store\u2010operated Ca<jats:sup>2+<\/jats:sup> entry (SOCE) by suppressing stromal interaction molecule 1 (STIM1) and further inhibited ASM cell contractility by suppressing Ca<jats:sup>2+<\/jats:sup>\u2010dependent myosin light chain (MLC) phosphorylation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data indicate that STC1 deficiency in asthmatic airways promotes STIM1 hyperactivity, enhanced ASM contraction, and AHR. STC1 may be a candidate EpDRF.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.14727","type":"journal-article","created":{"date-parts":[[2020,12,31]],"date-time":"2020-12-31T01:08:44Z","timestamp":1609376924000},"page":"2475-2487","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Epithelial expression and role of secreted STC1 on asthma airway hyperresponsiveness through calcium channel modulation"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1455-7358","authenticated-orcid":false,"given":"Jiayan","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Respiratory &amp; Critical Care Medicine The First Affiliated Hospital of Nanjing Medical University  Nanjing China"},{"name":"Department of Respiratory &amp; Critical Care Medicine Northern Jiangsu People's Hospital  Yangzhou 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Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingwei","family":"Ou","sequence":"additional","affiliation":[{"name":"Department of Respiratory &amp; Critical Care Medicine The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhui","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Respiratory &amp; Critical Care Medicine The First Affiliated Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9391-6573","authenticated-orcid":false,"given":"Xiaoyi","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Respiratory &amp; Critical Care Medicine Nanjing Jiangning People's Hospital  Nanjing 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