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The objective of the current study is to define the electrophysiologic characteristics of hypoxia in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cystic fibrosis bronchoepithelial cells expressing wild\u2010type cystic fibrosis transmembrane conductance regulator (CFTR) and human sinonasal epithelial cells were exposed to 1% or atmospheric O<jats:sub>2<\/jats:sub> for 24\u00a0h. Time\u2010dependent production of cytoplasmic free radicals was measured. Cells were subjected to Ussing chamber and patch clamp technique where CFTR currents were recorded in whole\u2010cell and cell\u2010attached mode for single channel studies. Indices of mucociliary transport (MCT) were measured using micro\u2010optical coherence tomography. In a rabbit hypoxic maxillary sinus model, tissue oxygenation, relative mRNA expression of HIF\u20101\u03b1, pH, sinus potential difference (SPD), and MCT were determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Ussing chamber (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05), whole\u2010cell (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001), and single channel patch\u2010clamp (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001) showed significant inhibition of Cl<jats:sup>\u2212<\/jats:sup> currents in hypoxic cells. Cytoplasmic free radicals showed time\u2010dependent elevation peaking at 4\u00a0h (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001). Airway surface liquid (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001), periciliary liquid (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001), and MCT (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.01) were diminished. Co\u2010incubation with the free radical scavenger glutathione negated the impact of hypoxia on single channel currents and MCT markers. In sinusitis rabbits, mucosa exhibited low tissue oxygenation (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001), increased HIF1\u03b1 mRNA (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.05), reduced pH (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.01), and decreased MCT (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.001). SPD measurements demonstrated markedly diminished transepithelial Cl<jats:sup>\u2212<\/jats:sup> transport (<jats:italic>p<\/jats:italic>\u00a0&lt;\u00a00.0001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Hypoxia induces severe CFTR dysfunction via free radical production causing reduced MCT in vitro and in vivo. Improved oxygenation is critical to reducing the impact of persistent mucociliary dysfunction.<\/jats:p><\/jats:sec>","DOI":"10.1002\/alr.23309","type":"journal-article","created":{"date-parts":[[2023,12,11]],"date-time":"2023-12-11T10:13:24Z","timestamp":1702289604000},"page":"1058-1069","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hypoxia\u2010induced cystic fibrosis transmembrane conductance regulator dysfunction is a universal mechanism underlying reduced mucociliary transport in sinusitis"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5173-8959","authenticated-orcid":false,"given":"Do\u2010Yeon","family":"Cho","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2013Head &amp; Neck Surgery University of Alabama at Birmingham  Birmingham Alabama USA"},{"name":"Gregory Fleming James Cystic Fibrosis Research Center University of Alabama at Birmingham  Birmingham Alabama USA"},{"name":"Division of Otolaryngology Department of Surgery Veteran Affairs Medical Center  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head &amp; Neck Surgery University of Alabama at Birmingham  Birmingham Alabama USA"},{"name":"Gregory Fleming James Cystic Fibrosis Research Center University of Alabama at Birmingham  Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. 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