{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T23:32:36Z","timestamp":1783035156141,"version":"3.54.6"},"reference-count":79,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"Australian National Health and Medical Research Council","doi-asserted-by":"publisher","award":["NHMRC_APP1188987"],"award-info":[{"award-number":["NHMRC_APP1188987"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rebecca L. Cooper Foundation","award":["NHMRC_APP1188987"],"award-info":[{"award-number":["NHMRC_APP1188987"]}]},{"name":"Cystic Fibrosis Australia","award":["NHMRC_APP1188987"],"award-info":[{"award-number":["NHMRC_APP1188987"]}]},{"name":"Sydney Children Hospital Network Foundation","award":["NHMRC_APP1188987"],"award-info":[{"award-number":["NHMRC_APP1188987"]}]},{"name":"Luminesce Alliance Research","award":["NHMRC_APP1188987"],"award-info":[{"award-number":["NHMRC_APP1188987"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Localized and chronic hypoxia of airway mucosa is a common feature of progressive respiratory diseases, including cystic fibrosis (CF). However, the impact of prolonged hypoxia on airway stem cell function and differentiated epithelium is not well elucidated. Acute hypoxia alters the transcription and translation of many genes, including the CF transmembrane conductance regulator (CFTR). CFTR-targeted therapies (modulators) have not been investigated in vitro under chronic hypoxic conditions found in CF airways in vivo. Nasal epithelial cells (hNECs) derived from eight CF and three non-CF participants were expanded and differentiated at the air\u2013liquid interface (26\u201330 days) at ambient and 2% oxygen tension (hypoxia). Morphology, global proteomics (LC-MS\/MS) and function (barrier integrity, cilia motility and ion transport) of basal stem cells and differentiated cultures were assessed. hNECs expanded at chronic hypoxia, demonstrating epithelial cobblestone morphology and a similar proliferation rate to hNECs expanded at normoxia. Hypoxia-inducible proteins and pathways in stem cells and differentiated cultures were identified. Despite the stem cells\u2019 plasticity and adaptation to chronic hypoxia, the differentiated epithelium was significantly thinner with reduced barrier integrity. Stem cell lineage commitment shifted to a more secretory epithelial phenotype. Motile cilia abundance, length, beat frequency and coordination were significantly negatively modulated. Chronic hypoxia reduces the activity of epithelial sodium and CFTR ion channels. CFTR modulator drug response was diminished. Our findings shed light on the molecular pathophysiology of hypoxia and its implications in CF. Targeting hypoxia can be a strategy to augment mucosal function and may provide a means to enhance the efficacy of CFTR modulators.<\/jats:p>","DOI":"10.3390\/ijms24076475","type":"journal-article","created":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T03:17:35Z","timestamp":1680146255000},"page":"6475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Molecular and Functional Characteristics of Airway Epithelium under Chronic Hypoxia"],"prefix":"10.3390","volume":"24","author":[{"given":"Sharon L.","family":"Wong","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8391-506X","authenticated-orcid":false,"given":"Egi","family":"Kardia","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-9080","authenticated-orcid":false,"given":"Abhishek","family":"Vijayan","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bala","family":"Umashankar","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elvis","family":"Pandzic","sequence":"additional","affiliation":[{"name":"Katharina Gaus Light Microscopy Facility, Mark Wainwright Analytical Centre, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3657-4092","authenticated-orcid":false,"given":"Ling","family":"Zhong","sequence":"additional","affiliation":[{"name":"Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Jaffe","sequence":"additional","affiliation":[{"name":"Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Department of Respiratory Medicine, Sydney Children\u2019s Hospital, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1144-5411","authenticated-orcid":false,"given":"Shafagh A.","family":"Waters","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Molecular and Integrative Cystic Fibrosis Research Centre (miCF_RC), University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW 2052, Australia"},{"name":"Department of Respiratory Medicine, Sydney Children\u2019s Hospital, Sydney, NSW 2052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3389\/fphar.2018.01429","article-title":"Human Primary 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