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The main goal of this review is to point out how the airway epithelium reacts to hypoxic conditions. Cells detect low oxygen levels using molecular mechanisms involving hypoxia-inducible factors (HIFs). In addition, the cells of the airway epithelium appear to overexpress HIFs in hypoxic conditions. HIFs then regulate many aspects of epithelial cell functions. The effects of hypoxia include secretory cell stimulation and hyperplasia, epithelial barrier changes, and ciliogenesis impairment. All the changes can impair mucociliary clearance, exacerbate infection, and promote inflammation leading to damage of airway epithelium and subsequent airway wall remodeling. The modulation of hypoxia regulatory mechanisms may be one of the strategies for the treatment of obstructive respiratory diseases or diseases with mucus hyperproduction.<\/jats:p>","DOI":"10.33549\/physiolres.935436","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T08:42:50Z","timestamp":1732524170000},"page":"S557-S568","source":"Crossref","is-referenced-by-count":2,"title":["Influence of Hypoxia on the Airway Epithelium"],"prefix":"10.33549","author":[{"given":"K","family":"Proch\u00e1zkov\u00e1","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Uhl\u00edk","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. jiri.uhlik@lfmotol.cuni.cz"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19169","published-online":{"date-parts":[[2024,11,25]]},"reference":[{"key":"ref0","doi-asserted-by":"publisher","unstructured":"Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. Journal of Applied Physiology 2000;88:1474-1480. https:\/\/doi.org\/10.1152\/jappl.2000.88.4.1474","DOI":"10.1152\/jappl.2000.88.4.1474"},{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Hsia CCW, Schmitz A, Lambertz M, Perry SF, Maina JN. Evolution of air breathing: oxygen homeostasis and the transitions from water to land and sky. Compr Physiol 2013;3:849-915. https:\/\/doi.org\/10.1002\/cphy.c120003","DOI":"10.1002\/cphy.c120003"},{"key":"ref2","doi-asserted-by":"crossref","unstructured":"Richalet JP. The invention of hypoxia. J Appl Physiol (1985) 2021;130:157315-82. https:\/\/doi.org\/10.1152\/japplphysiol.00936.2020","DOI":"10.1152\/japplphysiol.00936.2020"},{"key":"ref3","doi-asserted-by":"crossref","unstructured":"Sargon MF. Lungs and hypoxia: a review of the literature. Anatomy 2021;15:76-83. https:\/\/doi.org\/10.2399\/ana.21.841001","DOI":"10.2399\/ana.21.841001"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"O\u0161t'\u00e1dal B, Kol\u00e1\u0159 F. Myocardial Hypoxia and Ischemia. In:  Cardiac Ischemia: From Injury to Protection. B O\u0160\u0164\u00c1DAL, F KOL\u00c1\u0158 (eds), Boston, MA, Springer US, 1999, pp 1-44. https:\/\/doi.org\/10.1007\/978-1-4757-3025-8_1, https:\/\/doi.org\/10.1007\/978-1-4757-3025-8_1","DOI":"10.1007\/978-1-4757-3025-8_1"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Genbacev O, Zhou Y, Ludlow JW, Fisher SJ. Regulation of human placental development by oxygen tension. Science 1997;277:1669-1672. https:\/\/doi.org\/10.1126\/science.277.5332.1669","DOI":"10.1126\/science.277.5332.1669"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Wakeland AK, Soncin F, Moretto-Zita M, Chang CW, Horii M, Pizzo D, et al. Hypoxia directs human extravillous trophoblast differentiation in a hypoxia-inducible factor-dependent manner. Am J Pathol 2017;187:767-780. https:\/\/doi.org\/10.1016\/j.ajpath.2016.11.018","DOI":"10.1016\/j.ajpath.2016.11.018"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Robrahn L, Jiao L, Cramer T. Barrier integrity and chronic inflammation mediated by HIF-1 impact on intestinal tumorigenesis. Cancer Letters 2020;490:186-192. https:\/\/doi.org\/10.1016\/j.canlet.2020.07.002","DOI":"10.1016\/j.canlet.2020.07.002"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Taylor CT, Colgan SP. Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol 2017;17:774-785. https:\/\/doi.org\/10.1038\/nri.2017.103","DOI":"10.1038\/nri.2017.103"},{"key":"ref9","doi-asserted-by":"publisher","unstructured":"Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol 2020;21:268-283. https:\/\/doi.org\/10.1038\/s41580-020-0227-y","DOI":"10.1038\/s41580-020-0227-y"},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Nakano H, Ide H, Ogasa T, Osanai S, Imada M, Nonaka S, et al. Ambient oxygen regulates epithelial metabolism and nitric oxide production in the human nose. J Applied Physiol 2002;93:189-194. https:\/\/doi.org\/10.1152\/japplphysiol.00096.2002","DOI":"10.1152\/japplphysiol.00096.2002"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Nossol C, Diesing AK, Walk N, Faber-Zuschratter H, Hartig R, Post A, et al. Air-liquid interface cultures enhance the oxygen supply and trigger the structural and functional differentiation of intestinal porcine epithelial cells (IPEC). Histochem Cell Biol 2011;136:103-115. https:\/\/doi.org\/10.1007\/s00418-011-0826-y","DOI":"10.1007\/s00418-011-0826-y"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Mikami Y, Grubb BR, Rogers TD, Dang H, Asakura T, Kota P, et al. Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration. Sci Transl Med 2023;15:eabo7728. https:\/\/doi.org\/10.1126\/scitranslmed.abo7728","DOI":"10.1126\/scitranslmed.abo7728"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Ledford H, Callaway E. Biologists who decoded how cells sense oxygen win medicine Nobel. Nature 2019;574:161-2. https:\/\/doi.org\/10.1038\/d41586-019-02963-0","DOI":"10.1038\/d41586-019-02963-0"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A 1995;92:5510-4. https:\/\/doi.org\/10.1073\/pnas.92.12.5510","DOI":"10.1073\/pnas.92.12.5510"},{"key":"ref15","doi-asserted-by":"crossref","unstructured":"Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med 2011;364:656-65. https:\/\/doi.org\/10.1056\/NEJMra0910283","DOI":"10.1056\/NEJMra0910283"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Jorgensen K, Song D, Weinstein J, Garcia OA, Pearson LN, Incl\u00e1n M, et al. High-altitude andean H194R HIF2A allele is a hypomorphic allele. Mol Biol Evolution 2023;40:msad162. https:\/\/doi.org\/10.1093\/molbev\/msad162","DOI":"10.1093\/molbev\/msad162"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer 2015;15:55-64. https:\/\/doi.org\/10.1038\/nrc3844","DOI":"10.1038\/nrc3844"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Chen J, Khalil RA. 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Physiol Rev 2012;92:967-1003. https:\/\/doi.org\/10.1152\/physrev.00030.2011","DOI":"10.1152\/physrev.00030.2011"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, et al. HIF\u03b1 Targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001;292:464-468. https:\/\/doi.org\/10.1126\/science.1059817","DOI":"10.1126\/science.1059817"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271-275. https:\/\/doi.org\/10.1038\/20459","DOI":"10.1038\/20459"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Aronow ME, Wiley HE, Gaudric A, Krivosic V, Gorin MB, Shields CL, et al. Von Hippel-Lindau Disease: update on pathogenesis and systemic aspects. 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Oncogene 2019;38:6970-6984. https:\/\/doi.org\/10.1038\/s41388-019-0932-1","DOI":"10.1038\/s41388-019-0932-1"},{"key":"ref30","doi-asserted-by":"publisher","unstructured":"Ohh M, Yauch RL, Lonergan KM, Whaley JM, Stemmer-Rachamimov AO, Louis DN, et al. The von Hippel-Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Mol Cell 1998;1:959-968. https:\/\/doi.org\/10.1016\/S1097-2765(00)80096-9","DOI":"10.1016\/s1097-2765(00)80096-9"},{"key":"ref31","doi-asserted-by":"publisher","unstructured":"Kurban G, Duplan E, Ramlal N, Hudon V, Sado Y, Ninomiya Y, et al. Collagen matrix assembly is driven by the interaction of von Hippel-Lindau tumor suppressor protein with hydroxylated collagen IV alpha 2. Oncogene 2008;27:1004-1012. https:\/\/doi.org\/10.1038\/sj.onc.1210709","DOI":"10.1038\/sj.onc.1210709"},{"key":"ref32","doi-asserted-by":"publisher","unstructured":"Ohh M, Taber CC, Ferens FG, Tarade D. Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata. Elife 2022;11:e80774. https:\/\/doi.org\/10.7554\/eLife.80774","DOI":"10.7554\/elife.80774"},{"key":"ref33","doi-asserted-by":"publisher","unstructured":"Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ, Schraml P, et al. VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol 2009;11:994-1001. https:\/\/doi.org\/10.1038\/ncb1912","DOI":"10.1038\/ncb1912"},{"key":"ref34","doi-asserted-by":"publisher","unstructured":"Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W. Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 2003;5:64-70. https:\/\/doi.org\/10.1038\/ncb899","DOI":"10.1038\/ncb899"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Cao H, Yu D, Yan X, Wang B, Yu Z, Song Y, et al. Hypoxia destroys the microstructure of microtubules and causes dysfunction of endothelial cells via the PI3K\/Stathmin1 pathway. 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New evidence of genetic adaptation to high altitude in Andean populations. Europ Respir J 2018;52:PA1274. https:\/\/erj.ersjournals.com\/content\/52\/suppl_62\/PA1274, https:\/\/doi.org\/10.1183\/13993003.congress-2018.PA1274","DOI":"10.1183\/13993003.congress-2018.pa1274"},{"key":"ref54","doi-asserted-by":"publisher","unstructured":"Song D, Navalsky BE, Guan W, Ingersoll C, Wang T, Loro E, et al. Tibetan PHD2, an allele with loss-of-function properties. Proc Natl Acad Sci U S A 2020;117:12230-8. https:\/\/doi.org\/10.1073\/pnas.1920546117","DOI":"10.1073\/pnas.1920546117"},{"key":"ref55","doi-asserted-by":"publisher","unstructured":"Brutsaert TD, Kiyamu M, Elias Revollendo G, Isherwood JL, Lee FS, Rivera-Ch M, et al. Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude. 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