{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:17:56Z","timestamp":1791231476005,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T00:00:00Z","timestamp":1593993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI143731"],"award-info":[{"award-number":["R01AI143731"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["K23ES020859"],"award-info":[{"award-number":["K23ES020859"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Laryngoscope"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:sec><jats:title>Objectives\/Hypothesis<\/jats:title><jats:p>Oxidative stress has been postulated to play an important role in chronic rhinosinusitis. <jats:italic>Nrf2<\/jats:italic> is a transcription factor that is involved in the regulation of multiple antioxidant genes, and its function has been previously shown to be important in sinonasal inflammation. Although the sinonasal implications of whole body <jats:italic>Nrf2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> has been reported, the function of sinonasal epithelial expression of Nrf2 has not been studied. The primary aim of this study was to generate a mouse model that is genetically deficient in epithelial\u2010specific <jats:italic>Nrf2<\/jats:italic> and to understand its role in regulating sinonasal inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design<\/jats:title><jats:p>Basic science.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>An epithelial\u2010specific <jats:italic>Nrf2<\/jats:italic> knockout mouse was generated by crossing Krt5\u2010cre(K5) with <jats:italic>Nrf2<jats:sup>flox\/flox<\/jats:sup><\/jats:italic>. A papain\u2010induced model of rhinosinusitis was performed in the resulting K5 <jats:italic>Nrf2<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mouse. Immunohistochemistry was performed to quantify goblet cell hyperplasia. Mucosal cellular infiltrates were quantified using flow cytometry, and tissue cytokines were measured using an enzyme\u2010linked immunosorbent assay. Lastly, the cellular source of type 2 cytokines was determined using intracellular cytokine staining.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Papain\u2010sensitized mice lacking epithelial\u2010specific <jats:italic>Nrf2<\/jats:italic> demonstrate increased goblet cell hyperplasia, significant tissue eosinophilia, and statistically significant increase in mucosal IL\u201013 when compared to <jats:italic>Nrf2<\/jats:italic> wild\u2010type mice. Lastly, mucosal T cells were identified as the cellular source of IL\u201013.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We demonstrate enhanced severity of eosinophilic sinonasal inflammation from disruption of the epithelial\u2010specific <jats:italic>Nrf2<\/jats:italic> pathway. The responsiveness of Nrf2\u2010directed antioxidant pathways may act as a major determinant of susceptibility to eosinophilic inflammation and may have potential as a therapeutic target for chronic rhinosinusitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Level of Evidence<\/jats:title><jats:p>NA <jats:italic>Laryngoscope<\/jats:italic>, 131:713\u2013719, 2021<\/jats:p><\/jats:sec>","DOI":"10.1002\/lary.28884","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T18:39:12Z","timestamp":1594060752000},"page":"713-719","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Disruption of Sinonasal Epithelial Nrf2 Enhances Susceptibility to Rhinosinusitis in a Mouse Model"],"prefix":"10.1002","volume":"131","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7612-9586","authenticated-orcid":false,"suffix":"Jr.","given":"Murugappan","family":"Ramanathan","sequence":"first","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Johns Hopkins Medicine  Baltimore Maryland U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuj","family":"Tharakan","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Johns Hopkins Medicine  Baltimore Maryland U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkataramana K.","family":"Sidhaye","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Internal Medicine Johns Hopkins School of Medicine  Baltimore Maryland U.S.A."},{"name":"Department of Environmental Health Sciences Johns Hopkins Bloomberg School of Public Health  Baltimore Maryland U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew P.","family":"Lane","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Johns Hopkins Medicine  Baltimore Maryland U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyam","family":"Biswal","sequence":"additional","affiliation":[{"name":"Department of Environmental Health Sciences Johns Hopkins Bloomberg School of Public Health  Baltimore Maryland U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-4407","authenticated-orcid":false,"suffix":"Jr.","given":"Nyall R.","family":"London","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Johns Hopkins Medicine  Baltimore Maryland U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,6]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/00034894041130S502"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1067\/mhn.2002.129815"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0194-5998(95)70152-4"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21530"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1179\/1351000215Y.0000000001"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11882-004-0056-7"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2014.05.030"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.2174\/138945011794751573"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21916"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21827"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.06.027"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.239.117"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2019.104035"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22222"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.13766"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.15.8858"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620664114"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0906850106"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.10.001"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2011-0144OC"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22072"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035114"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.8.4417"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-052016-100401"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2015.05.014"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0424OC"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-015-0253-z"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/875403"}],"container-title":["The Laryngoscope"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Flary.28884","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lary.28884","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/lary.28884","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lary.28884","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T00:49:29Z","timestamp":1693702169000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/lary.28884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,6]]},"references-count":28,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["10.1002\/lary.28884"],"URL":"https:\/\/doi.org\/10.1002\/lary.28884","archive":["Portico"],"relation":{},"ISSN":["0023-852X","1531-4995"],"issn-type":[{"value":"0023-852X","type":"print"},{"value":"1531-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,6]]},"assertion":[{"value":"2020-04-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-08","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}