{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:49:36Z","timestamp":1786978176251,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T00:00:00Z","timestamp":1773360000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Laryngoscope"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Pepsin is a key driver of epithelial injury and inflammation in laryngopharyngeal reflux (LPR). Prior work in esophageal cells implicates hypoxia\u2010inducible factor\u20102\u03b1 (HIF\u20102\u03b1) in refluxate\u2010mediated cytokine secretion. We investigated whether pepsin increases HIF\u20102\u03b1 under neutral (pH\u20097) conditions in immortalized human true vocal cord (TVC) cells and whether amprenavir, a pepsin inhibitor, can reverse this response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>TVCs were treated with 0.1\u20131\u2009mg\/mL pepsin and\/or 10\u2009\u03bcM amprenavir at pH\u20097 for 2, 4, 6, and 24\u2009h. HIF\u20102\u03b1 protein levels were evaluated by Western blot. Based on the most inflammatory condition, expression of proinflammatory genes was assessed with or without a HIF\u20102\u03b1 transcriptional inhibitor.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The 6\u2010h 1\u2009mg\/mL pepsin treatment induced the highest HIF\u20102\u03b1 levels and was selected for further analysis. Pepsin significantly increased HIF\u20102\u03b1 expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), and amprenavir reduced it numerically (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.056). Pepsin significantly upregulated\n                      <jats:italic>ICAM1<\/jats:italic>\n                      ,\n                      <jats:italic>IL1B<\/jats:italic>\n                      , and\n                      <jats:italic>IL8<\/jats:italic>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05), while amprenavir significantly reduced\n                      <jats:italic>ICAM1<\/jats:italic>\n                      ,\n                      <jats:italic>IL8<\/jats:italic>\n                      , and\n                      <jats:italic>TNF<\/jats:italic>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05). Inhibition of HIF\u20102\u03b1 selectively reduced\n                      <jats:italic>IL1B<\/jats:italic>\n                      expression (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Pepsin exposure increased HIF\u20102\u03b1 and upregulated key inflammatory genes. While amprenavir significantly reduced cytokine expression, HIF\u20102\u03b1 inhibition alone had only a modest effect, suggesting additional pathways contribute to pepsin\u2010induced inflammation. Amprenavir's ability to attenuate this response supports its therapeutic potential in LPR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Level of Evidence<\/jats:title>\n                    <jats:p>N\/A.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/lary.70490","type":"journal-article","created":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T03:04:31Z","timestamp":1773457471000},"page":"3487-3493","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Modulation of Pepsin\u2010Mediated Inflammatory Responses in Vocal Cord Epithelial Cells by Amprenavir"],"prefix":"10.1002","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3155-0633","authenticated-orcid":false,"given":"Pelin","family":"Ergun","sequence":"first","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7045-357X","authenticated-orcid":false,"given":"Tina L.","family":"Samuels","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences Medical College of Wisconsin  Milwaukee Wisconsin USA"},{"name":"Department of Microbiology and Immunology Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,13]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.31134"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.anorl.2020.11.002"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.15242"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/000348940911800913"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0227408"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26136182"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.otc.2025.01.006"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076765"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms251910714"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.28636"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22685"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/lio2.1102"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-312595"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2004.11.009"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2017.10.004"},{"issue":"1","key":"e_1_2_10_17_1","first-page":"S1","article-title":"Oral and Inhaled Fosamprenavir Reverses Pepsin\u2010Induced Damage in a Laryngopharyngeal Reflux Mouse Model","volume":"133","author":"Johnston N.","year":"2023","journal-title":"Laryngoscope"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.5.9.1995"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/lio2.1219"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.30087"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00454.2011"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2024.156568"},{"key":"e_1_2_10_23_1","first-page":"184","article-title":"Laryngopharyngeal Reflux: Diagnosis, Treatment, and Latest Research","volume":"18","author":"Campagnolo A. 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