{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:29:11Z","timestamp":1786516151016,"version":"build-2736575974"},"reference-count":59,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"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"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Chronic reflux\u2010related microaspiration is increasingly recognized as a modifiable risk factor for progressive fibrotic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic lung allograft dysfunction (CLAD). Nonacid reflux constituents, including the gastric enzyme pepsin, are thought to be a primary source of aspiration\u2010attributed injury. We previously showed that the FDA\u2010approved HIV protease inhibitor amprenavir reduces pepsin\u2010mediated inflammation and fibrosis in in\u00a0vivo and in\u00a0vitro models of the upper airways. Repurposing amprenavir offers a novel strategy to prevent aspiration\u2010related lung disease progression. Our aim was to evaluate time\u2010 and dose\u2010dependent effects of pepsin on proinflammatory and fibrotic responses in human bronchial\/tracheal epithelial cells (HBECs) and assess the protective role of amprenavir.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>HBECs were treated in triplicate with 0.1 or 1\u2009mg\/mL pepsin and\/or 10\u2009\u03bcM amprenavir at pH\u20096.5 for 15 or 30\u2009min, followed by 6 or 24\u2009h rest. Cell secretions were assessed by IL\u20108 and fibronectin ELISA, and cell lysate was assessed by E\u2010cadherin, \u03b2\u2010catenin, and vimentin Western blot.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Low\u2010dose pepsin exposure (15\u2009min, 0.1\u2009mg\/mL, 6\u2009h rest) induced IL\u20108 (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), reversed by amprenavir (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). High\u2010dose pepsin (30\u2009min, 1\u2009mg\/mL, 24\u2009h rest) depleted E\u2010cadherin (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) and increased vimentin (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01), both reversed by amprenavir.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Pepsin elicited dose\u2010 and time\u2010dependent proinflammatory and fibrotic effects in airway epithelial cells in\u00a0vitro, which were prevented by amprenavir. This supports the capacity of amprenavir to mitigate airway damage caused by chronic reflux\u2010related microaspiration and highlights its potential therapeutic utility for progressive fibrotic lung diseases.<\/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.70818","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:47:58Z","timestamp":1786513678000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Amprenavir Protects Lung Epithelial Cells From Pepsin Induced Inflammation and Fibrotic Changes"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3478-2497","authenticated-orcid":false,"given":"Karolina","family":"Lungova","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\/0000-0002-3155-0633","authenticated-orcid":false,"given":"Pelin","family":"Ergun","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawjai","family":"Khampang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology and Communication Sciences Medical College of Wisconsin  Milwaukee Wisconsin USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Yan","sequence":"additional","affiliation":[{"name":"Pediatrics Bioinformatics and Quantitative Child Health 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":[[2026,8,11]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"StatPearls","author":"Ficke B.","year":"2026"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200103013440908"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1714562"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2009.07.033"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2004.10.035"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00101212"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.6.9804105"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.06.00037005"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02316\u20102014"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/634613"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00050911"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.246.147"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2018.07.038"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200610\u20101485OC"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2013.06.011"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2007.082719"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00064807"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0b013e3182a6589b"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2004.036426"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2020.08.2080"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20102600(16)00067\u20109"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2004.04.044"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.2011.216"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2005.10.014"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00488\u20102016"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.athoracsur.2021.05.098"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.21037\/ccts\u201025\u201012"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.5500\/wjt.v7.i2.103"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202202\u20100399ST"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20102600(18)30301\u20101"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOO.0000000000000664"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1177\/000348940911800913"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.22685"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.30242"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.70490"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/lio2.1102"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24097932"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24076765"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26136182"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22084275"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.29749"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1177\/0003489415593556"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1177\/0194599813517862"},{"issue":"6","key":"e_1_2_9_45_1","first-page":"790","article-title":"Pulmonary Complications of Gastric Fluid and Bile Salts Aspiration, an Experimental Study in Rat","volume":"16","author":"Samareh Fekri M.","year":"2013","journal-title":"Iranian Journal of Basic Medical Sciences"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11739\u2010018\u20101960\u20105"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.889800"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600\u20106143.2006.01331.x"},{"key":"e_1_2_9_49_1","unstructured":"GSK \u201cLexiva Prescribing Information \u201d2020 https:\/\/gskpro.com\/content\/dam\/global\/hcpportal\/en_US\/Prescribing_Information\/Lexiva\/pdf\/LEXIVA\u2010PI\u2010PIL.PDF."},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0149\u20102918(00)83038\u20106"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/jpm12081296"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22073384"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1177\/0300060518811560"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200111\u2010068OC"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2011.102"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20215276"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2013.03.006"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.12659\/MSM.915628"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935\u2010019\u20100772\u20107"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010019\u201050360\u20104"}],"container-title":["The Laryngoscope"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lary.70818","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/lary.70818","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/lary.70818","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:47:59Z","timestamp":1786513679000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/lary.70818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":59,"alternative-id":["10.1002\/lary.70818"],"URL":"https:\/\/doi.org\/10.1002\/lary.70818","archive":["Portico"],"relation":{},"ISSN":["0023-852X","1531-4995"],"issn-type":[{"value":"0023-852X","type":"print"},{"value":"1531-4995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]},"assertion":[{"value":"2026-04-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"lary.70818"}}