{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T02:52:43Z","timestamp":1792205563709,"version":"4.4.0"},"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T00:00:00Z","timestamp":1638748800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL12424"],"award-info":[{"award-number":["HL12424"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI144241"],"award-info":[{"award-number":["AI144241"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL14079501"],"award-info":[{"award-number":["HL14079501"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI007285"],"award-info":[{"award-number":["AI007285"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Airway epithelial barrier dysfunction is increasingly recognized as a key feature of asthma and other lung diseases. Respiratory viruses are responsible for a large fraction of asthma exacerbations, and are particularly potent at disrupting epithelial barrier function through pattern recognition receptor engagement leading to tight junction dysfunction. Although different mechanisms of barrier dysfunction have been described, relatively little is known about whether barrier integrity can be promoted to limit disease. Here, we tested three classes of drugs commonly prescribed to treat asthma for their ability to promote barrier function using a cell culture model of virus-induced airway epithelial barrier disruption. Specifically, we studied the corticosteroid budesonide, the long acting beta-agonist formoterol, and the leukotriene receptor antagonist montelukast for their ability to promote barrier integrity of a monolayer of human bronchial epithelial cells (16HBE) before exposure to the viral mimetic double-stranded RNA. Of the three, only budesonide treatment limited transepithelial electrical resistance and small molecule permeability (4 kDa FITC-dextran flux). Next, we used a mouse model of acute dsRNA challenge that induces transient epithelial barrier disruption <jats:italic>in vivo<\/jats:italic>, and studied the effects budesonide when administered prophylactically or therapeutically. We found that budesonide similarly protected against dsRNA-induced airway barrier disruption in the lung, independently of its effects on airway inflammation. Taken together, these data suggest that an under-appreciated effect of inhaled budesonide is to maintain or promote airway epithelial barrier integrity during respiratory viral infections.<\/jats:p>","DOI":"10.1371\/journal.pone.0260706","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T18:24:07Z","timestamp":1638815047000},"page":"e0260706","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Budesonide promotes airway epithelial barrier integrity following double-stranded RNA challenge"],"prefix":"10.1371","volume":"16","author":[{"given":"Clara","family":"Rimmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savas","family":"Hetelekides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia I.","family":"Eliseeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve N.","family":"Georas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3061-0251","authenticated-orcid":true,"given":"Janelle M.","family":"Veazey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,12,6]]},"reference":[{"issue":"3","key":"pone.0260706.ref001","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.jaci.2014.05.049","article-title":"Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation","volume":"134","author":"SN Georas","year":"2014","journal-title":"J Allergy Clin Immunol"},{"issue":"4","key":"pone.0260706.ref002","doi-asserted-by":"crossref","first-page":"e24997","DOI":"10.4161\/tisb.24997","article-title":"Barrier function of airway tract epithelium","volume":"1","author":"S Ganesan","year":"2013","journal-title":"Tissue Barriers"},{"issue":"6","key":"pone.0260706.ref003","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.jaci.2007.08.046","article-title":"Epithelium: at the interface of innate and adaptive immune responses","volume":"120","author":"RP Schleimer","year":"2007","journal-title":"J Allergy Clin Immunol"},{"issue":"1","key":"pone.0260706.ref004","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev-physiol-012110-142150","article-title":"Tight Junction Pore and Leak Pathways: A Dynamic Duo","volume":"73","author":"L Shen","year":"2011","journal-title":"Annual Review of Physiology"},{"issue":"2","key":"pone.0260706.ref005","doi-asserted-by":"crossref","first-page":"190278","DOI":"10.1098\/rsob.190278","article-title":"The multifarious regulation of the apical junctional complex","volume":"10","author":"AD Rusu","year":"2020","journal-title":"Open Biology"},{"issue":"6","key":"pone.0260706.ref006","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/S0092-8674(02)00912-1","article-title":"Adenovirus Fiber Disrupts CAR-Mediated Intercellular Adhesion Allowing Virus Escape","volume":"110","author":"RW Walters","year":"2002","journal-title":"Cell"},{"issue":"12","key":"pone.0260706.ref007","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1164\/rccm.200801-136OC","article-title":"Rhinovirus disrupts the barrier function of polarized airway epithelial cells","volume":"178","author":"U Sajjan","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"issue":"13","key":"pone.0260706.ref008","first-page":"6795","volume":"85","author":"AT Comstock","year":"2011","journal-title":"Rhinovirus-Induced Barrier Dysfunction in Polarized Airway Epithelial Cells Is Mediated by NADPH Oxidase 1"},{"issue":"20","key":"pone.0260706.ref009","doi-asserted-by":"crossref","first-page":"11088","DOI":"10.1128\/JVI.01573-13","article-title":"Sustained protein kinase D activation mediates respiratory syncytial virus-induced airway barrier disruption","volume":"87","author":"F Rezaee","year":"2013","journal-title":"J Virol"},{"issue":"2","key":"pone.0260706.ref010","doi-asserted-by":"crossref","first-page":"L358","DOI":"10.1152\/ajplung.00345.2018","article-title":"Disruption of the airway epithelial barrier in a murine model of respiratory syncytial virus infection","volume":"316","author":"CC Smallcombe","year":"2019","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"5","key":"pone.0260706.ref011","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1165\/rcmb.2013-0541RT","article-title":"Breaking barriers. New insights into airway epithelial barrier function in health and disease","volume":"50","author":"F Rezaee","year":"2014","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"6","key":"pone.0260706.ref012","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.jaci.2011.08.035","article-title":"Polyinosinic:polycytidylic acid induces protein kinase D-dependent disassembly of apical junctions and barrier dysfunction in airway epithelial cells","volume":"128","author":"F Rezaee","year":"2011","journal-title":"J Allergy Clin Immunol"},{"issue":"5","key":"pone.0260706.ref013","doi-asserted-by":"crossref","first-page":"e0216056","DOI":"10.1371\/journal.pone.0216056","article-title":"Distinct roles for MDA5 and TLR3 in the acute response to inhaled double-stranded RNA","volume":"14","author":"JM Veazey","year":"2019","journal-title":"PLOS ONE"},{"key":"pone.0260706.ref014","volume-title":"Sidhaye\/Koval -Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease","author":"J Veazey","year":"2017"},{"issue":"2","key":"pone.0260706.ref015","doi-asserted-by":"crossref","first-page":"e24333","DOI":"10.4161\/tisb.24333","article-title":"Interleukin-4 and interleukin-13 cause barrier dysfunction in human airway epithelial cells","volume":"1","author":"B Saatian","year":"2013","journal-title":"Tissue Barriers"},{"key":"pone.0260706.ref016","first-page":"23","article-title":"Innate Immune Sensing and Response to Influenza","volume":"386","author":"B Pulendran","year":"2014","journal-title":"Curr Top Microbiol Immunol: Springer International Publishing"},{"key":"pone.0260706.ref017","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.pupt.2016.07.001","article-title":"Molecular and cellular mechanisms underlying the therapeutic effects of budesonide in asthma","volume":"40","author":"G Pelaia","year":"2016","journal-title":"Pulmonary Pharmacology & Therapeutics"},{"key":"pone.0260706.ref018","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.antiviral.2018.01.012","article-title":"Antiviral and anti-inflammatory activity of budesonide against human rhinovirus infection mediated via autophagy activation","volume":"151","author":"S-R Kim","year":"2018","journal-title":"Antiviral Research"},{"issue":"2","key":"pone.0260706.ref019","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/pai.12124","article-title":"Systematic Review of Montelukast\u2019s Efficacy for Preventing Post-Bronchiolitis Wheezing","volume":"25","author":"W-S Peng","year":"2014","journal-title":"Pediatr Allergy Immunol"},{"issue":"6","key":"pone.0260706.ref020","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1006\/pupt.2002.0400","article-title":"The Long and Short of \u03b22-agonists","volume":"15","author":"J. 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