{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:34:01Z","timestamp":1792787641344,"version":"4.5.0"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000098","name":"Clinical Center","doi-asserted-by":"publisher","award":["Bench-to-Bedside"],"award-info":[{"award-number":["Bench-to-Bedside"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CHEN18G0"],"award-info":[{"award-number":["CHEN18G0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF003045F221-SUN"],"award-info":[{"award-number":["CFF003045F221-SUN"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF BOUCHE19R0"],"award-info":[{"award-number":["CFF BOUCHE19R0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF RDP ESTHER24R0"],"award-info":[{"award-number":["CFF RDP ESTHER24R0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF HILL20Y2-OUT"],"award-info":[{"award-number":["CFF HILL20Y2-OUT"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["ESTHER22Y2-SVC"],"award-info":[{"award-number":["ESTHER22Y2-SVC"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"name":"North Carolina Children\u2019s Hospital","award":["Chen2021"],"award-info":[{"award-number":["Chen2021"]}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["P30 DK065988"],"award-info":[{"award-number":["P30 DK065988"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Clinical Center","doi-asserted-by":"publisher","award":["Bench-to-Bedside"],"award-info":[{"award-number":["Bench-to-Bedside"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CHEN18G0"],"award-info":[{"award-number":["CHEN18G0"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF003045F221-SUN"],"award-info":[{"award-number":["CFF003045F221-SUN"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF BOUCHE19R0"],"award-info":[{"award-number":["CFF BOUCHE19R0"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF RDP ESTHER24R0"],"award-info":[{"award-number":["CFF RDP ESTHER24R0"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["CFF HILL20Y2-OUT"],"award-info":[{"award-number":["CFF HILL20Y2-OUT"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["ESTHER22Y2-SVC"],"award-info":[{"award-number":["ESTHER22Y2-SVC"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"name":"North Carolina Children\u2019s Hospital","award":["Chen2021"],"award-info":[{"award-number":["Chen2021"]}]},{"DOI":"10.13039\/100000098","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["P30 DK065988"],"award-info":[{"award-number":["P30 DK065988"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000098","name":"Division of Intramural Research","doi-asserted-by":"publisher","award":["Intramural Research Program"],"award-info":[{"award-number":["Intramural Research Program"]}],"id":[{"id":"10.13039\/100000098","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>Hyper-IgE syndrome (STAT3-HIES), also known as Job\u2019s syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES is characterized by chronic pulmonary infection and inflammation, suggesting impaired innate host defense.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>STAT3-HIES sputum was analyzed for biochemical and biophysical properties. STAT3-HIES excised lungs were harvested for histology, and bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES\u2013specific R382W mutation, expressed via lentivirus, and STAT3 knockout (CRISPR\/Cas9) were studied in normal human bronchial epithelial cells under basal or inflammatory (IL1\u03b2)-stimulated conditions. Effects of STAT3 deficiency on transcriptomics, epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>STAT3-HIES sputum showed increased mucus concentration and viscoelasticity. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1\u03b2 expression. STAT3 mutations reduced CFTR mRNA and protein amounts, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and after IL1\u03b2 exposure. Notably, mutant STAT3 suppressed IL1R1 expression. Furthermore, STAT3 mutations impaired multiciliogenesis by blocking commitment to ciliated cell lineages through inhibition of HES6, leading to defective mucociliary transport. Administration of a \u03b3-secretase inhibitor restored HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>STAT3 dysfunction leads to multicomponent defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.202407-1415oc","type":"journal-article","created":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T16:48:25Z","timestamp":1749833305000},"page":"1951-1969","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":6,"title":["STAT3-Dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome"],"prefix":"10.1093","volume":"211","author":[{"given":"Ling","family":"Sun","sequence":"first","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha A.","family":"Walls","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Dang","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy L.","family":"Quinney","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick R.","family":"Sears","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taraneh","family":"Sadritabrizi","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koichi","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9341-2730","authenticated-orcid":false,"given":"Kenichi","family":"Okuda","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Asakura","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuya","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Mikami","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia U.","family":"Dizmond","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Danilova","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn","family":"Zhou","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshulika","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah M.","family":"Cholon","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Radicioni","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Troy D.","family":"Rogers","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Kissner","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Markovetz","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara N.","family":"Guhr Lee","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"},{"name":"Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark I.","family":"Gutay","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8081-2986","authenticated-orcid":false,"suffix":"Jr.","given":"Charles R.","family":"Esther","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"},{"name":"Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Chua","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara R.","family":"Grubb","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Ehre","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"},{"name":"Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehmet","family":"Kesimer","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Hill","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"},{"name":"The Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence E.","family":"Ostrowski","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"},{"name":"Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Button","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Gentzsch","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"},{"name":"Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chevalia","family":"Robinson","sequence":"additional","affiliation":[{"name":"National Heart, Lung and Blood Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth N.","family":"Olivier","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra F.","family":"Freeman","sequence":"additional","affiliation":[{"name":"National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott H.","family":"Randell","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eszter","family":"Vladar","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Sciences and Critical Care, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanda K.","family":"O\u2019Neal","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Boucher","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Chen","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute and Cystic Fibrosis Research Center, School of Medicine, and"},{"name":"Division of Pediatric Pulmonology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"2026013020470894500_bib1","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1038\/nature06096","article-title":"Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome","volume":"448","author":"Minegishi","year":"2007","journal-title":"Nature"},{"key":"2026013020470894500_bib2","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1056\/NEJMoa073687","article-title":"STAT3 mutations in the hyper-IgE syndrome","volume":"357","author":"Holland","year":"2007","journal-title":"N Engl J Med"},{"key":"2026013020470894500_bib3","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1182\/blood-2016-02-702373","article-title":"Protein stabilization improves STAT3 function in autosomal dominant hyper-IgE syndrome","volume":"128","author":"Bocchini","year":"2016","journal-title":"Blood"},{"key":"2026013020470894500_bib4","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1016\/j.jaci.2010.01.047","article-title":"Invasive fungal disease in autosomal-dominant hyper-IgE syndrome","volume":"125","author":"Vinh","year":"2010","journal-title":"J Allergy Clin Immunol"},{"key":"2026013020470894500_bib5","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.jaci.2022.12.821","article-title":"STAT3 mutation-associated airway epithelial defects in Job syndrome","volume":"152","author":"Zhang","year":"2023","journal-title":"J Allergy Clin Immunol"},{"key":"2026013020470894500_bib6","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1007\/s10875-020-00836-0","article-title":"Spontaneous gastrointestinal perforations in STAT3-deficient hyper-IgE syndrome","volume":"40","author":"Bhattacharya","year":"2020","journal-title":"J Clin Immunol"},{"key":"2026013020470894500_bib7","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1007\/s10875-021-00971-2","article-title":"Hematopoietic stem cell transplantation resolves the immune deficit associated with STAT3-dominant-negative hyper-IgE syndrome","volume":"41","author":"Harrison","year":"2021","journal-title":"J Clin Immunol"},{"key":"2026013020470894500_bib8","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1182\/blood-2013-09-523167","article-title":"A mouse model of HIES reveals pro- and anti-inflammatory functions of STAT3","volume":"123","author":"Steward-Tharp","year":"2014","journal-title":"Blood"},{"key":"2026013020470894500_bib9","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1172\/JCI0215217","article-title":"Mucus clearance as a primary innate defense mechanism for mammalian airways","volume":"109","author":"Knowles","year":"2002","journal-title":"J Clin Invest"},{"key":"2026013020470894500_bib10","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1164\/rccm.202008-3198OC","article-title":"Secretory cells dominate airway CFTR expression and function in human airway superficial epithelia","volume":"203","author":"Okuda","year":"2021","journal-title":"Am J Respir Crit Care Med"},{"key":"2026013020470894500_bib11","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s41586-018-0394-6","article-title":"A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte","volume":"560","author":"Plasschaert","year":"2018","journal-title":"Nature"},{"key":"2026013020470894500_bib12","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1038\/s41586-018-0393-7","article-title":"A revised airway epithelial hierarchy includes CFTR-expressing ionocytes","volume":"560","author":"Montoro","year":"2018","journal-title":"Nature"},{"key":"2026013020470894500_bib13","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/s41591-021-01332-7","article-title":"Transcriptional analysis of cystic fibrosis airways at single-cell resolution reveals altered epithelial cell states and composition","volume":"27","author":"Carraro","year":"2021","journal-title":"Nat Med"},{"key":"2026013020470894500_bib14","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1172\/JCI73469","article-title":"Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure","volume":"124","author":"Henderson","year":"2014","journal-title":"J Clin Invest"},{"key":"2026013020470894500_bib15","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.ccm.2016.04.016","article-title":"Hyper-IgE syndromes and the lung","volume":"37","author":"Freeman","year":"2016","journal-title":"Clin Chest Med"},{"key":"2026013020470894500_bib16","first-page":"A2364","article-title":"Comparative proteomic analysis of airway secretions in patients with hyper-IgE syndrome, cystic fibrosis, and asthma (abstract)","volume":"187","author":"Binu-John","year":"2013","journal-title":"Am J Respir Crit Care Med"},{"key":"2026013020470894500_bib17","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1056\/NEJMra1813799","article-title":"Muco-obstructive lung diseases","volume":"380","author":"Boucher","year":"2019","journal-title":"N Engl J Med"},{"key":"2026013020470894500_bib18","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.2353\/ajpath.2008.071052","article-title":"GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium","volume":"172","author":"Kida","year":"2008","journal-title":"Am J Pathol"},{"key":"2026013020470894500_bib19","doi-asserted-by":"crossref","first-page":"E3641","DOI":"10.1073\/pnas.1409781111","article-title":"IL-6\/STAT3 promotes regeneration of airway ciliated cells from basal stem cells","volume":"111","author":"Tadokoro","year":"2014","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026013020470894500_bib20","doi-asserted-by":"crossref","first-page":"ra46","DOI":"10.1126\/scisignal.2003755","article-title":"Mechanosensitive ATP release maintains proper mucus hydration of airways","volume":"6","author":"Button","year":"2013","journal-title":"Sci Signal"},{"key":"2026013020470894500_bib21","doi-asserted-by":"crossref","first-page":"e87681","DOI":"10.1371\/journal.pone.0087681","article-title":"A biophysical basis for mucus solids concentration as a candidate biomarker for airways disease","volume":"9","author":"Hill","year":"2014","journal-title":"PLoS One"},{"key":"2026013020470894500_bib22","doi-asserted-by":"crossref","first-page":"L398","DOI":"10.1152\/ajplung.00398.2016","article-title":"Sialic acid-to-urea ratio as a measure of airway surface hydration","volume":"312","author":"Esther","year":"2017","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026013020470894500_bib23","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1016\/S2213-2600(21)00079-5","article-title":"Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort","volume":"9","author":"Radicioni","year":"2021","journal-title":"Lancet Respir Med"},{"key":"2026013020470894500_bib24","doi-asserted-by":"crossref","first-page":"1801297","DOI":"10.1183\/13993003.01297-2018","article-title":"Pathological mucus and impaired mucus clearance in cystic fibrosis patients result from increased concentration, not altered pH","volume":"52","author":"Hill","year":"2018","journal-title":"Eur Respir J"},{"key":"2026013020470894500_bib25","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1172\/JCI125669","article-title":"IL-1beta dominates the promucin secretory cytokine profile in cystic fibrosis","volume":"129","author":"Chen","year":"2019","journal-title":"J Clin Invest"},{"key":"2026013020470894500_bib26","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.jcf.2018.05.006","article-title":"Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis","volume":"17","author":"Montgomery","year":"2018","journal-title":"J Cyst Fibros"},{"key":"2026013020470894500_bib27","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1164\/rccm.202306-1093OC","article-title":"Proximal and distal bronchioles contribute to the pathogenesis of non-cystic fibrosis bronchiectasis","volume":"209","author":"Asakura","year":"2024","journal-title":"Am J Respir Crit Care Med"},{"key":"2026013020470894500_bib28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1513\/AnnalsATS.202204-314OC","article-title":"Airway inflammation in children with primary ciliary dyskinesia","volume":"20","author":"Sagel","year":"2023","journal-title":"Ann Am Thorac Soc"},{"key":"2026013020470894500_bib29","doi-asserted-by":"crossref","first-page":"219","DOI":"10.2147\/JAA.S295516","article-title":"A novel STAT3 mutation in a patient with hyper-IgE syndrome diagnosed with a severe necrotizing pulmonary infection","volume":"14","author":"Zhao","year":"2021","journal-title":"J Asthma Allergy"},{"key":"2026013020470894500_bib30","doi-asserted-by":"crossref","first-page":"dev177428","DOI":"10.1242\/dev.177428","article-title":"Novel dynamics of human mucociliary differentiation revealed by single-cell RNA sequencing of nasal epithelial cultures","volume":"146","author":"Ruiz Garcia","year":"2019","journal-title":"Development"},{"key":"2026013020470894500_bib31","doi-asserted-by":"crossref","first-page":"14875","DOI":"10.1074\/jbc.C109.000869","article-title":"Transmembrane protein 16A (TMEM16A) is a Ca2+-regulated Cl\u2212 secretory channel in mouse airways","volume":"284","author":"Rock","year":"2009","journal-title":"J Biol Chem"},{"key":"2026013020470894500_bib32","doi-asserted-by":"crossref","first-page":"3629","DOI":"10.1172\/JCI60429","article-title":"SLC26A9-mediated chloride secretion prevents mucus obstruction in airway inflammation","volume":"122","author":"Anagnostopoulou","year":"2012","journal-title":"J Clin Invest"},{"key":"2026013020470894500_bib33","first-page":"L318","article-title":"Lung disease phenotypes caused by over-expression of combinations of \u03b1-, \u03b2-, and \u03b3-subunits of the epithelial sodium channel in mouse airways","volume":"314","author":"Livraghi-Butrico","year":"2018","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026013020470894500_bib34","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/j.jaci.2016.04.020","article-title":"Elucidating the effects of disease-causing mutations on STAT3 function in autosomal-dominant hyper-IgE syndrome","volume":"138","author":"Pelham","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"2026013020470894500_bib35","first-page":"69","article-title":"Statistics corner: a guide to appropriate use of correlation coefficient in medical research","volume":"24","author":"Mukaka","year":"2012","journal-title":"Malawi Med J"},{"key":"2026013020470894500_bib36","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.144294","article-title":"The MUC5B-associated variant rs35705950 resides within an enhancer subject to lineage- and disease-dependent epigenetic remodeling","volume":"6","author":"Gally","year":"2021","journal-title":"JCI Insight"},{"key":"2026013020470894500_bib37","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1165\/rcmb.2023-0104OC","article-title":"Airway basal stem cells in COVID-19 exhibit a proinflammatory signature and impaired mucocililary differentiation","volume":"70","author":"Bankoti","year":"2024","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026013020470894500_bib38","doi-asserted-by":"crossref","first-page":"L765","DOI":"10.1152\/ajplung.00390.2022","article-title":"BPIFB1 loss alters airway mucus properties and diminishes mucociliary clearance","volume":"325","author":"Donoghue","year":"2023","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026013020470894500_bib39","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1165\/rcmb.2018-0141ED","article-title":"SPDEFending the lung through mucin expression","volume":"59","author":"Evans","year":"2018","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026013020470894500_bib40","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1172\/JCI0215218","article-title":"Antimicrobial polypeptides in host defense of the respiratory tract","volume":"109","author":"Ganz","year":"2002","journal-title":"J Clin Invest"},{"key":"2026013020470894500_bib41","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1165\/rcmb.2002-0272OC","article-title":"CCL20 is an inducible product of human airway epithelia with innate immune properties","volume":"29","author":"Starner","year":"2003","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026013020470894500_bib42","doi-asserted-by":"crossref","first-page":"382","DOI":"10.4049\/jimmunol.1001769","article-title":"Antimicrobial activity of PLUNC protects against Pseudomonas aeruginosa infection","volume":"187","author":"Lukinskiene","year":"2011","journal-title":"J Immunol"},{"key":"2026013020470894500_bib43","doi-asserted-by":"crossref","first-page":"4947","DOI":"10.4049\/jimmunol.0803282","article-title":"Lipocalin 2 is required for pulmonary host defense against Klebsiella infection","volume":"182","author":"Chan","year":"2009","journal-title":"J Immunol"},{"key":"2026013020470894500_bib44","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1165\/rcmb.2018-0377OC","article-title":"IL-17C protects nasal epithelium from Pseudomonas aeruginosa infection","volume":"62","author":"Jeon","year":"2020","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026013020470894500_bib45","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.jcmgh.2015.06.005","article-title":"Defects in NADPH oxidase genes NOX1 and DUOX2 in very early onset inflammatory bowel disease","volume":"1","author":"Hayes","year":"2015","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"2026013020470894500_bib46","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1172\/JCI83922","article-title":"Acidic pH increases airway surface liquid viscosity in cystic fibrosis","volume":"126","author":"Tang","year":"2016","journal-title":"J Clin Invest"},{"key":"2026013020470894500_bib47","doi-asserted-by":"crossref","first-page":"L320","DOI":"10.1152\/ajplung.00440.2002","article-title":"Regulation of MUC5AC mucin secretion and airway surface liquid metabolism by IL-1beta in human bronchial epithelia","volume":"286","author":"Gray","year":"2004","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026013020470894500_bib48","doi-asserted-by":"crossref","first-page":"13616","DOI":"10.1073\/pnas.0506769102","article-title":"The B1-subunit of the H(+) ATPase is required for maximal urinary acidification","volume":"102","author":"Finberg","year":"2005","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026013020470894500_bib49","doi-asserted-by":"crossref","first-page":"C331","DOI":"10.1152\/ajpcell.00112.2020","article-title":"TNFalpha and IL-17 alkalinize airway surface liquid through CFTR and pendrin","volume":"319","author":"Rehman","year":"2020","journal-title":"Am J Physiol Cell Physiol"},{"key":"2026013020470894500_bib50","doi-asserted-by":"crossref","first-page":"e75871","DOI":"10.7554\/eLife.75871","article-title":"Inhibition of the sodium-dependent HCO(3)(-) transporter SLC4A4, produces a cystic fibrosis-like airway disease phenotype","volume":"11","author":"Saint-Criq","year":"2022","journal-title":"Elife"},{"key":"2026013020470894500_bib51","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1165\/rcmb.2022-0172OC","article-title":"WNK inhibition increases surface liquid pH and host defense in cystic fibrosis airway epithelia","volume":"67","author":"Rehman","year":"2022","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026013020470894500_bib52","first-page":"A5708","article-title":"Airways mucus pathogenesis in patients with non-cystic fibrosis bronchiectasis and primary ciliary dyskinesia (abstract)","volume":"199","author":"Ramsey","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2026013020470894500_bib53","first-page":"18","article-title":"Genetics and biology of primary ciliary dyskinesia","volume":"18","author":"Horani","year":"2016","journal-title":"Paediatr Respir Rev"},{"key":"2026013020470894500_bib54","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.semcdb.2020.04.007","article-title":"Transcriptional regulation of multiciliated cell differentiation","volume":"110","author":"Lewis","year":"2021","journal-title":"Semin Cell Dev Biol"},{"key":"2026013020470894500_bib55","doi-asserted-by":"crossref","first-page":"4713","DOI":"10.1016\/j.cell.2021.07.023","article-title":"Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19","volume":"184","author":"Ziegler","year":"2021","journal-title":"Cell"},{"key":"2026013020470894500_bib56","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S1525-0016(03)00221-1","article-title":"Targeting expression of a transgene to the airway surface epithelium using a ciliated cell-specific promoter","volume":"8","author":"Ostrowski","year":"2003","journal-title":"Mol Ther"},{"key":"2026013020470894500_bib57","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.cell.2011.10.052","article-title":"Coordinated ciliary beating requires Odf2-mediated polarization of basal bodies via basal feet","volume":"148","author":"Kunimoto","year":"2012","journal-title":"Cell"},{"key":"2026013020470894500_bib58","doi-asserted-by":"crossref","first-page":"2297","DOI":"10.1242\/dev.034884","article-title":"Notch signaling controls the balance of ciliated and secretory cell fates in developing airways","volume":"136","author":"Tsao","year":"2009","journal-title":"Development"},{"key":"2026013020470894500_bib59","doi-asserted-by":"crossref","first-page":"L771","DOI":"10.1152\/ajplung.00382.2022","article-title":"Notch signaling inactivation by small molecule gamma-secretase inhibitors restores the multiciliated cell population in the airway epithelium","volume":"324","author":"Vladar","year":"2023","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026013020470894500_bib60","doi-asserted-by":"crossref","first-page":"e0116507","DOI":"10.1371\/journal.pone.0116507","article-title":"Activation of NOTCH1 or NOTCH3 signaling skews human airway basal cell differentiation toward a secretory pathway","volume":"10","author":"Gomi","year":"2015","journal-title":"PLoS One"},{"key":"2026013020470894500_bib61","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1038\/nature06764","article-title":"Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome","volume":"452","author":"Milner","year":"2008","journal-title":"Nature"},{"key":"2026013020470894500_bib62","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1084\/jem.20120260","article-title":"Innate Stat3-mediated induction of the antimicrobial protein Reg3gamma is required for host defense against MRSA pneumonia","volume":"210","author":"Choi","year":"2013","journal-title":"J Exp Med"},{"key":"2026013020470894500_bib63","doi-asserted-by":"crossref","first-page":"9152","DOI":"10.3390\/ijms21239152","article-title":"Staphylococcus aureus and hyper-IgE syndrome","volume":"21","author":"Park","year":"2020","journal-title":"Int J Mol Sci"},{"key":"2026013020470894500_bib64","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1128\/CMR.00068-09","article-title":"The changing microbial epidemiology in cystic fibrosis","volume":"23","author":"Lipuma","year":"2010","journal-title":"Clin Microbiol Rev"},{"key":"2026013020470894500_bib65","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/mi.2016.63","article-title":"Contribution of mucus concentration and secreted mucins Muc5ac and Muc5b to the pathogenesis of muco-obstructive lung disease","volume":"10","author":"Livraghi-Butrico","year":"2017","journal-title":"Mucosal Immunol"},{"key":"2026013020470894500_bib66","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nm1028","article-title":"Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice","volume":"10","author":"Mall","year":"2004","journal-title":"Nat Med"},{"key":"2026013020470894500_bib67","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1038\/mi.2016.27","article-title":"The innate immune properties of airway mucosal surfaces are regulated by dynamic interactions between mucins and interacting proteins: the mucin interactome","volume":"9","author":"Radicioni","year":"2016","journal-title":"Mucosal Immunol"},{"key":"2026013020470894500_bib68","doi-asserted-by":"crossref","first-page":"4354","DOI":"10.1038\/s41467-021-24521-x","article-title":"SARS-CoV-2 infection induces the dedifferentiation of multiciliated cells and impairs mucociliary clearance","volume":"12","author":"Robinot","year":"2021","journal-title":"Nat Commun"},{"key":"2026013020470894500_bib69","doi-asserted-by":"crossref","first-page":"e183978","DOI":"10.1172\/JCI183978","article-title":"Activation of STAT3-mediated ciliated cell survival protects against severe infection by respiratory syncytial virus","volume":"134","author":"Zhao","year":"2024","journal-title":"J Clin Invest"},{"key":"2026013020470894500_bib70","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1152\/physrev.00004.2021","article-title":"Physiology and pathophysiology of human airway mucus","volume":"102","author":"Hill","year":"2022","journal-title":"Physiol Rev"},{"key":"2026013020470894500_bib71","doi-asserted-by":"crossref","first-page":"32R","DOI":"10.1203\/PDR.0b013e31819dc8c5","article-title":"Clinical manifestations, etiology, and pathogenesis of the hyper-IgE syndromes","volume":"65","author":"Freeman","year":"2009","journal-title":"Pediatr Res"},{"key":"2026013020470894500_bib72","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1164\/rccm.200804-551OC","article-title":"Lung function in infants with cystic fibrosis diagnosed by newborn screening","volume":"178","author":"Linnane","year":"2008","journal-title":"Am J Respir Crit Care Med"},{"key":"2026013020470894500_bib73","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/S0002-9378(87)80312-5","article-title":"Hyperimmunoglobulinemia E and pregnancy: a case report","volume":"157","author":"Lindenbaum","year":"1987","journal-title":"Am J Obstet Gynecol"},{"key":"2026013020470894500_bib74","doi-asserted-by":"crossref","first-page":"eabo7728","DOI":"10.1126\/scitranslmed.abo7728","article-title":"Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration","volume":"15","author":"Mikami","year":"2023","journal-title":"Sci Transl Med"},{"key":"2026013020470894500_bib75","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1164\/rccm.202307-1266OC","article-title":"Increased Muc5AC and decreased ciliated cells in severe asthma partially restored by inhibition of IL-4R\u03b1 receptor","volume":"210","author":"Boomer","year":"2024","journal-title":"Am J Respir Crit Care Med"},{"key":"2026013020470894500_bib76","doi-asserted-by":"crossref","first-page":"107872","DOI":"10.1016\/j.celrep.2020.107872","article-title":"Single-cell and population transcriptomics reveal pan-epithelial remodeling in type 2-high asthma","volume":"32","author":"Jackson","year":"2020","journal-title":"Cell Rep"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/211\/10\/1951\/66621321\/ajrccm_211_10_1951.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/211\/10\/1951\/66621321\/ajrccm_211_10_1951.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T01:47:30Z","timestamp":1769824050000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/211\/10\/1951\/8444196"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,1]]},"references-count":76,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10,1]]},"published-print":{"date-parts":[[2025,10,1]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.202407-1415oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,10,1]]},"assertion":[{"value":"2024-07-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}