{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:15:21Z","timestamp":1792721721400,"version":"4.5.0"},"reference-count":90,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2009,4,1]],"date-time":"2009-04-01T00:00:00Z","timestamp":1238544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Overexpression of the epithelial Na+ channel \u03b2 subunit (Scnn1b gene, \u03b2ENaC protein) in transgenic (Tg) mouse airways dehydrates mucosal surfaces, producing mucus obstruction, inflammation, and neonatal mortality. Airway inflammation includes macrophage activation, neutrophil and eosinophil recruitment, and elevated KC, TNF-\u03b1, and chitinase levels. These changes recapitulate aspects of complex human obstructive airway diseases, but their molecular mechanisms are poorly understood. We used genetic and pharmacologic approaches to identify pathways relevant to the development of Scnn1b-Tg mouse lung pathology. Genetic deletion of TNF-\u03b1 or its receptor, TNFR1, had no measurable effect on the phenotype. Deletion of IL-4R\u03b1 abolished transient mucous secretory cell (MuSC) abundance and eosinophilia normally observed in neonatal wild-type mice. Similarly, IL-4R\u03b1 deficiency decreased MuSC and eosinophils in neonatal Scnn1b-Tg mice, which correlated with improved neonatal survival. However, chronic lung pathology in adult Scnn1b-Tg mice was not affected by IL-4R\u03b1 status. Prednisolone treatment ablated eosinophilia and MuSC in adult Scnn1b-Tg mice, but did not decrease mucus plugging or neutrophilia. These studies demonstrate that: 1) normal neonatal mouse airway development entails an IL-4R\u03b1-dependent, transient abundance of MuSC and eosinophils; 2) absence of IL-4R\u03b1 improved neonatal survival of Scnn1b-Tg mice, likely reflecting decreased formation of asphyxiating mucus plugs; and 3) in Scnn1b-Tg mice, neutrophilia, mucus obstruction, and airspace enlargement are IL-4R\u03b1- and TNF-\u03b1-independent, and only MuSC and eosinophilia are sensitive to glucocorticoids. Thus, manipulation of multiple pathways will likely be required to treat the complex pathogenesis caused by airway surface dehydration.<\/jats:p>","DOI":"10.4049\/jimmunol.0802557","type":"journal-article","created":{"date-parts":[[2009,3,19]],"date-time":"2009-03-19T16:57:19Z","timestamp":1237481839000},"page":"4357-4367","source":"Crossref","is-referenced-by-count":81,"title":["Airway and Lung Pathology Due to Mucosal Surface Dehydration in \u03b2-Epithelial Na+ Channel-Overexpressing Mice: Role of TNF-\u03b1 and IL-4R\u03b1 Signaling, Influence of Neonatal Development, and Limited Efficacy of Glucocorticoid Treatment"],"prefix":"10.1093","volume":"182","author":[{"given":"Alessandra","family":"Livraghi","sequence":"first","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara R","family":"Grubb","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J","family":"Hudson","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen J","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K","family":"Sheehan","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus A","family":"Mall","sequence":"additional","affiliation":[{"name":"Department of Pediatrics III, Pediatric Pulmonology and Cystic Fibrosis Center, University of Heidelberg , Heidelberg,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanda K","family":"O'Neal","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C","family":"Boucher","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott H","family":"Randell","sequence":"additional","affiliation":[{"name":"Cystic Fibrosis\/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill , Chapel Hill, NC, 27599"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,4,1]]},"reference":[{"key":"2026012806354951600_R1","first-page":"487","article-title":"Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice.","volume-title":"Nat. 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