title: Airway and lung pathology due to mucosal surface dehydration in {beta}-epithelial Na+ channel-overexpressing mice: role of TNF-{alpha} and IL-4R{alpha} signaling, influence of neonatal development, and limited efficacy of glucocorticoid treatment.
abstract: Overexpression of the epithelial Na(+) channel beta subunit (Scnn1b gene, betaENaC 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-alpha, 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-alpha or its receptor, TNFR1, had no measurable effect on the phenotype. Deletion of IL-4Ralpha abolished transient mucous secretory cell (MuSC) abundance and eosinophilia normally observed in neonatal wild-type mice. Similarly, IL-4Ralpha 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-4Ralpha 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-4Ralpha-dependent, transient abundance of MuSC and eosinophils; 2) absence of IL-4Ralpha 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-4Ralpha- and TNF-alpha-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.
authors.affiliation: Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, 27599, USA. alessandra_livraghi@med.unc.edu
authors.forename: Alessandra
authors.initials: A
authors.lastname: Livraghi
authors.forename: Barbara R
authors.initials: BR
authors.lastname: Grubb
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hudson
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Wilkinson
authors.forename: John K
authors.initials: JK
authors.lastname: Sheehan
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.forename: Wanda K
authors.initials: WK
authors.lastname: O'Neal
authors.forename: Richard C
authors.initials: RC
authors.lastname: Boucher
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018925:Chemokines / Q000032:analysis; D003681:Dehydration / Q000150:complications; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000188:drug therapy / Q000209:etiology; D053503:Epithelial Sodium Channels / Q000235:genetics; D005938:Glucocorticoids / Q000627:therapeutic use; D018928:Immunity, Mucosal / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D011239:Prednisolone / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000254:growth & development / Q000378:metabolism / Q000503:physiopathology*; D012137:Respiratory System / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D018925:Chemokines; D053503:Epithelial Sodium Channels; D005938:Glucocorticoids; D011239:Prednisolone; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C507049:Scnn1b protein, mouse