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Airway and Lung Pathology Due to Mucosal Surface Dehydration in β-Epithelial Na⁺ Channel-Overexpressing Mice: Role of TNF- and IL-4R Signaling, Influence of Neonatal Development, and Limited Efficacy of Glucocorticoid Treatment¹

Alessandra Livraghi^2,*, Barbara R. Grubb^*, Elizabeth J. Hudson^*, Kristen J. Wilkinson^*, John K. Sheehan^*, Marcus A. Mall, Wanda K. O'Neal^*, Richard C. Boucher^* and Scott H. Randell^*

^* Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599; and Department of Pediatrics III, Pediatric Pulmonology and Cystic Fibrosis Center, University of Heidelberg, Heidelberg, Germany

Overexpression of the epithelial Na⁺ channel β subunit (Scnn1b gene, βENaC 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-, 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- or its receptor, TNFR1, had no measurable effect on the phenotype. Deletion of IL-4R abolished transient mucous secretory cell (MuSC) abundance and eosinophilia normally observed in neonatal wild-type mice. Similarly, IL-4R 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 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-dependent, transient abundance of MuSC and eosinophils; 2) absence of IL-4R 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- and TNF--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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by North American Cystic Fibrosis Foundation (CFF) Grant LIVRAG04I0 (to A.L.), Deutsche Forschungsgemeinschaft MA2081/2-1 grant (to M.A.M.), National Institutes of Health (NIH) Grant P30 DK065988 and CFF grant R026-CR02 (to W.K.O.), NIH Grants P50 HL060280, P01 HL034322, P30 DK065988, and P50 HL084934 (to R.C.B.), and CFF Grant RANDEL07P0 (to S.H.R.).

² Address correspondence and reprint requests to Dr. Alessandra Livraghi, Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, CB 7248 Thurston Bowles Building, Room 6029, Chapel Hill, NC 27599. E-mail address: alessandra_livraghi{at}med.unc.edu

³ Abbreviations used in this paper: CCSP, Clara cell secretory protein; Tg, transgenic; ASL, airway surface liquid; CF, cystic fibrosis; CB, chronic bronchitis; COPD, chronic obstructive pulmonary disease; MuSC, mucous secretory cells; BAL, bronchoalveolar lavage; WT, wild type; KO, knockout; BALF, bronchoalveolar lavage fluid; AB/PAS, Alcian blue/periodic acid-Schiff; Scnn1b, sodium channel nonvoltage gated 1, β subunit.

⁴ The online version of this article contains supplemental material.