Lung disease phenotypes caused by over-expression of combinations of alpha, beta, and gamma subunits of the epithelial sodium channel in mouse airways

The epithelial Na+ channel (ENaC) regulates airway surface hydration. In mouse airways, ENaC is composed of three subunits, alpha (α), beta (β), and gamma (), which are differentially expressed (α > β > ). Airway-targeted overexpression of the β subunit results in Na+ hyperabsorption causing airway surface dehydration, hyperconcentrated mucus with delayed clearance, lung inflammation, and perinatal mortality. Notably, mice overexpressing the α or subunit do not exhibit airway Na+ hyperabsorption nor lung pathology. To test whether overexpression of multiple ENaC subunits produced Na+ transport and disease severity exceeding that of βENaC-Tg mice, we generated double (αβ, α, β) and triple (αβ) transgenic mice and characterized their lung phenotypes. Double αENaC-Tg mice were undistinguishable from WT littermates. In contrast, double βENaC-Tg mice exhibited airway Na+ absorption greater than βENaC-Tg mice, which was paralleled by worse survival, decreased mucociliary clearance, and more severe lung pathology. Double αβENaC-Tg mice exhibited Na+ transport rates comparable to βENaC-Tg littermates. However, αβENaC-Tg mice had poorer survival and developed severe parenchymal consolidation. In situ hybridization (RNAscope®) analysis revealed both alveolar and airway αENaC-Tg overexpression. Triple αβENaC-Tg mice were born in Mendelian proportions but died within the first day of life and the small sample size prevented analyses of cause(s) of death. Cumulatively, these results indicate that over-expression of βENaC is rate limiting for generation of pathologic airway surface dehydration. Notably, airway co-overexpression of β and ENaC had additive effects on Na+ transport and disease severity, suggesting dose-dependency of these two variables.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2yPY6M0
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