| First Author | Livraghi-Butrico A | Year | 2018 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 314 |
| Issue | 2 | Pages | L318-L331 |
| PubMed ID | 29074490 | Mgi Jnum | J:257602 |
| Mgi Id | MGI:6116122 | Doi | 10.1152/ajplung.00382.2017 |
| Citation | Livraghi-Butrico A, et al. (2018) Lung disease phenotypes caused by overexpression of combinations of alpha-, beta-, and gamma-subunits of the epithelial sodium channel in mouse airways. Am J Physiol Lung Cell Mol Physiol 314(2):L318-L331 |
| abstractText | The epithelial Na(+) channel (ENaC) regulates airway surface hydration. In mouse airways, ENaC is composed of three subunits, alpha, beta, and gamma, which are differentially expressed (alpha > beta > gamma). Airway-targeted overexpression of the beta subunit results in Na(+) hyperabsorption, causing airway surface dehydration, hyperconcentrated mucus with delayed clearance, lung inflammation, and perinatal mortality. Notably, mice overexpressing the alpha- or gamma-subunit do not exhibit airway Na(+) hyperabsorption or lung pathology. To test whether overexpression of multiple ENaC subunits produced Na(+) transport and disease severity exceeding that of betaENaC-Tg mice, we generated double (alphabeta, alphagamma, betagamma) and triple (alphabetagamma) transgenic mice and characterized their lung phenotypes. Double alphagammaENaC-Tg mice were indistinguishable from WT littermates. In contrast, double betagammaENaC-Tg mice exhibited airway Na(+) absorption greater than that of betaENaC-Tg mice, which was paralleled by worse survival, decreased mucociliary clearance, and more severe lung pathology. Double alphabetaENaC-Tg mice exhibited Na(+) transport rates comparable to those of betaENaC-Tg littermates. However, alphabetaENaC-Tg mice had poorer survival and developed severe parenchymal consolidation. In situ hybridization (RNAscope) analysis revealed both alveolar and airway alphaENaC-Tg overexpression. Triple alphabetagammaENaC-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 overexpression of betaENaC is rate limiting for generation of pathological airway surface dehydration. Notably, airway co-overexpression of beta- and gammaENaC had additive effects on Na(+) transport and disease severity, suggesting dose dependency of these two variables. |
