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首页> 外文期刊>American Journal of Physiology >Lung disease phenotypes caused by overexpression of combinations of α-, β-, and γ-subunits of the epithelial sodium channel in mouse airways
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Lung disease phenotypes caused by overexpression of combinations of α-, β-, and γ-subunits of the epithelial sodium channel in mouse airways

机译：由小鼠气道上皮钠通道的α-，β-和γ-亚基组合引起的肺病表型

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摘要

The epithelial Na+ channel (ENaC) regulates airway surface hydration. In mouse airways, ENaC is composed of three subunits, a, p, and 7, which are differentially expressed (α >β >γ). 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 γ-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 βENaC-Tg mice, we generated double (αβ, αγ, βγ) and triple (αβγ) transgenic mice and characterized their lung phenotypes. Double αγENaC-Tg mice were indistinguishable from WT littermates. In contrast, double βγENaC-Tg mice exhibited airway Na+ absorption greater than that of pENaC-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 those of 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 αβγENaC-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 βENaC is rate limiting for generation of pathological airway surface dehydration. Notably, airway co-overexpression of β- and γENaC had additive effects on Na+ transport and disease severity, suggesting dose dependency of these two variables.
机译：上皮NA +通道（ENAC）调节气道表面水合。在小鼠气道中，ENAC由三个亚基，A，P和7组成，其差异表达（α>β>γ）。 β亚基的气道靶向过度表达导致Na +过度吸附，导致气道表面脱水，具有延迟间隙，肺炎和围产期死亡率的血管表面脱水，过度浓缩的粘液。值得注意的是，过表达α-或γ-亚基的小鼠不表现出气道Na +过吸收或肺病理学。为了测试多种ENAC亚基的过表达是否产生Na +运输和疾病严重程度超过βenac-Tg小鼠的严重程度，我们产生了双（αβ，αγ，βγ）和三（αβγ）转基因小鼠并表征其肺表型。双αγAc-TG小鼠与WT凋落物无法区分。相反，双βγAc-Tg小鼠表现出呼吸道Na +的吸收大于PENAC-TG小鼠的吸收，这些小鼠与更差的存活率，减少粘蛋白间隙和更严重的肺病学平行。双αβ-TG小鼠表现出与βenac-TG凋落物相当的Na +传输速率。然而，αβ-TG小鼠的存活较差，并且发育严重的实质巩固。原位杂交（Rnascope）分析显示肺泡和气道αenac-Tg过表达。三重αβγAc-TG小鼠出生于孟德尔的比例，但在寿命的第一天死亡，小样本尺寸防止了死亡原因的分析。累积地，这些结果表明βenac的过表达是对病态气道表面脱水产生的速率限制。值得注意的是，β-和γAc的呼吸道共同表达对Na +运输和疾病严重程度具有添加剂影响，表明这两个变量的剂量依赖性。

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