Knockout Mice Reveal a Major Role for Alveolar Epithelial Type I Cells in Alveolar Fluid Clearance
Knockout Mice Reveal a Major Role for Alveolar Epithelial Type I Cells in Alveolar Fluid Clearance
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DOI：
10.1165/rcmb.2016-0005oc
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发表时间：
2016-09-01
影响因子：
6.4
通讯作者：
Crandall, Edward D.
中科院分区：
文献类型：
--
作者：
Flodby, Per;Kim, Yong Ho;Crandall, Edward D.
基底外侧Na-K-ATP酶（Na泵）的主动离子转运产生Na+梯度，驱动肺泡上皮细胞的液体吸收。α（1）和β（1）亚基是肺泡上皮细胞（AEC）中表达最高的钠泵亚基。使用两种细胞类型特异性的小鼠基因敲除系研究了β 1亚基的特异性贡献以及肺泡上皮II型（AT 2）与I型（AT 1）细胞对肺泡液体清除率（AFC）的相对贡献，其中在AT 1细胞或AT 1和AT 2细胞中敲除β 1亚基。AFC显着下降，在两个基因敲除线，揭示，我们相信第一次，AT 1细胞在AFC中发挥了重要作用，并提供了对肺泡内稳态AEC的特定作用的见解。来自敲除小鼠的AEC单层表现出短路电流和活性Na+吸收降低，与体内观察结果一致。与对照组相比，高氧或呼吸机诱导的肺损伤均未增加敲除肺的湿干肺重量比。敲除小鼠显示Na泵β 3亚单位表达和β 2肾上腺素能受体表达增加。这些结果表明，钠泵β 1亚基在肺泡离子和液体运输的关键作用，并表明，AT 1和AT 2细胞作出重大贡献，这些过程和AFC。此外，他们支持以细胞特异性方式改变肺泡上皮功能的通用方法的可行性，该方法可以直接洞察AT 1与AT 2在肺部的细胞特异性作用。
Active ion transport by basolateral Na-K-ATPase (Na pump) creates an Na+ gradient that drives fluid absorption across lung alveolar epithelium. The alpha(1) and beta(1) subunits are the most highly expressed Na pump subunits in alveolar epithelial cells (AEC). The specific contribution of the beta 1 subunit and the relative contributions of alveolar epithelial type II (AT2) versus type I (AT1) cells to alveolar fluid clearance (AFC) were investigated using two cell type-specific mouse knockout lines in which the beta 1 subunit was knocked out in either AT1 cells or both AT1 and AT2 cells. AFC was markedly decreased in both knockout lines, revealing, we believe for the first time, that AT1 cells play a major role in AFC and providing insights into AEC-specific roles in alveolar homeostasis. AEC monolayers derived from knockout mice demonstrated decreased short-circuit current and active Na+ absorption, consistent with in vivo observations. Neither hyperoxia nor ventilator-induced lung injury increased wet-to-dry lung weight ratios in knockout lungs relative to control lungs. Knockout mice showed increases in Na pump beta 3 subunit expression and beta(2)-adrenergic receptor expression. These results demonstrate a crucial role for the Na pump beta 1 subunit in alveolar ion and fluid transport and indicate that both AT1 and AT2 cells make major contributions to these processes and to AFC. Furthermore, they support the feasibility of a general approach to altering alveolar epithelial function in a cell-specific manner that allows direct insights into AT1 versus AT2 cell-specific roles in the lung.