Flodby Per, Kim Yong Ho, Beard LaMonta L, Gao Danping, Ji Yanbin, Kage Hidenori, Liebler Janice M, Minoo Parviz, Kim Kwang-Jin, Borok Zea, Crandall Edward D
1 Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.
2 Division of Neonatology, Department of Pediatrics, and.
Am J Respir Cell Mol Biol. 2016 Sep;55(3):395-406. doi: 10.1165/rcmb.2016-0005OC.
Active ion transport by basolateral Na-K-ATPase (Na pump) creates an Na(+) gradient that drives fluid absorption across lung alveolar epithelium. The α1 and β1 subunits are the most highly expressed Na pump subunits in alveolar epithelial cells (AEC). The specific contribution of the β1 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 β1 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 β3 subunit expression and β2-adrenergic receptor expression. These results demonstrate a crucial role for the Na pump β1 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.
基底外侧钠钾ATP酶（钠泵）介导的主动离子转运产生了一个钠梯度，该梯度驱动液体跨肺肺泡上皮的吸收。α1和β1亚基是肺泡上皮细胞（AEC）中表达最为丰富的钠泵亚基。利用两种细胞类型特异性的小鼠基因敲除品系，研究了β1亚基的具体作用以及肺泡II型上皮细胞（AT2）与I型上皮细胞（AT1）对肺泡液体清除（AFC）的相对贡献，在这两种敲除品系中，β1亚基分别在AT1细胞或同时在AT1和AT2细胞中被敲除。在这两种敲除品系中，AFC均显著降低，我们认为这首次揭示了AT1细胞在AFC中起主要作用，并为AEC在肺泡稳态中的特定作用提供了见解。源自敲除小鼠的AEC单层显示短路电流和主动钠吸收降低，这与体内观察结果一致。相对于对照肺，高氧或呼吸机诱导的肺损伤均未增加敲除肺的湿重与干重之比。敲除小鼠的钠泵β3亚基表达和β2肾上腺素能受体表达增加。这些结果证明了钠泵β1亚基在肺泡离子和液体转运中起关键作用，并表明AT1和AT2细胞对这些过程和AFC均有主要贡献。此外，它们支持以细胞特异性方式改变肺泡上皮功能这一通用方法的可行性，该方法能够直接洞察AT1和AT2细胞在肺中的特异性作用。
