Ridge K M, Olivera W G, Saldias F, Azzam Z, Horowitz S, Rutschman D H, Dumasius V, Factor P, Sznajder J I
Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, Ill 60611, USA.
Circ Res. 2003 Mar 7;92(4):453-60. doi: 10.1161/01.RES.0000059414.10360.F2. Epub 2003 Jan 30.
The alveolar epithelium is composed of alveolar type 1 (AT1) and alveolar type 2 (AT2) cells, which represent approximately 95% and approximately 5% of the alveolar surface area, respectively. Lung liquid clearance is driven by the osmotic gradient generated by the Na,K-ATPase. AT2 cells have been shown to express the alpha1 Na,K-ATPase. We postulated that AT1 cells, because of their larger surface area, should be important in the regulation of active Na+ transport. By immunofluorescence and electron microscopy, we determined that AT1 cells express both the alpha1 and alpha2 Na,K-ATPase isoforms. In isolated, ouabain-perfused rat lungs, the alpha2 Na,K-ATPase in AT1 cells mediated 60% of the basal lung liquid clearance. The beta-adrenergic agonist isoproterenol increased lung liquid clearance by preferentially upregulating the alpha2 Na,K-ATPase protein abundance in the plasma membrane and activity in alveolar epithelial cells (AECs). Rat AECs and human A549 cells were infected with an adenovirus containing the rat Na,K-ATPase alpha2 gene (Adalpha2), which resulted in the overexpression of the alpha2 Na,K-ATPase protein and caused a 2-fold increase in Na,K-ATPase activity. Spontaneously breathing rats were also infected with Adalpha2, which increased alpha2 protein abundance and resulted in a approximately 250% increase in lung liquid clearance. These studies provide the first evidence that alpha2 Na,K-ATPase in AT1 cells contributes to most of the active Na+ transport and lung liquid clearance, which can be further increased by stimulation of the beta-adrenergic receptor or by adenovirus-mediated overexpression of the alpha2 Na,K-ATPase.
肺泡上皮由1型肺泡上皮细胞（AT1）和2型肺泡上皮细胞（AT2）组成，它们分别占肺泡表面积的约95%和约5%。肺液清除是由Na，K - ATP酶产生的渗透梯度驱动的。已证明AT2细胞表达α1 Na，K - ATP酶。我们推测，由于AT1细胞表面积较大，它们在主动Na⁺转运的调节中应该很重要。通过免疫荧光和电子显微镜，我们确定AT1细胞表达α1和α2 Na，K - ATP酶同工型。在离体的、哇巴因灌注的大鼠肺中，AT1细胞中的α2 Na，K - ATP酶介导了60%的基础肺液清除。β - 肾上腺素能激动剂异丙肾上腺素通过优先上调质膜中α2 Na，K - ATP酶蛋白丰度和肺泡上皮细胞（AECs）中的活性来增加肺液清除。大鼠AECs和人A549细胞用含有大鼠Na，K - ATP酶α2基因的腺病毒（Adα2）感染，这导致α2 Na，K - ATP酶蛋白过表达并使Na，K - ATP酶活性增加2倍。自主呼吸的大鼠也用Adα2感染，这增加了α2蛋白丰度并导致肺液清除增加约250%。这些研究提供了首个证据，即AT1细胞中的α2 Na，K - ATP酶促成了大部分的主动Na⁺转运和肺液清除，通过刺激β - 肾上腺素能受体或通过腺病毒介导的α2 Na，K - ATP酶过表达可进一步增加肺液清除。
