The constant transport of ions across the alveolar epithelial barrier regulates alveolar fluid homeostasis. Dysregulation or inhibition of Na⁺ transport causes fluid accumulation in the distal airspaces resulting in impaired gas exchange and respiratory failure. Previous studies have primarily focused on the critical role of amiloride-sensitive epithelial sodium channel (ENaC) in alveolar fluid clearance (AFC), yet activation of ENaC failed to attenuate pulmonary edema in clinical trials. Since 40% of AFC is amiloride-insensitive, Na⁺ channels/transporters other than ENaC such as Na⁺-coupled neutral amino acid transporters (SNATs) may provide novel therapeutic targets. Here, we identified a key role for SNAT2 (SLC38A2) in AFC and pulmonary edema resolution. In isolated perfused mouse and rat lungs, pharmacological inhibition of SNATs by HgCl₂ and α-methylaminoisobutyric acid (MeAIB) impaired AFC. Quantitative RT-PCR identified SNAT2 as highest expressed System A transporter in pulmonary epithelial cells. Pharmacological inhibition or siRNA-mediated knockdown of SNAT2 reduced transport of L-alanine across pulmonary epithelial cells. Homozygous Slc38a2^-/- mice were subviable and died shortly after birth with severe cyanosis. Isolated lungs of Slc38a2^+/- mice developed higher wet-to-dry weight ratios (W/D) as compared to WT in response to hydrostatic stress. Similarly, W/D ratios were increased in Slc38a2^+/- mice as compared to controls in an acid-induced lung injury model. Our results identify SNAT2 as functional transporter for Na⁺ and neutral amino acids in pulmonary epithelial cells with a relevant role in AFC and the resolution of lung edema. Activation of SNAT2 may provide a new therapeutic strategy to counteract and/or reverse pulmonary edema.

中文翻译：

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钠偶联中性氨基酸转运蛋白SNAT2通过驱动肺泡液清除来抵消心源性肺水肿

离子穿过肺泡上皮屏障的持续转运调节了肺泡液的体内平衡。Na ⁺转运的失调或抑制会导致远端气隙中积聚液体，从而导致气体交换受损和呼吸衰竭。先前的研究主要集中在阿米洛利敏感的上皮钠通道（ENaC）在肺泡液清除（AFC）中的关键作用，但是在临床试验中，ENaC的激活未能减弱肺水肿。由于40％的AFC对阿米洛利不敏感，因此，除了ENaC以外的Na ⁺通道/转运蛋白，例如Na ⁺偶联的中性氨基酸转运蛋白（SNAT）可能提供新的治疗目标。在这里，我们确定了SNAT2（SLC38A2）在AFC和肺水肿消退中的关键作用。在分离的小鼠和大鼠肺灌注中，HgCl ₂和α-甲基氨基异丁酸（MeAIB）对SNAT的药理抑制作用会损害AFC。定量RT-PCR鉴定SNAT2为肺上皮细胞中表达最高的系统A转运蛋白。SNAT2的药理抑制或siRNA介导的敲低降低了L-丙氨酸跨肺上皮细胞的转运。纯合子Slc38a2 ^-/-小鼠可存活，出生后不久就死于严重的紫。Slc38a2 ^+/-的孤立肺与WT相比，小鼠对静水压力产生更高的干重比（W / D）。类似地，与酸诱导的肺损伤模型中的对照相比，Slc38a2 ^+/-小鼠的W / D比增加。我们的结果确定SNAT2是肺上皮细胞中Na ⁺和中性氨基酸的功能性转运蛋白，在AFC和肺水肿的缓解中具有重要作用。SNAT2的激活可能提供一种新的治疗策略，以抵消和/或逆转肺水肿。