{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:36:45Z","timestamp":1784011005165,"version":"3.55.0"},"reference-count":47,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":["journals.physiology.org"],"crossmark-restriction":true},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2021,4,1]]},"abstract":"<jats:p> The constant transport of ions across the alveolar epithelial barrier regulates alveolar fluid homeostasis. Dysregulation or inhibition of Na<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> channels\/transporters other than ENaC such as Na<jats:sup>+<\/jats:sup>-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 HgCl<jats:sub>2<\/jats:sub> and \u03b1-methylaminoisobutyric acid (MeAIB) impaired AFC. Quantitative RT-PCR identified SNAT2 as the 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<jats:sup>\u2212\/\u2212<\/jats:sup> mice were subviable and died shortly after birth with severe cyanosis. Isolated lungs of Slc38a2<jats:sup>+\/\u2212<\/jats:sup> mice developed higher wet-to-dry weight ratios (W\/D) as compared to wild type (WT) in response to hydrostatic stress. Similarly, W\/D ratios were increased in Slc38a2<jats:sup>+\/\u2212<\/jats:sup> mice as compared to controls in an acid-induced lung injury model. Our results identify SNAT2 as a functional transporter for Na<jats:sup>+<\/jats:sup> 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. <\/jats:p>","DOI":"10.1152\/ajplung.00461.2020","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T16:37:12Z","timestamp":1610555832000},"page":"L486-L497","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Sodium-coupled neutral amino acid transporter SNAT2 counteracts cardiogenic pulmonary edema by driving alveolar fluid clearance"],"prefix":"10.1152","volume":"320","author":[{"given":"Sarah","family":"Weidenfeld","sequence":"first","affiliation":[{"name":"Keenan Research Centre for Biomedical Science, St. Michael\u2019s Hospital, Toronto, Ontario, Canada"},{"name":"Institute of Physiology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, 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