Sodium-coupled neutral amino acid transporter SNAT2 regulates alveolar epithelial cell metabolism and homeostasis in acute lung injury

作者：J. Falivene, Gefei Li, S. Weidenfeld, S. Schultz, L. Erfinanda, P. Pennitz, G. Nouailles, P. Shen, M. Löhning, W. Kuebler · 发表于：Physiology · 年份：2026 · DOI：10.1152/physiol.2026.41.s1.2300070

Acute Respiratory Distress Syndrome (ARDS) is the most frequent cause of death in intensive care units, yet effective pharmacological treatments are still lacking. Hallmarks of ARDS include dysfunctional alveolar fluid clearance (AFC) and loss of alveolar-capillary barrier function due to alveolar epithelial cell (AEC) death. The Na + -coupled neutral amino acid (AA) transporter, SNAT2 (SLC38 family), transports one AA along with one Na + . We previously showed that SNAT2 expression in AEC promotes AFC via its Na + transport function. We now hypothesize that SNAT2, through its AA transport function, is a central regulator of AEC metabolism and cell fate in acute lung injury (ALI)/ARDS, and could thus represent a novel therapeutic target. Hence, we aim to investigate SNAT2 as AA transporter and its role in regulating AEC metabolism and homeostasis. Analysis of publicly available single cell RNA sequencing (scRNAseq) data showed that SNAT2 is abundantly expressed in human and mouse AEC. In vivo, LPS intranasal administration (5 mg/kg) to wild type (WT) mice increased lung barrier permeability (bronchoalveolar lavage fluid -BALF- protein), neutrophil infiltration and histological injury. These pathologic features were associated with a metabolic shift in lung tissue from tricarboxylic acid (TCA) cycle metabolites to glycolytic metabolites. Interestingly, glutamate (Glu), which derives from glutamine (Gln), was significantly reduced in the lungs of LPS-treated mice. In vitr...