| First Author | Weidenfeld S | Year | 2021 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 320 |
| Issue | 4 | Pages | L486-L497 |
| PubMed ID | 33439101 | Mgi Jnum | J:304644 |
| Mgi Id | MGI:6514695 | Doi | 10.1152/ajplung.00461.2020 |
| Citation | Weidenfeld S, et al. (2021) Sodium-coupled neutral amino acid transporter SNAT2 counteracts cardiogenic pulmonary edema by driving alveolar fluid clearance. Am J Physiol Lung Cell Mol Physiol 320(4):L486-L497 |
| abstractText | 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 alpha-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(-/-) 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 wild type (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 a 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. |
