Sodium-coupled neutral amino acid transporter SNAT2 counteracts cardiogenic pulmonary edema by driving alveolar fluid clearance.

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 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.

MRI measurements of the normal pediatric optic nerve pathway.

The purpose of this work is to establish a reference scale of optic nerve pathway measurements in pediatric patients according to age using MRI. Optic nerve pathway measurements were retrospectively analyzed using an orbits equivalent sequence on brain MRI scans of 137 pediatric patients (72 male, 65 female, average age = 7.7 years, standard deviation  = 5.3). The examinations were performed on a 1.5-T or 3-T Siemens MR system using routine imaging protocols. Measurements include diameters of the orbital optic nerves (OON), prechiasmatic optic nerves (PON), optic tracts (OT), and optic chiasm (OC). Measurements were performed manually by 2 neuroradiologists, using post-processing software. Patients were stratified into five age groups for measurement analyses: (I) 0-1.49 years, (II) 1.5-2.99 years, (III) 3-5.99 years, (IV) 6-11.99 years, and (V) 12-18 years. The observed value range of OON mean diameter was 2.7 mm (Interquartile range (IQR) = 2.4-2.9), PON was 3.2 mm (IQR  =  3.05-3.5), OT 2.6 mm (IQR = 2-2.9). A strong positive correlation was established between age and mean diameter of OON (r = 0.73, p < .001), PON (r = 0.59, p < .001), and OT (r = 0.72, p < .001). A significant difference in mean OON diameters was found between age groups I-II (d = 0.3, p = .01), II-III (d = 0.5, p < .001), III-IV (d = 0.5, p < .001) followed by a plateau between IV-V (d = 0.l0, p = .19). OON/OT ratio maintained a steady mean value 1 (IQR = 0.93-1.1) regardless of age (p = .7). The diameter of optic pathways was found to increase as a function of age with consistent positive correlation between nerve and tract for all ages.

Chloride transport-driven alveolar fluid secretion is a major contributor to cardiogenic lung edema.

Alveolar fluid clearance driven by active epithelial Na(+) and secondary Cl(-) absorption counteracts edema formation in the intact lung. Recently, we showed that impairment of alveolar fluid clearance because of inhibition of epithelial Na(+) channels (ENaCs) promotes cardiogenic lung edema. Concomitantly, we observed a reversal of alveolar fluid clearance, suggesting that reversed transepithelial ion transport may promote lung edema by driving active alveolar fluid secretion. We, therefore, hypothesized that alveolar ion and fluid secretion may constitute a pathomechanism in lung edema and aimed to identify underlying molecular pathways. In isolated perfused lungs, alveolar fluid clearance and secretion were determined by a double-indicator dilution technique. Transepithelial Cl(-) secretion and alveolar Cl(-) influx were quantified by radionuclide tracing and alveolar Cl(-) imaging, respectively. Elevated hydrostatic pressure induced ouabain-sensitive alveolar fluid secretion that coincided with transepithelial Cl(-) secretion and alveolar Cl(-) influx. Inhibition of either cystic fibrosis transmembrane conductance regulator (CFTR) or Na(+)-K(+)-Cl(-) cotransporters (NKCC) blocked alveolar fluid secretion, and lungs of CFTR(-/-) mice were protected from hydrostatic edema. Inhibition of ENaC by amiloride reproduced alveolar fluid and Cl(-) secretion that were again CFTR-, NKCC-, and Na(+)-K(+)-ATPase-dependent. Our findings show a reversal of transepithelial Cl(-) and fluid flux from absorptive to secretory mode at hydrostatic stress. Alveolar Cl(-) and fluid secretion are triggered by ENaC inhibition and mediated by NKCC and CFTR. Our results characterize an innovative mechanism of cardiogenic edema formation and identify NKCC1 as a unique therapeutic target in cardiogenic lung edema.