Sodium‐coupled neutral amino acid transporter SNAT2 is critical for alveolar fluid transport and resolution of pulmonary edema
Bibliographic record
Abstract
Objective In the intact lung, constant movement of Na + and Cl − across the epithelial barrier regulates alveolar liquid volume and maintains a balance between fluid secretion and clearance, which is critical for normal lung function. Dysregulation or inhibition of Na + transport can lead to accumulation of fluid in the airspace resulting in impaired gas exchange and respiratory failure. Previous studies have largely focused on the critical role of the amiloride‐sensitive epithelial sodium channel (ENaC) in alveolar fluid transport, yet activation of ENaC failed to reverse edema formation in clinical trials. Since 40–50% of alveolar fluid clearance is amiloride‐insensitive, sodium channels other than ENaC such as sodium‐coupled neutral amino acid transporter (SNAT, Slc38a2) 2 may provide for new potential therapeutic targets. SNAT2 co‐transports a neutral amino acid along with Na + and may promote alveolar fluid clearance by mediating epithelial Na + uptake. Here, we studied the role of SNAT2 in a murine model of lung injury, in isolated perfused lungs (IPL) and in a pulmonary epithelial cell culture System. Methods For functional in vitro analyses, L‐alanine transport across NCI‐H441 cells was analyzed by ELISA, with cells cultured in the presence or absence of amino acids, and following treatment with HgCl 2 , a SNAT inhibitor, or siRNA (control or siSNAT2). In IPL of slc38a2 +/− and wildtype mice, edema formation was induced by hydrostatic stress (7 cm H 2 O) and fluid transport was assessed in the absence or presence of the SNAT2 inhibitor methylaminoisobutyric acid (MeAIB) or SNAT2 substrate L‐alanine in the alveolar instillate. Edema formation was assessed after 30 min of perfusion and ventilation by measurement of wet‐to‐dry lung weight ratio (W/D). For in vivo measurements of edema formation and resolution, acid (HCl) or saline was instilled intratracheally in slc38a2 +/− and wildtype mice. After 2 h of mechanical ventilation, lungs were collected for W/D measurement. Results In vitro, L‐alanine transport was significantly decreased in H441 cells treated with HgCl 2 or SNAT2‐siRNA as compared to respective controls. In vivo , SNAT2 knockout ( slc38a2 −/− ) mice were found to be sublethal and newborn pups typically succumbed to cyanotic dyspnea. In IPL, lungs of slc38a2 +/− showed elevated W/D ratio as compared to wildtype lungs in response to hydrostatic stress and after treatment with the SNAT2 inhibitor MeAIB. Similarly, in HCl‐induced ALI, W/D ratio was increased in slc38a2 +/− mice. Conclusion In its function as Na + transporter, we propose a crucial role for SNAT2 in alveolar fluid transport. Our results indicate that SNAT2 is functional relevant for alveolar fluid absorption and may contribute to the resolution of pulmonary edema. Hence, activation of SNAT2 may, provide a new therapeutic strategy to counteract and/or reverse formation of pulmonary edema. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".