Amino acid transporter SNAT2 is critical for resolution of pulmonary edema and regulation of ER stress‐ and autophagy‐induced apoptosis in ARDS
Bibliographic record
Abstract
Objective The disruption of the alveolar‐epithelial barrier is a central pathophysiologic factor in acute respiratory distress syndrome (ARDS), the most frequent cause of death in critical ill patients. Loss of barrier integrity leads to edema formation, impaired gas exchange and respiratory failure. Recent studies propose that unavailability of essential amino acids may promote lung epithelial apoptosis in response to lung injury, putatively by mechanisms involving autophagy and the ER stress response. This suggests a critical role for amino acid transporter in the pathophysiology of ARDS. Sodium‐coupled neutral amino acid transporter 2 (SNAT2) co‐transports 1 amino acid along with 1 Na + and may promote alveolar fluid clearance by mediating epithelial Na + uptake, but may also be involved in regulation of epithelial apoptosis, autophagy and ER stress. Here, we studied the role of SNAT2 in a murine model of acute lung injury (ALI), in isolated perfused lungs (IPL) and in a pulmonary epithelial cell culture system. Methods Expression of SNAT2 in epithelial cell line NCI‐H441 was determined under basal conditions or after cytomix (TNFα, IFN‐γ, IL‐1β, LPS) treatment by Western blot. For measurement of L‐alanine transport, H441 cells were cultured in the absence of amino acids and treated with HgCl 2 , which inhibits SNATs, or siRNA (control or siSNAT2). L‐alanine transport was analyzed by ELISA. For in vivo experiments, slc38a2 +/− and wildtype mice were anesthetized and acid (HCl) or saline was instilled intratracheally. After 2 h of mechanical ventilation, lungs were collected for wet/dry lung weight (W/D) measurement, tissue and protein extraction. Edema formation in IPL from slc38a2 +/− mice and wildtype was assessed by continuous measurement of lung weight gain. Results SNAT2 protein expression was decreased after cytomix treatment. L‐alanine transport was significantly decreased in H441 cells either treated with HgCl 2 or SNAT2‐siRNA under amino acid deprivation as compared to control. SNAT2 knockout ( slc38a2 −/− ) mice were found to be sublethal and newborn pups typically succumbed to cyanotic dyspnea. In HCl‐induced ALI, expression of ER stress marker IRE1a, pro‐apoptotic protein CHOP and autophagy marker Beclin1 in lung protein lysates was elevated in slc38a2 +/− mice compared to wildtype. In parallel, W/D ratio was increased in slc38a2 +/− mice. Similarly, in IPL, unstimulated lungs of slc38a2 +/− showed increased weight gain and elevated W/D ratio as compared to wildtype lungs. Conclusion SNAT2 counteracts lung edema formation, probably by mediating Na + uptake that drives alveolar fluid clearance. Additionally, SNAT2 reduces ER stress‐ and autophagy‐induced apoptosis, presumably through its role as amino acid transporter. Loss of SNAT2 under inflammatory conditions may thus enhance epithelial apoptosis, ER stress, and autophagy as well as lung edema, hence promoting development of lung injury. SNAT2 activation may thus provide for a novel multi‐pronged strategy to counteract lung injury. This abstract is from the Experimental Biology 2018 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 machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".