Sodium‐coupled neutral amino acid transporter SNAT2 counteracts edema formation and reduces autophagy and ER stress in acute lung injury
Bibliographic record
Abstract
Objective Acute respiratory distress syndrome (ARDS), the most frequent cause of death in intensive care, is characterized by an excessive inflammatory response, increased vascular permeability, edema formation, and impaired gas exchange. Recent studies have suggested deprivation of amino acids may aggravate lung injury while promoting apoptosis, ER stress, and autophagy. However, RCTs have failed to identify beneficial pharmaco‐nutritional interventions. This may point to a critical role of amino acid transporters in ARDS pathophysiology and its non‐human analogue acute lung injury (ALI). Sodium‐coupled neutral amino acid transporters (SNATs) mediate cellular uptake of amino acids along with Na + and are known to be upregulated in response to amino acid starvation. Here, we probed for the role of SNATs in a murine model of HCl‐ and LPS‐induced ALI and in a pulmonary epithelial cell culture system. Methods Expression of SNATs under basal conditions or after amino acid deprivation in epithelial cell lines (NCI‐H441/A549) and in isolated rat type‐I (ATI cells) was determined by PCR and Western blot. For measurement of L‐alanine transport, H441 cells were cultured on Transwell inserts in the presence or absence of amino acids and treated either with HgCl 2 , which inhibits SNATs, or siRNA (scramble or siSNAT2). Transport of L‐alanine from the upper to the lower compartment was analyzed by ELISA. For in vivo experiments, SNAT2 knockout ( slc38a2 −/− ), heterozygous ( slc38a2 +/− ) and wildtype ( slc38a2 +/+ ) mice were anesthetized and HCl or saline was instilled intratracheally. After 2 h of mechanical ventilation, lungs were collected for measurement of wet–to‐dry lung weight ratio (W/D) and protein extraction. In a second model of ALI, mice were anesthetized and LPS (0.4 mg/kg) was given intranasally. After 24 h, mice were euthanized and lungs were collected for protein extraction. Results Isolated ATI, H441, and A549 cells showed strong expression of SNAT2 after incubation in amino acid free medium. Under amino acid deprivation, H441 cells showed quantitative L‐alanine transport that was significantly decreased by treatment with HgCl 2 or siRNA silencing of SNAT2. Homozygous SNAT2 knockout mice were found to be sublethal and newborn pups typically succumbed to cyanotic dyspnea. In HCl‐induced ALI, W/D was elevated in slc38a2 −/− and slc38a2 +/− mice as compared to wildtype. Expression of ER stress and autophagy markers was increased in whole protein lysates of heterozygous mice compared to control in both models of ALI. Conclusion SNAT2 counteracts lung edema formation in acid‐induced ALI, presumably by mediating Na + uptake that drives alveolar fluid clearance. In LPS‐ and HCl‐induced lung injury, SNAT2 reduces ER stress and autophagy, putatively through its role as amino acid transporter. SNAT2 activation may, hence, provide a new multi‐pronged strategy to counteract ALI/ARDS. Support or Funding Information Supported by a CIHR grant to Dr. W.M. Kuebler
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| 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".