Sodium‐coupled neutral amino acid transporter SNAT2 counteracts edema formation and reduces autophagy and ER stress in acute lung injury
Notice bibliographique
Résumé
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
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».