Amino acid transporter SNAT2 is critical for resolution of pulmonary edema and regulation of ER stress‐ and autophagy‐induced apoptosis in ARDS
Notice bibliographique
Résumé
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 .
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) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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 | 0,000 |
| 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 ».