LOW-DOSE ALCOHOL REDIRECTS POSTPRANDIAL CHOLINERGIC-STIMULATED APICAL EXOCYTOSIS TO THE BASOLATERAL MEMBRANE IN PANCREATIC ACINAR CELLS, THE SUSCEPTIBILITY MECHANISM OF ALCOHOLIC PANCREATITIS
Notice bibliographique
Résumé
Background: We previously demonstrated that alcohol (EtOH) pretreatment of pancreatic acini caused the basal plasma membrane (BPM) to become receptive to aberrant BPM exocytosis upon stimulation with submaximal CCK-8. These actions of alcohol on the acinar cell were due to induction of PM-bound Munc18c to dissociate into the cytosol, rendering the PM Syntaxin4 to interact with PM-SNAP-23 and granule-VAMP to form a complex capable of mediating basolateral exocytosis into the interstitial space, which we had postulated to be a mechanism of alcoholic pancreatitis. Rat pancreas however lacks CCK receptors and instead responds to cholinergic stimulation. Aim: We therefore examined whether 1- low EtOH concentration (20 mM) is able to alter submaximal cholinergic stimulation of rat pancreatic acinar cell secretion and exocytosis; 2- alcohol diet-fed rats are susceptible to develop pancreatitis upon low postprandial cholinergic stimulation. Methods: 1- Dispersed rat pancreatic acini were pretreated with non-stimulatory EtOH (20 mM-1 h) followed by stimulation with postprandial carbachol (3 uM-1 h), a dose stimulating only half maximal amylase secretion; 2- rats were fed with either a control or ethanol (36% of total calories intake replacement) liquid diet for 6 weeks and then challenged with low carbachol (5 ip injections of 0.5 uM/kg/h) stimulation.We then examined: a) PM levels of Munc18c and SNARE proteins, and Munc18c displacement into the cytosol by confocal microscopy and cell subfractionation; b) amylase release; c) real-time epifluorescent imaging of exocytosis using FM1-43; d) electron microscopy to visualize the distribution of granules within the cell; e) tissue hematoxylin and eosin (H&E) staining to examine morphologic changes of pancreatitis; f) serum amylase, lipase and ethanol concentrations as clinical parameters of pancreatitis. Results: 1- a) Whereas 20 mM EtOH has no effect on amylase secretion, pretreatment with 20 mM EtOH inhibited 3 uM carbachol stimulated secretion. b) Whereas 3 uM carbachol evokes apical exocytosis, pretreatment with 20 mM EtOH redirected exocytosis to the basal (by FM1-43 imaging) and lateral plasma membrane (by E.M.). c) While neither 20 mM EtOH nor 3 uM carbachol affected PM-Munc18c (confocal microscopy and subcellular fractionation), pretreatment of acini with 20 mM ETOH induced 3 uM carbachol to displace Munc18c from the BPM into the cytosol. 2-Alcohol diet-fed rats (serum ETOH levels of 20-30 mM) were normal and did not exhibit major morphologic defects in the pancreas. However, subsequent exposure to low-dose carbachol induced mild pancreatitis, observed as altered morphology (E.M and H&E) showing vacuolization in acinar cells, leukocyte infiltrate, hemorrhage and necrotic spots; along with clinical parameters of elevated serum levels of amylase and lipase. These morphologic changes correlated to Munc18c displacement from the BPM and its degradation in the cytosol. Conclusion: Postprandial EtOH renders acini PM-Munc18c conducive for postprandial cholinergic stimulation to displace into the cytosol, relieving Syntaxin4 to bind SNAP-23 and ZG VAMP proteins to promote basolateral exocytosis. We propose this to be a 'susceptibility' mechanism by which alcohol predisposes to human pancreatitis. (Funded by: Alcohol Beverage Medical Research Foundation and NIH -R21 AA015579-01).
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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) | 0,000 | 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 tête enseignante, 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 ».