The effect of bile salts on the pancreatic duct mucosal barrier

Reber, Howard A.; Mosley, J. G.

doi:10.1002/bjs.1800670119

Cited by 28 publications

(14 citation statements)

References 10 publications

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“…The issue is far from resolved, since some studies question the role of bile in the pathology of acute pancreatitis (60,61). However, bile acids have a drastic effect on the permeability of the pancreatic duct mucosal barrier (62), and two recent studies demonstrated that bile acids are capable of inducing sustained toxic calcium signals in pancreatic acinar cells (20,44).…”

Section: Discussionmentioning

confidence: 99%

Effects of Secretagogues and Bile Acids on Mitochondrial Membrane Potential of Pancreatic Acinar Cells

Voronina¹,

Barrow²,

Gerasimenko

et al. 2004

Journal of Biological Chemistry

123

129

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In this study, we investigated the effects of secretagogues and bile acids on the mitochondrial membrane potential of pancreatic acinar cells. We measured the mitochondrial membrane potential using the tetramethylrhodamine-based probes tetramethylrhodamine ethyl ester and tetramethylrhodamine methyl ester. At low levels of loading, these indicators appeared to have a low sensitivity to the uncoupler carbonyl cyanide m-chlorophenylhydrazone, and no response was observed to even high doses of cholecystokinin. When loaded at high concentrations, tetramethylrhodamine methyl ester and tetramethylrhodamine ethyl ester undergo quenching and can be dequenched by mitochondrial depolarization. We found the dequench mode to be 2 orders of magnitude more sensitive than the low concentration mode. Using the dequench mode, we resolved mitochondrial depolarizations produced by supramaximal and by physiological concentrations of cholecystokinin. Other calcium-releasing agonists, acetylcholine, JMV-180, and bombesin, also produced mitochondrial depolarization. Secretin, which employs the cAMP pathway, had no effect on the mitochondrial potential; dibutyryl cAMP was also ineffective. The cholecystokinin-induced mitochondrial depolarizations were abolished by buffering cytosolic calcium. A non-agonist-dependent calcium elevation induced by thapsigargin depolarized the mitochondria. These experiments suggest that a cytosolic calcium concentration rise is sufficient for mitochondrial depolarization and that the depolarizing effect of cholecystokinin is mediated by a cytosolic calcium rise. Bile acids are considered possible triggers of acute pancreatitis. The bile acids taurolithocholic acid 3-sulfate, taurodeoxycholic acid, and taurochenodeoxycholic acid, at low submillimolar concentrations, induced mitochondrial depolarization, resolved by the dequench mode. Our experiments demonstrate that physiological concentrations of secretagogues and pathologically relevant concentrations of bile acids trigger mitochondrial depolarization in pancreatic acinar cells.

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Section: Discussionmentioning

confidence: 99%

Effects of Secretagogues and Bile Acids on Mitochondrial Membrane Potential of Pancreatic Acinar Cells

Voronina¹,

Barrow²,

Gerasimenko

et al. 2004

Journal of Biological Chemistry

123

129

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“…Although bile acids can cause some change in the permeability of the pancreatic duct mucosal barrier (42), their major effects appear to occur on the pancreatic acinar cell, the initiating site for pancreatitis. One of the earliest pathological changes observed in the acinar cell is the emergence of high-amplitude, globalized cytosolic Ca 2ϩ signals (40).…”

mentioning

confidence: 99%

Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice

Husain

Orabi

Muili

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Biliary pancreatitis is the most common etiology for acute pancreatitis, yet its pathophysiological mechanism remains unclear. Ca2+ signals generated within the pancreatic acinar cell initiate the early phase of pancreatitis, and bile acids can elicit anomalous acinar cell intracellular Ca2+ release. We previously demonstrated that Ca2+ released via the intracellular Ca2+ channel, the ryanodine receptor (RyR), contributes to the aberrant Ca2+ signal. In this study, we examined whether RyR inhibition protects against pathological Ca2+ signals, acinar cell injury, and pancreatitis from bile acid exposure. The bile acid tauro-lithocholic acid-3-sulfate (TLCS) induced intracellular Ca2+ oscillations at 50 μM and a peak-plateau signal at 500 μM, and only the latter induced acinar cell injury, as determined by lactate dehydrogenase (LDH) leakage. Pretreatment with the RyR inhibitors dantrolene or ryanodine converted the peak-plateau signal to a mostly oscillatory pattern ( P < 0.05). They also reduced acinar cell LDH leakage, basolateral blebbing, and propidium iodide uptake ( P < 0.05). In vivo, a single dose of dantrolene (5 mg/kg), given either 1 h before or 2 h after intraductal TLCS infusion, reduced the severity of pancreatitis down to the level of the control ( P < 0.05). These results suggest that the severity of biliary pancreatitis may be ameliorated by the clinical use of RyR inhibitors.

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“…At severely low [ATP] the Cl − /HCO 3 − exchanger function is suppressed. As a consequence, low fluid secretion rate favors ductal cell injury and the damage of ductal integrity, thus acute pancreatitis [31,[33][34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Bile acids activate ryanodine receptors in pancreatic acinar cells via a direct allosteric mechanism

et al. 2015

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a b s t r a c tThe earliest critical event of pancreatitis is a long lasting high amplitude rise of intracellular Ca 2+ concentration of the acinar cell, which can be triggered by high concentration of bile acids. Although, Ca 2+ -release through ryanodine receptors (RyR) is involved in the process, the significance and the exact mechanism of bile acid's action on RyR has not been fully elucidated yet. Therefore, we aimed to test with various techniques and aspects whether bile acids exert a direct effect on RyR and SERCA pump.Our data show that taurocholic acid (TCA)-induced Ca 2+ release in pancreatic acinar cells was significantly reduced by the RyR antagonist dantrolene. Further, we show that TCA enhanced RyR's 3 H-ryanodine binding and triggered robust Ca 2+ -release from RyR-enriched vesicles in the pathologically relevant concentration range. RyR single channel current analysis demonstrated that 200 M TCA induced a 5-fold increase in the channel's open probability and caused a significant lengthening of the mean open time. TCA also suppressed Ca 2+ -uptake rate and ATP-ase activity of SERCA-enriched vesicles, but interestingly, failed to decrease Ca 2+ elimination rate in intact cells. Overall, our results strongly suggest that TCA opens RyR by an allosteric mechanism, which contribute significantly to bile acid-induced pathologic Ca 2+ -leak from the endoplasmic reticulum in pancreatic acinar cells.

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The effect of bile salts on the pancreatic duct mucosal barrier

Cited by 28 publications

References 10 publications

Effects of Secretagogues and Bile Acids on Mitochondrial Membrane Potential of Pancreatic Acinar Cells

Effects of Secretagogues and Bile Acids on Mitochondrial Membrane Potential of Pancreatic Acinar Cells

Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice

Bile acids activate ryanodine receptors in pancreatic acinar cells via a direct allosteric mechanism

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