Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Muili, Kamaldeen; Wang, Dong; Orabi, Abrahim I.; Sarwar, Sheharyar; Luo, Yuhuan; Javed, Tanveer A.; Eisses, John F.; Mahmood, Syeda Maham; Jin, Shunqian; Singh, Vijay; Ananthanaravanan, Meena; Perides, George; Williams, John A.; Molkentin, Jeffery D.; Husain, Sohail Z.

doi:10.1074/jbc.m112.428896

Cited by 75 publications

(73 citation statements)

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“…Bile Acids Cause NF-B Activation, and NF-B Mediates TLCS-induced acinar Cell Injury-We and others have demonstrated that bile acids cause injury to isolated pancreatic acinar cells (8,10,11,15). The injury is dependent on an early, aberrant rise in cytosolic Ca 2ϩ , which triggers several downstream pathways.…”

Section: Resultsmentioning

confidence: 99%

“…Among these is the translocation of NF-B to the nucleus (22, 25, 42, 43). We used a reporter system to evaluate NF-B activation by infecting acinar cells with an adenovirus containing an NF-B-driven luciferase gene (15).…”

Section: Resultsmentioning

confidence: 99%

“…Recent work, however, has implicated a critical role for calcineurin in mediating Ca 2ϩ -dependent NF-B translocation (31, 32). We and others have demonstrated that calcineurin is a primary target of aberrant Ca 2ϩ signals in pancreatic acinar cells and plays a key role in the pathogenesis of both caerulein-, muscarinic-, and bile acid-induced pancreatitis (11,12,15,(33)(34)(35)). …”

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confidence: 99%

“…The exposure of bile acids also initiates early inflammatory signals, notably the transcription factor or nuclear factor light chain enhancer of activated B cells (NF-B) (11)(12)(13)(14)(15). NF-B is a heterodimeric complex composed of members of the Rel protein family (16 -18).…”

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confidence: 99%

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Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin

Muili

Jin

Orabi

et al. 2013

Journal of Biological Chemistry

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Background: Bile acids cause activation of NF-B and lead to injury in pancreatic acinar cells, but the mechanism is unknown. Results: Pharmacologic and genetic inhibition of calcineurin reduces bile acid-induced NF-B activation and PKC-␦ translocation. Conclusion: Calcineurin facilitates bile-induced NF-B activation. The mechanism is at the level of PKC activation. Significance: We have identified a novel mechanism by which bile acids facilitate NF-B activation in pancreatic acinar cells.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin

Muili

Jin

Orabi

et al. 2013

Journal of Biological Chemistry

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“…Inhibition of pathologic calcium stimulation through calcineurin activation was able to stop biliary AP development (14). In that study, 1,2-bis (o-aminophenoxy) ethane-N,N,N' ,N'-tetraacetic acid (acetoxymethyl ester) (BAPTA-AM) or three specific calcineurin inhibitors, i.e.…”

Section: Pathophysiologymentioning

confidence: 99%

Pathophysiology, classification and available guidelines of acute pancreatitis

İnce

Baysal²

2014

Turk J Gastroenterol

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Acute pancreatitis (AP) constitutes the majority of cases requiring hospital admission in gastroenterology. We are yet to know many things about its pathophysiology which is a certain drawback for the progress in its treatment. Prediction of severity is necessary for the plan of the management. The existing scoring systems are yet to be satisfactory. However our progress in the field was significant in the recent decade and a leap forward is expected in this cumbersome-to-manage condition which has many unmet needs. In this review, we are going to summarize the hitherto data in pathogenesis and would weigh the usefulnes and weaknes of each of existing scoring systems in the management of AP. Keywords: Acute pancreatitis, guideline, pathophysiology, scoring systems, classifications, insights Pancreas was first discovered by Herophilus, a Greek anatomist and surgeon, in Chalcedon (now Kadıkoy, Istanbul) in 336 BC. Despite the many years since its discovery, a lot remains unknown about pancreas. The coming decade would, probably, witness several advances in our understanding of pancreas and its diseases.This review aims to describe the hitherto knowledge in pancreas pathophysiology and classification systems of severity scoring. PATHOPHYSIOLOGYThe main reason for the lack of successful treatment in acute pancreatitis (AP) is that many aspects of this condition regarding the pathophysiology are still unknown. AP has a severe course in 20% of the cases and may be associated with high morbidity and mortality in 2-3%. Pancreatic autodigestion (trypsinogen-centered) theory has been in use in the AP pathogenesis for over a hundred year. In this theory, premature activation of pancreatic proenzymes (zymogens) induces autolysis, which triggers inflammatory events followed by continued damage to the pancreas and/or non-pancreatic tissues in some way.Experimental models (1,2) have demonstrated the involvement of trypsin activation in hereditary pancreatitis (3). Along with zymogen activation, natural factor kappa beta (NFkB) activation is also important in the development of AP. Whether both are involved or are independently-acting parallel factors in AP is controversial. It was shown, in vitro, that trypsinogen expression did not activate NFkB (4

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Pathobiology of the acinar cell in acute pancreatitis

Pandol

2017

Pancreatitis

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Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Cited by 75 publications

References 73 publications

Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin

Pancreatic Acinar Cell Nuclear Factor κB Activation Because of Bile Acid Exposure Is Dependent on Calcineurin

Pathophysiology, classification and available guidelines of acute pancreatitis

Pathobiology of the acinar cell in acute pancreatitis

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