The Pancreas Misled: Signals to Pancreatitis

Criddle, David N.; McLaughlin, Euan; Murphy, John A.; Petersen, O. H.; Sutton, Robert

doi:10.1159/000108960

Cited by 58 publications

(48 citation statements)

References 106 publications

(224 reference statements)

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“…These findings support the view that p38 MAP kinase regulates proinflammatory transcription factors such as NF-ĸB in pancreatic exocrine cells. This is significant because of the roles that CCK and TNF-α play in exacerbating acute inflammation in experimental models of acute pancreatitis [1,19,20,21,22,23]. Investigations using the donor rat model have shown that bile-pancreatic juice exclusion from gut exacerbates duct ligation-induced acute pancreatitis and also increases pancreatic phosphorylation of stress kinases (JNK, ERK, p38), activation of NF-ĸB, and production of proinflammatory mediators [15,24,25,26,27].…”

Section: Discussionmentioning

confidence: 99%

Dominant Negative p38 Mitogen-Activated Protein Kinase Expression Inhibits NF-κB Activation in AR42J Cells

2010

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Background: The role of the p38 mitogen-activated protein (MAP) kinase in acute pancreatitis pathogenesis is controversial. We hypothesize that p38 plays a role in regulating NF-ĸB activation in exocrine pancreatic cells. Methods: AR42J cells incorporating an NF-ĸB-responsive luciferase reporter, with and without adenoviral transduction of DNp38, were stimulated with cholecystokinin (CCK) or tumor necrosis factor-α (TNF-α) prior to measuring NF-ĸB activation. Results: CCK- or TNF-α-stimulated NF-ĸB-dependent gene transcription (luciferase assay) was substantially subdued by DNp38 expression. These findings were confirmed by electrophoretic mobility shift assay. Nuclear translocation of the p65 NF-ĸB subunit following agonist stimulation was evident (supershift). Characterization studies showed excellent adenoviral infection efficiency and cell viability in our AR42J cell model. Agonist-stimulated dose- and time-dependent p38 activation, with inhibition by DNp38 expression, was also confirmed. Conclusion: The p38 MAP kinase regulates NF-ĸB pathway activation in exocrine pancreatic cells, and thus potentially plays a role in the mechanism of acute pancreatitis pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Dominant Negative p38 Mitogen-Activated Protein Kinase Expression Inhibits NF-κB Activation in AR42J Cells

2010

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“…Abnormal (global and sustained) increases in acinar cell cytosolic Ca 2 + , and oxidative stress are key pathological signals associated with acute pancreatitis (16,46,70). Elevations of cytosolic Ca 2 + , which can locally reach low micromolar concentrations (as shown in experimental pancreatitis), are believed to mediate trypsinogen activation and other pathological responses of pancreatitis (70,74).…”

Section: Bcl-2 Proteins Are Key Regulators Of Mitochondrial Permeabilmentioning

confidence: 99%

Organellar Dysfunction in the Pathogenesis of Pancreatitis

Gukovsky

Pandol

Gukovskaya

2011

Antioxidants & Redox Signaling

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Significance: Acute pancreatitis is an inflammatory disease of exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. During the past decade, new insights have been gained into signaling pathways and molecules that mediate the inflammatory response of pancreatitis and death of acinar cells (the main exocrine pancreas cell type). By contrast, much less is known about the acinar cell organellar damage in pancreatitis and how it contributes to the disease pathogenesis. Recent Advances: This review summarizes recent findings from our group, obtained on experimental in vivo and ex vivo models, which reveal disordering of key cellular organelles, namely, mitochondria, autophagosomes, and lysosomes, in pancreatitis. Our results indicate a critical role for mitochondrial permeabilization in determining the balance between apoptosis and necrosis in pancreatitis, and thus the disease severity. We further investigate how the mitochondrial dysfunction (and hence acinar cell death) is regulated by Ca 2+ , reactive oxygen species, and BclxL, in relation to specific properties of pancreatic mitochondria. Our results also reveal that autophagy, the principal cellular degradative, lysosome-driven pathway, is impaired in pancreatitis due to inefficient lysosomal function, and that impaired autophagy mediates two key pathological responses of pancreatitis-accumulation of vacuoles in acinar cells and the abnormal, intra-acinar activation of digestive enzymes such as trypsinogen. Critical Issues and Future Directions: The findings discussed in this review indicate critical roles for mitochondrial and autophagic/lysosomal dysfunctions in the pathogenesis of pancreatitis and delineate directions for detailed investigations into the molecular events that underlie acinar cell organellar damage. Antioxid. Redox Signal. 15, 2699-2710.

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“…Bile acids, ethanol, and fatty acids were shown to be responsible for around 80% of the etiological factors initiating AP [6]. All of these factors were shown to induce a toxic calcium signal and severe mitochondrial damage in both acinar and ductal cells [3,[7][8][9][10][11]. Importantly, direct administration of ATP (i.e., energy) into the cells restored their functions and prevented cell death [12,13].…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of early nutrition: the benefits of enteral feeding compared to a nil per os diet not only in severe, but also in mild and moderate acute pancreatitis

2017

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Abstract:The recently published guidelines for acute pancreatitis (AP) suggest that enteral nutrition (EN) should be the primary therapy in patients suffering from severe acute pancreatitis (SAP); however, none of the guidelines have recommendations on mild and moderate AP (MAP). A meta-analysis was performed using the preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P). The following PICO (problem, intervention, comparison, outcome) was applied: P: nutrition in AP; I: enteral nutrition (EN); C: nil per os diet (NPO); and O: outcome. There were 717 articles found in Embase, 831 in PubMed, and 10 in the Cochrane database. Altogether, seven SAP and six MAP articles were suitable for analyses. In SAP, forest plots were used to illustrate three primary endpoints (mortality, multiorgan failure, and intervention). In MAP, 14 additional secondary endpoints were analyzed (such as CRP (C-reactive protein), WCC (white cell count), complications, etc.). After pooling the data, the Mann-Whitney U test was used to detect significant differences. Funnel plots were created for testing heterogeneity. All of the primary endpoints investigated showed that EN is beneficial vs. NPO in SAP. In MAP, all of the six articles found merit in EN. Analyses of the primary endpoints did not show significant differences between the groups; however, analyzing the 17 endpoints together showed a significant difference in favor of EN vs. NPO. EN is beneficial compared to a nil per os diet not only in severe, but also in mild and moderate AP.

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The Pancreas Misled: Signals to Pancreatitis

Cited by 58 publications

References 106 publications

Dominant Negative p38 Mitogen-Activated Protein Kinase Expression Inhibits NF-κB Activation in AR42J Cells

Dominant Negative p38 Mitogen-Activated Protein Kinase Expression Inhibits NF-κB Activation in AR42J Cells

Organellar Dysfunction in the Pathogenesis of Pancreatitis

Meta-analysis of early nutrition: the benefits of enteral feeding compared to a nil per os diet not only in severe, but also in mild and moderate acute pancreatitis

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