Free radicals and the pancreatic acinar cells: role in physiology and pathology

Chvanov, Michael; Petersen, O. H.; Tepikin, Alexei V.

doi:10.1098/rstb.2005.1757

Cited by 68 publications

(44 citation statements)

References 158 publications

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“…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). Oxidative stress is also implicated in the pathogenesis of pancreatitis; however, the roles of ROS and the targets of ROS in the acinar cell have not been elucidated (14,18,46). Both Ca 2 + and ROS are major inducers of MMP, leading to cell death in other organs (24,44).…”

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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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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“…Oxidative stress has been implicated in the development of acute pancreatitis in diverse animal experimental models, including fatty acid infusion, ischemia, pancreatic duct obstruction, gallstone pancreatitis, and alcohol ingestion (3)(4)(5)(6), and measured in patients with mild and severe acute pancreatitis (7). While evidence suggests that oxidative stress may be an important determinant of disease severity (7,8), the precise underlying mechanisms are still poorly understood and the extent of involvement unclear (9).…”

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confidence: 99%

Menadione-induced Reactive Oxygen Species Generation via Redox Cycling Promotes Apoptosis of Murine Pancreatic Acinar Cells

Criddle

Gillies

Baumgartner-Wilson

et al. 2006

Journal of Biological Chemistry

317

243

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Oxidative stress may be an important determinant of the severity of acute pancreatitis. One-electron reduction of oxidants generates reactive oxygen species (ROS) via redox cycling, whereas two-electron detoxification, e.g. by NAD(P)H:quinone oxidoreductase, does not. The actions of menadione on ROS production and cell fate were compared with those of a non-cycling analogue (2,4-dimethoxy-2-methylnaphthalene (DMN)) using real-time confocal microscopy of isolated perfused murine pancreatic acinar cells. Menadione generated ROS with a concomitant decrease of NAD(P)H, consistent with redox cycling. The elevation of ROS was prevented by the antioxidant N-acetyl-L-cysteine but not by the NADPH oxidase inhibitor diphenyliodonium. DMN produced no change in reactive oxygen species per se but significantly potentiated menadione-induced effects, probably via enhancement of one-electron reduction, since DMN was found to inhibit NAD(P)H:quinone oxidoreductase detoxification. Menadione caused apoptosis of pancreatic acinar cells that was significantly potentiated by DMN, whereas DMN alone had no effect. Furthermore, bile acid (taurolithocholic acid 3-sulfate)-induced caspase activation was also greatly increased by DMN, whereas DMN had no effect per se. These results suggest that acute generation of ROS by menadione occurs via redox cycling, the net effect of which is induction of apoptotic pancreatic acinar cell death. Two-electron detoxifying enzymes such as NAD(P)H:quinone oxidoreductase, which are elevated in pancreatitis, may provide protection against excessive ROS and exert an important role in determining acinar cell fate.

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“…Severe acute pancreatitis (SAP) induces inflammatory reactions of pancreatic tissue itself or even systemic reactions, which is by a large portion related to excessive generation and cascade reactions of inflammatory mediators, mainly including endotoxin, oxygen-free radical, PLA2, bradykinin, complement, acute-phase protein, vasoactive amine, arachidonic acid metabolite, cytokine (lymphokine) and PAF [10][11][12][13][14] . This study mainly investigates the therapeutic effects of Baicalin and octreotide by observing plasma amylase content and serum TNF-α and IL-6 content.…”

Section: Discussionmentioning

confidence: 99%

Experimental study of therapeutic efficacy of Baicalin in rats with severe acute pancreatitis

Zhang

Zhang²,

He³

et al. 2007

WJG

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AIM:To observe the therapeutic efficacy of Baicalin in rats with severe acute pancreatitis (SAP) and explore its therapeutic mechanisms. METHODS:The SAP rat models were randomly divided into the model control group, Baicalin treatment group, octreotide treatment group and sham operation group. All groups were randomly subdivided into 3 h, 6 h and 12 h groups with 15 rats in each group. The survival, ascites volume and pathological changes of pancreas in all rats were observed at different time points after operation. The plasma amylase content and serum TNF-α, IL-6, malonaldehyde (MDA) and PLA2 contents were also determined. RESULTS:The survival was not obviously different between the treated groups, and was significantly higher in treated groups at 12 h compared to the model control group (P < 0.05, 15 vs 10). The ascites/body weight ratio at 3 h and 6 h was significantly lower in Baicalin treatment group compared to the model control group and octreotide treatment group (P < 0.05, 1.00 vs 2.02 and 1.43 and P < 0.001, 2.29 (1.21) vs 2.70 (0.80) and 2.08 (2.21), respectively). The contents of amylase, TNF-α, IL-6, MDA and PLA2 were significantly lower in the treated groups than in the model control group (P < 5.36 in IL-6, respectively). The pathological scores of pancreas in the treated groups were significantly lower than that in the model control group (P < 0.05, 9.00 vs 10.05, 6.00 vs 9.00, 8.00 vs 10.05), but no marked difference was found between the treated groups. CONCLUSION:The Baicalin injection has significant therapeutic effects on SAP rats, its effects are similar to those of octreotide. The Baicalin injection is also cheap and has a big application range, quite hopefully to be used in clinical treatment of SAP.

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Free radicals and the pancreatic acinar cells: role in physiology and pathology

Cited by 68 publications

References 158 publications

Organellar Dysfunction in the Pathogenesis of Pancreatitis

Organellar Dysfunction in the Pathogenesis of Pancreatitis

Menadione-induced Reactive Oxygen Species Generation via Redox Cycling Promotes Apoptosis of Murine Pancreatic Acinar Cells

Experimental study of therapeutic efficacy of Baicalin in rats with severe acute pancreatitis

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