Mechanisms of cell death after pancreatic duct obstruction in the opossum and the rat

Gukovskaya, Anna S.; Perkins, Penny; Zaninovic, Vjekoslav; Sandoval, Darleen A.; Rutherford, Robin E.; Fitzsimmons, Tracy; Pandol, S. J.; Poucell-Hatton, Siria

doi:10.1053/gast.1996.v110.pm8608898

Cited by 145 publications

(97 citation statements)

References 7 publications

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“…Besides caspase and Bcl-2 family proteins, other components of the death machinery (for example, X-linked inhibitor of apoptosis and p53) are involved in the regulation of extrinsic or intrinsic apoptosis in AP. Given that apoptosis generally limits the inflammatory cascade, the apoptosis level of acinar cells is inversely related to AP severity (35,51). Thus, induction of apoptosis in pancreatic acinar cells exerts a protective effect (52,53), whereas suppression of apoptosis by caspase inhibitors increases the severity of AP (54).…”

Section: Apoptosismentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

128

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The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

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Section: Apoptosismentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

128

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“…In these models, such as pancreatitis induced in rats or mice by administration of high-dose cerulein (CR) or L-arginine (L-arg), or in mice by feeding them choline-deficient, ethionine-supplemented (CDE) diet, acinar cells have been shown to die through both necrosis and apoptosis (9,10,27,29,30,39,52,73,76,80). Of note, the severity of experimental pancreatitis directly correlates with the extent of necrosis and inversely with that of apoptosis (9,10,27,29,30,39,52,73,76,80). Thus, shifting death responses away from necrosis toward apoptosis may have a therapeutic value.…”

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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“…The greatest extent of acinar tissue necrosis and the greatest difference between the CTSB +/+ and the CTSB -/-groups of mice were found after 24 hours of secretagogue-induced pancreatitis. Because cell death during the course of acute pancreatitis is known to occur not only as a consequence of autodigestion and necrosis but also owing to a greatly increased rate of acinar cell apoptosis (37,38), and given that CTSB has been implicated in the development of apoptosis (39), we compared the rate of apoptosis in the pancreas of CTSB +/+ and CTSB -/-mice. Based on the number of fluorescein-labeled DNA-strand brakes, approximately 9% of all cells had undergone cell death by apoptosis at the end of the 24-hour observation period.…”

Section: Figurementioning

confidence: 99%