Acute pancreatitis and organ failure: Pathophysiology, natural history, and management strategies

Raraty, Michael; Connor, Saxon; Criddle, David N.; Neoptolemos, John P.

doi:10.1007/s11894-004-0035-0

Cited by 103 publications

(68 citation statements)

References 59 publications

(49 reference statements)

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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). 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).…”

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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“…However, severe pancreatitis is characterized by high mortality as a result of the uncontrolled systemic inflammatory response syndrome (SIRS) and multiple organ failure. Although the molecular mechanisms of the pathophysiology are not completely understood, data from experimental pancreatitis models strongly imply that the release of proinflammatory mediators by acinar cells and the recruitment of immune cells are crucial events in the induction of SIRS (8). The relationship between the pancreatic injury and this uncontrolled systemic inflammation remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Baumann¹,

Wagner²,

Aleksic³

et al. 2007

J. Clin. Invest.

111

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Activation of the inhibitor of NF-κB kinase/NF-κB (IKK/NF-κB) system and expression of proinflammatory mediators are major events in acute pancreatitis. However, the in vivo consequences of IKK activation on the onset and progression of acute pancreatitis remain unclear. Therefore, we modulated IKK activity conditionally in pancreatic acinar cells. Transgenic mice expressing the reverse tetracycline-responsive transactivator (rtTA) gene under the control of the rat elastase promoter were generated to mediate acinar cell-specific expression of IKK2 alleles. Expression of dominant-negative IKK2 ameliorated cerulein-induced pancreatitis but did not affect activation of trypsin, an initial event in experimental pancreatitis. Notably, expression of constitutively active IKK2 was sufficient to induce acute pancreatitis. This acinar cell-specific phenotype included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels as well as pancreatic fibrosis. IKK2 activation caused increased expression of known NF-κB target genes, including mediators of the inflammatory response such as TNF-α and ICAM-1. Indeed, inhibition of TNF-α activity identified this cytokine as an important effector of IKK2-induced pancreatitis. Our data identify the IKK/NF-κB pathway in acinar cells as being key to the development of experimental pancreatitis and the major factor in the inflammatory response typical of this disease. IntroductionThe NF-κB transcription factors play a prominent role in controlling the integration of innate immunity into the inflammatory response and adaptive immunity. The activation and nuclear translocation of NF-κB induces the expression of a diverse range of proinflammatory genes, including chemokines, cytokines, and cell adhesion molecules, all necessary for an effective defense response to infectious agents. However, failure to terminate or resolve the inflammatory response has detrimental consequences for the organism. As NF-κB is one of the main transcriptional regulators of inflammation, pathological activation of NF-κB is often associated with chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, asthma, and multiple sclerosis (1-3).NF-κB represents a family of homodimeric and heterodimeric transcription factors composed of 5 members, namely p50, p52, RelA/p65, RelB, and c-Rel. NF-κB is activated by a large number of inducers, including factors critically involved in the inflammatory response such as TNF-α, IL-1β, and microbial products. These factors activate the TNF, IL-1, Nod-like, and Toll-like receptor systems and thereby initiate signaling cascades that converge on the classical NF-κB pathway. This induces the nuclear translocation of NF-κB dimers typically composed of p50 and RelA/p65. The pivotal regulatory step in this pathway is the signal-induced phosphorylation of inhibitor of NF-κB (IκB) proteins, which are mediated by the IκB kinase (IKK) complex. In unstimulated cells, IκB proteins interact with the NF-κB proteins and inhibit their nuclear translo...

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“…Acute pancreatitis is an inflammatory disorder of exocrine pancreas, which carries considerable morbidity and mortality, and the pathophysiology of which remains obscure (1). During the past decade, significant progress has been achieved in our understanding of the inflammatory response in pancreatitis (2)(3)(4)(5).…”

mentioning

confidence: 99%

“…The mechanisms of RIP action, as well as its targets, are poorly understood (15)(16)(17)30). Acinar cell necrosis, and in particular, recurrent necrosis, is one of the most serious complications of acute pancreatitis (1,35,36). Based on the above-described observations that milder forms of experimental pancreatitis are associated with more apoptosis and the relatively severe forms, with more necrosis, it has been hypothesized (6 -12) that switching from the necrotic pattern of cell death to apoptosis could be beneficial in treatment of acute pancreatitis.…”

mentioning

confidence: 99%

Cell Death in Pancreatitis

Mareninova

Sung

Hong

et al. 2006

Journal of Biological Chemistry

243

135

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Mechanisms of cell death in pancreatitis remain unknown. Parenchymal necrosis is a major complication of pancreatitis; also, the severity of experimental pancreatitis correlates directly with necrosis and inversely with apoptosis. Thus, shifting death responses from necrosis to apoptosis may have a therapeutic value. To determine cell death pathways in pancreatitis and the possibility of necrosis/apoptosis switch, we utilized the differences between the rat model of cerulein pancreatitis, with relatively high apoptosis and low necrosis, and the mouse model, with little apoptosis and high necrosis. We found that caspases were greatly activated during cerulein pancreatitis in the rat but not mouse. Endogenous caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP) underwent complete degradation in the rat but remained intact in the mouse model. Furthermore, XIAP inhibition with embelin triggered caspase activation in the mouse model, implicating XIAP in caspase blockade in pancreatitis. Caspase inhibitors decreased apoptosis and markedly stimulated necrosis in the rat model, worsening pancreatitis parameters. Conversely, caspase induction with embelin stimulated apoptosis and decreased necrosis in mouse model. Thus, caspases not only mediate apoptosis but also protect from necrosis in pancreatitis. One protective mechanism is through degradation of receptor-interacting protein (RIP), a key mediator of "programmed" necrosis. We found that RIP was cleaved (i.e. inactivated) in the rat but not the mouse model. Caspase inhibition restored RIP levels; conversely, caspase induction with embelin triggered RIP cleavage. Our results indicate key roles for caspases, XIAP, and RIP in the regulation of cell death in pancreatitis. Manipulating these signals to change the pattern of death responses presents a therapeutic strategy for treatment of pancreatitis.

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Acute pancreatitis and organ failure: Pathophysiology, natural history, and management strategies

Cited by 103 publications

References 59 publications

Organellar Dysfunction in the Pathogenesis of Pancreatitis

Organellar Dysfunction in the Pathogenesis of Pancreatitis

Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo

Cell Death in Pancreatitis

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