Alcohol Abuse, Endoplasmic Reticulum Stress and Pancreatitis

Pandol, Stephen J.; Gorelick, Fred S.; Gerloff, Andreas; Lugea, Aurelia

doi:10.1159/000327212

Cited by 78 publications

(73 citation statements)

References 127 publications

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“…In general, activation of the unfolded protein response decreases the production of cellular proteins and increases the expression of proteins involved in protein folding. It is thought that this adaptive response is protective and aids cells in riding themselves of misfolded proteins, the presence of which can be detrimental to cells [47,48] . It has been shown in mice that administration of ethanol by the intragastric feeding model causes ER stress in pancreatic acinar cells [49] .…”

Section: Er-stress In Alcoholic Pancreatitismentioning

confidence: 99%

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Clemens

Schneider

Arkfeld

et al. 2016

WJGP

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Acute pancreatitis is a necro-inflammatory disease of the exocrine pancreas that is characterized by inappropriate activation of zymogens, infiltration of the pancreas by inflammatory cells, and destruction of the pancreatic exocrine cells. Acute pancreatitis can progress to a severe life-threatening disease. Currently there is no pharmacotherapy to prevent or treat acute pancreatitis. One of the more common factors associated with acute pancreatitis is alcohol abuse. Although commonly associated with pancreatitis alcohol alone is unable to cause pancreatitis. Instead, it appears that alcohol and its metabolic by-products predispose the pancreas to damage from agents that normally do not cause pancreatitis, or to more severe disease from agents that normally cause mild pancreatic damage. Over the last 10 to 20 years, a tremendous amount of work has defined a number of alcohol-mediated biochemical changes in pancreatic cells. Among these changes are: Sustained levels of intracellular calcium, activation of the mitochondrial permeability transition pore, endoplasmic reticulum stress, impairment in autophagy, alteration in the activity of transcriptional activators, and colocalization of lysosomal and pancreatic digestive enzymes. Elucidation of these changes has led to a deeper understanding of the mechanisms by which ethanol predisposes acinar cells to damage. This greater understanding has revealed a number of promising targets for therapeutic intervention. It is hoped that further investigation of these targets will lead to the development of pharmacotherapy that is effective in treating and preventing the progression of acute pancreatitis. Core tip: There is currently no specific pharmacotherapy for pancreatitis. Although ethanol abuse is commonly associated with both acute and chronic pancreatitis, ethanol does not itself cause pancreatitis. Instead it appears that ethanol and its metabolic by-products sensitize the pancreas to damage from other factors. Detailed understanding of the mechanisms by which ethanol sensitizes the pancreas to damage has identified a number of promising targets for therapy. It is hoped that further preclinical and clinical studies will lead to the development of successful treatment of both acute and chronic pancreatitis. REVIEWClemens DL, Schneider KJ, Arkfeld CK, Grode JR, Wells MA, Singh S. Alcoholic pancreatitis: New insights into the pathogenesis and treatment.

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Section: Er-stress In Alcoholic Pancreatitismentioning

confidence: 99%

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Clemens

Schneider

Arkfeld

et al. 2016

WJGP

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“…ER malfunction leads to accumulation of unfolded proteins and activation of the protective UPR, whose goal is to improve protein folding, reduce protein synthesis, and eliminate misfolded protein aggregates (40,41). Possessing extremely high rates of protein secretion, pancreatic acinar cells are highly susceptible to ER perturbations, and ER stress occurs in pancreatitis (11,42,43). Reduced expression of Grp78/Bip, a critical ER chaperone and UPR component, blocks autophagosome formation and causes massive ER expansion and disorganization in acinar cells of cerulein-treated mice (11).…”

Section: Figurementioning

confidence: 99%

Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice

Li¹,

Wu²,

Holzer³

et al. 2013

J. Clin. Invest.

111

130

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Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKα (Ikkα Δpan ) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. Loss of pancreatic IKKα causes defective autophagic protein degradation, leading to accumulation of p62-mediated protein aggregates and enhanced oxidative and ER stress in acinar cells, but none of these effects is related to NF-κB. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in Ikkα Δpan mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKKα and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKKα, which may control autophagic protein degradation through its interaction with ATG16L2, plays a critical role in maintaining pancreatic acinar cell homeostasis, whose dysregulation promotes pancreatitis through p62 aggregate accumulation.

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“…Theories implicating alcohol in AP include direct mitochondrial injury by metabolic end products of fatty acid ethanol esters, intracellular activation of pancreatic enzymes, pancreatic duct obstruction by alterations in the lithogenicity and viscosity of pancreatic secretions, sensitization of the exocrine pancreas to secretaogues, oxidative stress within pancreatic tissue and destabilization of zymogen membranes. 9,27,28 Emerging evidence indicates that genetic polymorphisms play a role in susceptibility to alcoholic AP. [28][29][30] Of note, this research focuses on mechanisms of direct acinar toxicity.…”

Section: Discussionmentioning

confidence: 99%

Patients With Sentinel Acute Pancreatitis of Alcoholic Etiology Are at Risk for Organ Failure and Pancreatic Necrosis

et al. 2016

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Objectives-Assess the relationship between alcoholic etiology, tobacco use and severe acute pancreatitis (SAP).Methods-Smoking and alcohol exposure were recorded upon admission in a cohort of acute pancreatitis patients within the United States (U.S.). Patients with first, "sentinel" attack of acute pancreatitis (AP) were identified for analysis.Associations between alcohol, smoking and SAP were validated in an independent cohort of patients from Spain.Results-U.S. cohort (n=222): Thirty-five% developed organ failure (OF), 35% Pancreatic Necrosis (PNec), and 7% died. OF (54% vs. 33%, p=0.03), PNec (62% vs. 31%, p=0.006), intensive care (ICU) admission (58% vs. 36%, p=0.03) and length of stay (LOS) (20 vs. 8 days, p= 0.007) were greater in alcoholic when compared to other etiologies.Spanish cohort (n=366): Similar differences in outcomes were also found with between alcoholic and non-alcoholic etiologies: OF (24% vs. 8%, p=0.001), PNec (38% vs. 14%, p<0.001), ICU admission (20% vs. 3%, p<0.001), and LOS (17 vs. 11 days, p=0.04).Multivariable analysis confirmed alcoholic etiology to be independently associated with OF and PNec in both cohorts. U.S. Department of Veterans Affairs VA Author ManuscriptVA Author Manuscript VA Author ManuscriptConclusions-Alcoholic etiology is independently associated with OF and PNec in patients with sentinel AP and is important when evaluating risk for severe disease in AP.

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Alcohol Abuse, Endoplasmic Reticulum Stress and Pancreatitis

Cited by 78 publications

References 127 publications

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice

Patients With Sentinel Acute Pancreatitis of Alcoholic Etiology Are at Risk for Organ Failure and Pancreatic Necrosis

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