Exocrine Hyperstimulation but Not Pancreatic Duct Obstruction Increases the Susceptibility to Alcohol-Related Pancreatic Injury

Foitzik, Thomas; Lewandrowski, Kent; Castillo, Carlos Fernández‐del; Rattner, David W.; Klar, E.; Warshaw, Andrew L.

doi:10.1001/archsurg.1994.01420340095018

Cited by 24 publications

(14 citation statements)

References 21 publications

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“…As calculated by Ammann et al (1), only 5% of all alcohol abusers will develop alcoholic pancreatitis. Interestingly enough, this can also be observed in setups with animals where acute pancreatitis cannot be induced by alcohol itself (8,15,25). Therefore, additional factors accompanying alcohol intake must be coresponsible for the induction of the disease.…”

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confidence: 84%

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confidence: 87%

“…Therefore, additional factors accompanying alcohol intake must be coresponsible for the induction of the disease. Some of these cofactors such as stimulation of pancreatic secretion and/or obstruction of pancreatic outflow have been experimentally observed by us and others (8,12,25,26).Clinical experience has taught us that a large number of patients presenting an acute event of alcoholic pancreatitis have drunk lots of alcohol together with an opulent (fat enriched) meal the day before onset of the disease. In the present study, we focused on the effects of lipids in combination with alcohol on acinar cell injury and fibrogenesis.…”

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confidence: 97%

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Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

Siech

Zhou

Zhou³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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MG. Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL). Am J Physiol Gastrointest Liver Physiol 297: G1163-G1171, 2009. First published September 24, 2009 doi:10.1152/ajpgi.90468.2008.-Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 g/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL-treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC).ethanol; free radicals; pancreas THE MECHANISM OF ALCOHOLIC PANCREATITIS is incompletely understood. Despite the fact that about 40% of acute pancreatitis and 70% of chronic pancreatitis in humans are induced by alcohol, most alcoholics will never be affected by any of these diseases. As calculated by Ammann et al. (1), only 5% of all alcohol abusers will develop alcoholic pancreatitis. Interestingly enough, this can also be observed in setups with animals where acute pancreatitis cannot be induced by alcohol itself (8,15,25). Therefore, additional factors accompanying alcohol intake must be coresponsible for the induction of the disease. Some of these cofactors such as stimulation of pancreatic secretion and/or obstruction of pancreatic outflow have been experimentally observed by us and others (8,12,25,26).Clinical experience has taught us that a large number of patients presenting an acute event of alcoholic pancreatitis have drunk lots of alcohol together with an opulent (fat enriched) meal the day before onset of the disease. In the present ...

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confidence: 84%

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confidence: 87%

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confidence: 97%

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Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

Siech

Zhou

Zhou³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, the combination of caerulein hyperstimulation with an additional noxious factor, e.g. ischemia and alcohol [36, 37, 38], as well as short-term ductal obstruction [39]and repeated ductal obstructions [40]can aggravate the severity of pancreatitis. Similarly, low doses of caerulein which did not cause pancreatitis at normocalcemia did cause acute pancreatitis when serum calcium levels were increased [41].…”

Section: Potential Of Therapeutic Application Of Cholecystokinin Recementioning

confidence: 99%

Role of Cholecystokinin in the Development and Progression of Acute Pancreatitis and the Potential of Therapeutic Application of Cholecystokinin Receptor Antagonists

Niederau

Grendell

1999

Digestion

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This presentation reviews the role of cholecystokinin (CCK) as a contributory factor for the development and progression of acute pancreatitis (AP) and the perspective of CCK receptor antagonists for treatment of AP. High, supraphysiological concentrations of CCK induce AP in various species including man. There is also evidence that physiological increases in plasma CCK deteriorates AP in several animal models. The latter findings support the hypothesis that CCK plays a contributory or permissive role for the development of AP. The majorities of experimental studies show that the prophylactic and therapeutic use of CCK antagonists ameliorates AP. The latter effects were clearly shown for models of biliary AP in which plasma CCK is increased due to a feedback mechanism. However, CCK antagonists also had beneficial effects in models in which plasma CCK is not increased. In animal strains which do not have a CCK-A-receptor due to a genetic abnormality AP induced by a certain noxious factor does not develop to the same severity when compared to animals with a normal CCK-A-receptor. Thus, CCK acts as a permissive or contributory factor for the development and progression of AP. There is also evidence that CCK antagonists have a potential therapeutic benefit. Clinical studies will evaluate their therapeutic potential for patients with AP.

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“…In another protocol, stimulation of pancreatic secretion with caerulein together with acute ethanol application led to acute necrotizing pancreatitis. Caerulein application alone induced only edematous pancreatic injury demonstrating the enhanced vulnerability of the pancreas under ethanol administration [62] .…”

Section: Acute Ethanol Administrationmentioning

confidence: 93%

Animal Models and Their Results in Gastrointestinal Alcohol Research

Siegmund

Haas

Singer

2005

Dig Dis

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Alcohol-induced diseases of the gastrointestinal tract play an important role in clinical gastroenterology. However, the precise pathophysiological mechanisms are still largely unknown. Alcohol research depends essentially on animal models due to the fact that controlled experimental studies of ethanol-induced diseases in humans are unethical. Animal models have already been successfully applied to disclose and analyze molecular mechanisms in alcohol-induced diseases, partially by using knockout technology. Because of a lack of transferability of some animal models to the human condition, results have to be interpreted cautiously. For some alcohol-related diseases like chronic alcoholic pancreatitis, the ideal animal model does not yet exist. Here we provide an overview of the most commonly used animal models in gastrointestinal alcohol research. We will also briefly discuss the findings based on animal models as well as the current concepts of pathophysiological mechanisms involved in acute and chronic alcoholic damage of the esophagus, stomach, small and large intestine, pancreas and liver.

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Exocrine Hyperstimulation but Not Pancreatic Duct Obstruction Increases the Susceptibility to Alcohol-Related Pancreatic Injury

Abstract: Our findings suggest that the pathogenesis of acute alcoholic pancreatitis may require a state of exocrine hyperstimulation, perhaps via cholecystokinin, but do not support a role for constriction or obstruction of Oddi's sphincter.

Cited by 24 publications

References 21 publications

Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL)

Role of Cholecystokinin in the Development and Progression of Acute Pancreatitis and the Potential of Therapeutic Application of Cholecystokinin Receptor Antagonists

Animal Models and Their Results in Gastrointestinal Alcohol Research

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