PATHOGENESIS OF ALCOHOLIC PANCmATITIS—A PEAK INTO A BLACK BOX

Buckelew, Daryl Q.; Schenker, Steven

doi:10.1111/j.1530-0277.1998.tb03688.x

Cited by 11 publications

(5 citation statements)

References 17 publications

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“…In the present study, enteral feeding with a higher delivery of ethanol increased formation of both carbon-centered free radicals and 4-hydroxynonenal-modified proteins in the pancreas (Figs. [6][7][8]. These data are consistent with the hypothesis that oxidative stress is involved in the pathogenesis of early alcohol-induced pancreatic injury (see Fig.…”

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confidence: 90%

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Development of an animal model of chronic alcohol-induced pancreatitis in the rat

Kono¹,

Nakagami²,

Rusyn³

et al. 2001

American Journal of Physiology-Gastrointestinal and Liver Physi

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This study was designed to develop an animal model of alcoholic pancreatitis and to test the hypothesis that the dose of ethanol and the type of dietary fat affect free radical formation and pancreatic pathology. Female Wistar rats were fed liquid diets rich in corn oil (unsaturated fat), with or without a standard or high dose of ethanol, and medium-chain triglycerides (saturated fat) with a high dose of ethanol for 8 wk enterally. The dose of ethanol was increased as tolerance developed, which allowed approximately twice as much alcohol to be delivered in the high-dose group. Serum pancreatic enzymes and histology were normal after 4 wk of diets rich in unsaturated fat, with or without the standard dose of ethanol. In contrast, enzyme levels were elevated significantly by the high ethanol dose. Increases were blunted significantly by dietary saturated fat. Fibrosis and collagen alpha1(I) expression in the pancreas were not detectable after 4 wk of enteral ethanol feeding; however, they were enhanced significantly by the high dose after 8 wk. Furthermore, radical adducts detected by electron spin resonance were minimal with the standard dose; however, the high dose increased carbon-centered radical adducts as well as 4-hydroxynonenal, an index of lipid peroxidation, significantly. Radical adducts were also blunted by approximately 70% by dietary saturated fat. The animal model presented here is the first to demonstrate chronic alcohol-induced pancreatitis in a reproducible manner. The key factors responsible for pathology are the amount of ethanol administered and the type of dietary fat.

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confidence: 90%

“…standing of the mechanisms of pathophysiology, and progress has been slow because an appropriate animal model for alcohol-induced pancreatitis is lacking (6). The pathology of chronic alcoholic pancreatitis consists of both intralobular fibrosis involving pancreatic acini and interlobular fibrosis with fibrotic strictures of pancreatic ducts (8).…”

mentioning

confidence: 99%

Development of an animal model of chronic alcohol-induced pancreatitis in the rat

Kono¹,

Nakagami²,

Rusyn³

et al. 2001

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Thus, liver is certainly the major target of alcohol‐induced oxidant stress. However, recent data have shown that cytochrome P4502E1 is also present in the pancreas and, moreover, is induced by chronic alcohol administration12, 13, similarly to what happens in the liver of chronic alcohol abusers. In addition, acute ethanol administration increases the levels of lipid peroxidation products in rat pancreas, thus providing direct evidence that alcohol induces oxidant stress in this organ14.…”

Section: Introductionmentioning

confidence: 99%

Collagen type I synthesized by pancreatic periacinar stellate cells (PSC) co-localizes with lipid peroxidation-derived aldehydes in chronic alcoholic pancreatitis

et al. 2000

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Chronic alcoholic pancreatitis (CAP) is characterized by progressive pancreatic fibrosis and loss of the acinar cell mass, but the pathogenesis of pancreatic fibrosis in the human is poorly understood. It has been recently suggested that lipid peroxidation-derived aldehydes such as 4-hydroxynonenal (HNE) are involved in tissue damage and fibrosis in other organs. The aim of this study was to evaluate the role of oxidative stress in the development of alcohol-induced pancreatic fibrosis in humans, and to assess the contribution of pancreatic periacinar stellate cells (PSC) in the in vivo synthesis of extracellular matrix components during CAP. Lipid peroxidation was evaluated in tissue specimens obtained from patients with CAP who underwent surgical procedures, by immunohistochemistry using a monoclonal antibody directed against HNE-protein adducts. Immunohistochemical determination of collagen type I, alpha-smooth muscle actin (alpha-SMA), and the beta subunit of human platelet-derived growth factor (PDGF-Rbeta) was also performed. In addition, the tissue mRNA expression of procollagen I, PDGF-Rbeta, and transforming growth factor-beta1 (TGF-beta1) was evaluated by in situ hybridization. In CAP, increased formation of HNE-protein adducts was evident in acinar cells adjacent to the interlobular connective tissue that stained positively for collagen type I. HNE staining was absent in normal pancreas. Several non-parenchymal periacinar cells (PSC) underlay the HNE-stained acinar cells. Those PSC stained positively for alpha-SMA and PDGF-Rbeta and showed active synthesis of procollagen type I by in situ expression of the specific mRNAs. The pattern of expression of PDGF-Rbeta mRNA reflected that observed in immunostaining, showing increased amounts of transcripts in PSC. TGF-beta1 mRNA expression was increased in CAP, but transcripts were found in several cell types including PSC, acinar, and ductal cells. These results indicate that significant lipid peroxidation phenomena occur in CAP and that they are associated with active synthesis of collagen by PSC.

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“…[3][4][5][6][7] In general, the lack of models is due to the fact that ethanol feeding alone in animals causes mild and variable pathological responses in the pancreas, making investigations into the cellular and molecular mechanisms of ethanol's effect exceedingly difficult.…”

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confidence: 99%

Emerging concepts for the mechanism of alcoholic pancreatitis from experimental models

Pandol

Gukovsky

Satoh

et al. 2003

Journal of Gastroenterology

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The pathophysiologic mechanisms that underlie acute and chronic pancreatitis arising from alcohol abuse are poorly understood. The reasons for this state of knowledge result historically from a lack of models for experimental investigation. Ethanol feeding alone, even at high doses, has minimal and inconsistent effects on morphologic findings in the pancreas in experimental animals. This experience, plus the fact that alcohol abuse causes pancreatic pathology in only a minority of patients, suggest that ethanol acts to sensitize the pancreas to the deleterious effects of other stimuli. In this article, we discuss findings to support this concept of ethanol as a sensitizing agent and experimental models developed that can be used to investigate the effects of ethanol on the pathologic processes of pancreatitis. These pathologic processes include inflammation, cell death, intrapancreatic digestive enzyme activation, and fibrosis.

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PATHOGENESIS OF ALCOHOLIC PANCmATITIS—A PEAK INTO A BLACK BOX

Cited by 11 publications

References 17 publications

Development of an animal model of chronic alcohol-induced pancreatitis in the rat

Development of an animal model of chronic alcohol-induced pancreatitis in the rat

Collagen type I synthesized by pancreatic periacinar stellate cells (PSC) co-localizes with lipid peroxidation-derived aldehydes in chronic alcoholic pancreatitis

Emerging concepts for the mechanism of alcoholic pancreatitis from experimental models

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