Acute Experimental Hemorrhagic-Necrotizing Pancreatitis Induced by Feeding a Choline-Deficient, Ethionine-Supplemented Diet

Abstract

The present work evaluates the methodology and standards of acute hemorrhagic-necrotizing pancreatitis induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet to mice. The diet model appears to be a good approximation of severe necrotizing human pancreatitis. Both the gross and histological appearance of the pancreatic and peripancreatic inflammation as well as the clinical and biochemical course of diet-induced pancreatitis resemble human disease. By limiting the period of feeding the diet, one can control the mortality at any desired level between 0 and 100%. Ascites, acidosis, hypoxia and hypovolemia occur in this model as well as in human pancreatitis. The time course of the morphological and biochemical alterations have extensively been studied and are, thus, well defined in this model. Despite the differences in pathogenesis of pancreatitis induced in this model versus human disease, the experimental pancreatitis and clinical pancreatitis share several pathophysiologic features. Therefore, the model is suitable to study pathophysiologic aspects of this disease. The diet model is particularly well suitable to study the potential for new therapeutic substances. The small size of the animals used, however, is a limitation for the evaluation of surgical procedures and of new diagnostic tools. Several pitfalls and problems have to be considered in order to obtain valuable data. The amount of injury produced by the CDE diet depends critically on sex, age and weight of the mice. Special care has to be taken to guarantee that the intake of the CDE diet is identical between different experimental groups. Therefore, each set of experiments needs to include a separate control group of mice which receive the CDE diet without any other special treatment. The potential benefit of an experimental therapy can be assessed by measuring survival, various biochemical and histological features, and alterations in hematocrit, pH and blood gases.

5,10-Methylenetetrahydrofolate Reductase Polymorphisms and the Risk of Pancreatic Cancer

“…A methyl (methionine and choline) -deficient diet indeed causes abnormal cellular differentiation, reduced exocrine function of the pancreas, and increased sensitivity to toxic injury and carcinogenicity in rats (42). In addition, animals treated with ethionine, an inhibitor of cellular methylation reactions, develop acute hemorrhagic pancreatitis (43) as a consequence of autolytic destruction of the pancreas (44), and chronic pancreatitis has been associated with increased pancreatic cancer risk (5).…”

Adenoviral Delivery of Human and Viral IL-10 in Murine Sepsis

“…16 and 17). The CDE diet induces a severe necrotizing pancreatitis in mice as described previously (18,19).…”

“…Additional mice (n ϭ 15) were sacrificed by cervical dislocation 66 h after induction of pancreatitis (19). Blood was again collected via retroorbital venipuncture, and liver and lungs were removed en bloc and snap-frozen in liquid nitrogen.…”

“…A significant neutrophil infiltration was seen in the lungs of mice pretreated with the buffer (A) and the Ad/hIL-10 (B), whereas the lungs from the Ad/vIL-10-treated animals (C) had minimal neutrophil infiltration with preservation of the normal lung architecture. Unlike the zymosan model, which has a well-described associated hemorrhagic lung injury (16,17), the pathology seen in the CDE model of pancreatitis is primarily restricted to the pancreas and liver (18,19). With lung myeloperoxidase levels as an indicator of neutrophil infiltration, there was not an associated lung infiltration in mice with CDE-induced pancreatitis (0.41 Ϯ 0.07 U/gww in healthy animals vs 0.41 Ϯ 0.04 U/gww in buffer-treated mice with pancreatitis).…”

Liver Injury Models for Induction of Hepatic Oval Cells in Rodents

“…Choline-deficient diets can be supplemented with ethionine in drinking water to exacerbate their toxicity [97]. Ethionine is the ethyl antagonist of methionine and results in hypomethylation of hepatic DNA due to the accumulation of S-adenosyl ethionine [98].…”