A novel animal model of severe pancreatitis in mice and its differences to the rat.
BACKGROUND
A noninvasive model of necrohemorrhagic pancreatitis induced by simultaneous intravenous cerulein/enterokinase (EK) infusion has recently been established in rats. The aim of the present study was to establish this new model in mice and to compare it with the rat model.


METHODS
Male Balb/C mice (20 to 25 g) were used for the experiments. Pancreatitis was induced by simultaneous intravenous infusion of cerulein and EK. Controls were infused with either 0.9% NaCl, cerulein, or EK. Animals were humanely killed 6 hours after start of infusions. Pancreatic and pulmonary injury was assessed by histology, wet-to-dry weight ratio, and myeloperoxidase activity. Systemic cytokine, amylase, and lactate dehydrogenase (LDH) levels in blood were measured to assess pancreatic and systemic inflammatory response. To evaluate the role of protease activity in this model, trypsin, cathepsin B, and elastase activity were measured in pancreatic tissue. Survival experiments were performed to determine survival time and tissue injury in the later course of the disease.


RESULTS
Mice with simultaneous cerulein/EK infusion developed marked local and systemic organ injury compared with those animals who received cerulein or EK alone. Pancreatic and pulmonary injury increased with high concentrations of cerulein/EK infusions. Survival decreased in these animals. Whereas acinar cell apoptosis was an early finding, pancreatic necrosis was observed later in the course of the disease. Serum levels of LDH, interleukin (IL)-1 alpha, and IL-1 beta reflected cell damage and the systemic inflammatory response. Protease activity in pancreatic tissue was greatest in animals with simultaneous cerulein/EK infusion.


CONCLUSIONS
Using intravenous cerulein/EK infusions, a model of lethal acute pancreatitis has been established in mice. Major pancreatic edema, acinar cell apoptosis and necrosis, and pulmonary leukocyte sequestration are characteristic findings in this model. Although pancreatic injury was not as strong as in the rat model, this model may prove useful for future studies in transgenic mice.
Hartwig
Werner
W
Department of General Surgery, University of Heidelberg, Heidelberg, Germany. werner_hartwig@med.uni-heidelberg.de
Schimmel
Eik
E
Hackert
Thilo
T
Fortunato
Franco
F
Bergmann
Frank
F
Baczako
Andrea
A
Strobel
Oliver
O
Büchler
Markus W
MW
Werner
Jens
J
D000818:Animals; D002108:Ceruletide / Q000009:adverse effects; D004195:Disease Models, Animal; D004765:Enteropeptidase / Q000009:adverse effects; D005765:Gastrointestinal Agents / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010195:Pancreatitis / Q000139:chemically induced*; D051381:Rats
D005765:Gastrointestinal Agents; D002108:Ceruletide; D004765:Enteropeptidase