Enterokinase induces severe necrosis and rapid mortality in cerulein pancreatitis: characterization of a novel noninvasive rat model of necro-hemorrhagic pancreatitis.
BACKGROUND
Unlike edematous pancreatitis, induction of severe necrotizing pancreatitis in rats generally requires an invasive laparotomy with infusion and/or ligation of the pancreatic duct or duodenal or arterial occlusion. The aim of this study was to establish and characterize a noninvasive model of severe acute pancreatitis in rats.


METHODS
Wistar rats were infused intravenously with cerulein or a combination of cerulein and enterokinase. Saline (154-mmol/L NaCl) or enterokinase only was infused in controls. In a first set of experiments, intrapancreatic protease activation and the release of cytokines were correlated with the severity of organ injury. Pancreatic and pulmonary injuries were determined at 6 h. In a second set of experiments, we assessed 24-h survival, serum parameters possibly reflecting the course of the disease, and morphologic changes later in the course of the disease.


RESULTS
The severity of pancreatic injury and survival were correlated strongly with the amount of enterokinase infused simultaneously with cerulein. Trypsin as well as elastase and cathepsin B activity in pancreatic tissue samples were increased markedly in these animals. Marked pancreatic hemorrhage, necrosis, and leukocyte infiltration were present in animals with the greatest amounts of enterokinase infused. IL-6 and LDH, but not IL-1beta, CRP, and amylase, in serum correlated with the severity of pancreatitis.


CONCLUSIONS
This noninvasive rat model of acute pancreatitis is characterized by major pancreatic necrosis, hemorrhage, and fatality. The simple and noninvasive induction technique may have advantages for future studies on inflammatory changes and sepsis in necrotizing pancreatitis compared with other currently available invasive models.
Hartwig
Werner
W
Department of General, Visceral, and Transplant Surgery, University of Heidelberg, Heidelberg, Germany.
Kolvenbach
Mareike
M
Hackert
Thilo
T
Fortunato
Franco
F
Schneider
Lutz
L
Büchler
Markus W
MW
Werner
Jens
J
D000818:Animals; D002401:Cathepsin B / Q000378:metabolism; D002108:Ceruletide; D004195:Disease Models, Animal; D004338:Drug Combinations; D004765:Enteropeptidase / Q000009:adverse effects*; D015850:Interleukin-6 / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010196:Pancreatic Elastase / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index
D004338:Drug Combinations; D015850:Interleukin-6; D002108:Ceruletide; D007770:L-Lactate Dehydrogenase; D010196:Pancreatic Elastase; D004765:Enteropeptidase; D002401:Cathepsin B