Animal and in vitro models of alcoholic pancreatitis: role of cholecystokinin.
Although ethanol abuse is the major etiologic factor in the development of acute and chronic pancreatitis, the mechanisms of ethanol effects to cause pancreatitis are poorly understood. The major reason for the lack of progress is the relative lack of animal models that reproduce the deleterious effects of ethanol on the pancreas that are observed in human disease. We propose that the effect of ethanol on the pancreas is due to its ability to sensitize animals and humans to the potentially injurious effects of other stimuli. We have developed models of ethanol-induced acute and chronic pancreatitis in rats as well as pancreatic acinar cells in primary culture demonstrating that ethanol sensitizes the pancreas to the inflammatory, cell death, and fibrosing responses caused by cholecystokinin (CCK). Our results indicate that the ethanol-sensitized inflammatory response is the key or trigger event for the development of the other pathologic responses in both acute and chronic pancreatitis, such as cell death, intracellular digestive enzyme activation, and fibrosis. These findings suggest that experimental strategies designed to reveal the modulating effects of ethanol on the mechanisms underlying the inflammatory, cell death, and fibrosing responses stimulated by CCK will provide the key information needed to understand how ethanol abuse causes pancreatitis.
Pandol
Stephen J
SJ
Department of Medicine, Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, California 90073, USA. Stephen.Pandol@med.va.gov
Gukovsky
Ilya
I
Satoh
Akihiko
A
Lugea
Aurelia
A
Gukovskaya
Anna S
AS
D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D016328:NF-kappa B / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019512:Pancreatitis, Alcoholic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D012844:Sincalide / Q000008:administration & dosage; D018808:Transcription Factor AP-1 / Q000378:metabolism
D016328:NF-kappa B; D018808:Transcription Factor AP-1; D000431:Ethanol; D012844:Sincalide