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The Role of Alcohol in Pancreatic Acinar Cell Death

Duane Smoot, M.D.
Principal Investigator, Howard University Hospital
dsmoot@howard.edu

ABSTRACT

Chronic ethanol ingestion is responsible for 70 to 80 percent of the cases of chronic pancreatitis. However, the mechanism(s) by which ethanol causes pancreatitis is not known. Only five to ten percent of alcoholics develop pancreatitis, which would suggest that factors other than the amount or type of alcohol ingested is important in the development of this disease. Pancreatitis is a disorder of the exocrine pancreas with processes of inflammation and parenchymal cell death. Models of experimental pancreatitis show that the types of cell death include both apoptosis in the pancreatic acinar cells of the pancreas.

For the present project we hypothesize that ethanol and /or its metabolite cause apoptosis and necrosis cell death in pancreatic acinar cells by regulating pathways involving caspases and mitochondrial depolarization. We further postulate that the effect of ethanol and/or its metabolites on the cell death processes occurs through their ability to modulate the caspase and mitochondrial responses to neurohumoral agents (i.e. cholecystokinin and acetylcholine) and cytokines (i.e. TNPα).

The studies proposed in this grant application are designed to determine the effect of ethanol and its metabolites on apoptosis and necrosis and the pathways that regulate these processes in pancreatic acinar cells in order to further elucidate the mechanism of alcoholic pancreatitis. The specific aims of this proposal are:

  1. Determine the effect of ethanol, acetaldehyde and fatty acid ethyl ester treatments of dispersed pancreatic acini from rats incubated in the presence and absence of cholecystokinin or TNF-α on apoptosis and necrosis rates, initiator and effector caspase activation, mitochondrial polarity and mitochondrial cytochrome c release;
  2. Measure apoptosis and necrosis rates, initiator and effector caspase activation, mitochondrial polarity and mitochondrial cytochrome c release in the pancreas from rates after the initiation of experimental "acute" or "chronic" pancreatitis with parenteral infusions of cholecystokinin analogues;
  3. Determine the roles of nuclear factor-κB (NF-κB) and poly (ADP-ribose) polymerase (PARP) in regulating the effects of ethanol and its metabolites on apoptosis and necrosis rates as well as the caspase and mitochondrial pathways that mediate the effects.

The project described in this application is designed to elucidate the effects ethanol and its metabolites on the various components of these pathways regulating apoptosis and necrosis using in vivo models of experimental acute and chronic pancreatitis as well as in vitro cultures of pancreatic acini. The results should provide insights into strategies that can be developed to ameliorate the severity of pancreatitis due to alcohol abuse.

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