Funding Opportunity Description

Research Objectives - Background

Long-term heavy alcohol consumption is associated with both acute and chronic pancreatitis. Acute pancreatitis is characterized by pain, edema, hemorrhage, acinar cell vacuolation, necrosis and increased serum levels of amylase and lipase. Chronic pancreatitis is characterized by features of acute pancreatitis superimposed on a background of chronic changes that include fibrosis, inflammation, some level of calcification, and loss of exocrine tissue. Progression of pancreatitis may lead to multiple co-morbidities including maldigestion, diabetes, and pancreatic cancer. A recent advance in our understanding of pancreatitis is the development of animal models of alcoholic pancreatitis using co-factors such as cholecystokinin-8 (CCK-8), unsaturated fat, and viral infection. However, further refinement is required in the development of animal models of pancreatitis that more closely mimic human conditions. 

Premature activation of zymogens (inactive digestive enzymes) within the pancreatic acinar cell results in the release of active enzymes within pancreatic tissue, leading to autodigestion that may initiate pancreatitis. Cerulin, an analogue of CCK has been shown to cause zymogen activation in a time- and dose-dependent manner in pancreatic acinar ells, an effect which is enhanced by alcohol. Moreover, ethanol increased rat pancreatic amylase secretion and plasma CCK levels, which were mediated through CCK-releasing factor. Further research is required to understand the interactive effect of alcohol and CCK on zymogen activation.   

The pancreas can metabolize ethanol via oxidative as well as non-oxidative pathways, generating acetaldehyde and fatty acid ethyl esters (FAEE), respectively. The major oxidative enzyme system employs alcohol dehydrogenase (ADH), and the non-oxidative pathway utilizes FAEE synthases. Acetaldehyde causes tissue injury through genotoxicity, adduct formation and associated immunotoxicity, but its role in causing pancreatitis needs clarification. In the oxidative pathway, in addition to ADH, alcohol may also be metabolized by cytochrome P4502E1 (CYP2E1), which has been shown to be induced in rat pancreas by chronic ethanol administration. Alcohol's metabolism by CYP2E1 results in the generation of reactive oxygen species (ROS), which may initiate tissue injury via activation of nuclear factor kappaB (NF-kB) and increased transcription of proinflammatory cytokines. Fatty acid ethyl esters have been shown to increase the fragility of pancreatic lysosomes which may release hydrolases capable of activating trypsinogen within the pancreas, thereby predisposing the pancreas to autodigestive injury. Additional studies are required to understand the relative role of oxidative and non-oxidative metabolism in ethanol-induced pancreatic injury. 

One of the major features of chronic alcoholic pancreatitis is fibrosis resulting from increased production of extracellular matrix proteins, including collagen, by activated pancreatic stellate cells (PSCs). Although several factors such as acetaldehyde, oxidative stress, and cytokines have been implicated in mediating alcohol's effect on PSCs activation, the underlying molecular mechanisms need to be elucidated.  

In addition to direct effects of alcohol, various factors such as substance abuse, genetic makeup, bacterial and viral infection, smoking, high fat diet, compromised immune function, gallstones, and drinking patterns may render the pancreas more susceptible to alcohol-induced tissue injury. Mechanisms underlying the interactive effects of alcohol and these predisposing factors need to be elucidated.

Research Scope:

Appropriate topics for investigation under this PA would include, but are not limited to:

• Elucidation of mechanisms by which alcohol induces or promotes premature activation of pancreatic enzymes (zymogens) within the pancreas directly or indirectly.       
• Characterization of the interactive effects of alcohol and cholecystokinin on the initiation and perpetuation of alcoholic pancreatitis.
• Determination of the role of diet, including fat and protein, in the modulation of gene expression and synthesis of various secretagogues.
• Investigation of the role of acetaldehyde and fatty acid ethyl esters in the initiation and progression of alcoholic pancreatitis.
• Determination of the role of oxidative stress in the activation of transcription factors that are involved in regulating proinflammatory cytokines. 
• Determination of the roles of cytokines, chemokines, adhesion molecules, and inflammatory leukocytes in the initiation and progression of inflammation of the pancreas.  
• Investigation of the role of gut-derived endotoxin in triggering the process of inflammation through activation of pancreatic acinar cells and inflammatory leukocytes.
• Characterization of the molecular mechanisms of pancreatic stellate cell activation leading to increased deposition of extracellular matrix proteins and fibrosis.    
• Investigation of the role of impaired immune function in rendering the pancreas more susceptible to the injurious effect of alcohol.   
• Determination of the influence of drinking patterns on the pathogenesis of the disease.    
• Investigation of the role of other factors such as substance abuse, smoking, bacterial and viral infection, gallstones, and genetic susceptibility in the initiation and progression of alcoholic pancreatitis.  
• Determination of the influence of gender and ethnicity on the course of alcoholic pancreatitis.
• Characterization of the relationship between pancreatitis, diabetes, obesity, and pancreatic cancer.
• Identification and characterization of biomarkers of early cell or tissue perturbation that can be used for diagnosis of the disease.   
• Study of pharmacology of drug-induced pancreatitis including that caused by non-nucleotide and protease inhibitor anti-retroviral therapeutic agents.    

Prepared:  March 9, 2006