One of the most devastating consequences of alcohol abuse is fibrosis of the exocrine pancreas. Fibrosis is the result of a failure in the repairing processes following organ injury. Two main degrading systems participate in tissue remodeling: matrix metalloproteinases (MMPs) and serine proteases from the plasminogen (Plg) system. The Plg system plays a central role in extracellular matrix (ECM) turnover both by the ECM-proteolytic activity of the serine protease plasmin and by its ability to activate MMPs. Although little is known about the role of the Plg system in pancreas, studies in humans suggest that alterations in the Plg system are important factors contributing to the pathogenesis of chronic pancreatitis. Furthermore, alcohol consumption is associated with changes in the blood Plg system. Preliminary studiesperformed in our laboratory with Plg deficient mice and rats fed the Lieber-Decarli diet (ethanol as 35% of total calories) indicate that ECM-degrading proteases of the Plg system participate in the development of pancreatic fibrosis and that ethanol intake induce changes in both the activity and expression of these proteases and its inhibitors. Based in our results and others reported in the literature, we hypothesize that ECM-degrading proteases including the Plg system, play a key role in the pathogenesis of alcohol-induced chronic pancreatitis. The overall goals of the present project are to determine the role of the Plg system in the remodeling processes following pancreas injury (i.e. acute pancreatitis), and to examine the alterations of the Plg system induced by ethanol and the consequences of these alterations on the development of the features of chronic pancreatitis, including fibrosis, stellate cell proliferation, parenchymal cell loss andchronic inflammation. The specific objectives of this project are to: 1. Determine the effect of ethanol and its metabolites, acetaldehyde and fatty acid ethyl esters (FAEEs), on components of the Plg system in rat pancreas, both in vitro and in vivo. 2. Examine the consequences of plasminogen deficiency (i.e. using genetically deficient mice) on the progression of pancreatic fibrosis, inflammation and parenchymal cell loss after cerulein-induced pancreatitis.3. Determine whether plasminogen deficiency alters the pancreatic response to ethanol after anepisode of acute pancreatitis.
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