Alcohol abuse is an important factor in the etiology of acute and chronic pancreatitis (CP) but the mechanisms leading to alcoholic pancreatitis remains unknown. The experiments are framed in the SAPE hypothesis model, which postulates that recurrent acute episodes lead to CP. Chronic alcohol users have increased gut permeability, bacterial translocation and release of bacterial factors such as LPS. Chronic alcohol exposure also induces acinar cell mitochondria damage.
This proposal therefore will facilitate the development of new tools and new directions in the study of alcoholic CP with respect to mitochondrial function. We will use LPS to initiate the acute inflammatory response. We will determine the adaptive response to repeat exposure to LPS in the p resents of alcohol representing acute episodes of pancreatitis. Chronic alcohol exposure increases acinar cell mitochondrial damage and suppresses the intrinsic apoptotic pathway. Acinar cells containing the damaged mitochondria are insufficiently removed. This leads to an increased vulnerability to LPS, which results in acute pancreatitis episodes. Furthermore severe acute pancreatitis episodes may lead to CP. Using a commercial available alcohol/control diet and LPS treatment, we will provide important in formation in understanding the mechanisms leading to CP.
The specific aims are: to determine that chronic alcohol exposure alters the functional property of acinar cell mitochondria, increasing the threshold of apoptosis initiation in response to LPS; to determine that chronic alcohol exposure exacerbates pancreatic injury in response to LPS in a dose-dependent fashion and that the pancreatic injury persists under alcohol exposure; to determine that the highest possible LPS dose induces severe necrotizing a cute pancreatitis in alcohol treated animals and to determine that multiple episodes of LPS-mediated acute pancreatic injury lead to chronic pancreatic inflammation, fibrosis and CP in alcohol fed animals.
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