CHRONIC PANCREATITIS · General mechanisms predisposing to acute and chronic pancreatitis in alcoholics

Final Activity Report Summary - CHRONIC PANCREATITIS (General mechanisms predisposing to acute and chronic pancreatitis in alcoholics)

Acute pancreatitis constitutes a life-threatening condition in which pancreatic acinar cells undergo massive necrotic cell death. One of the earliest pathological signs during the course of AP is acinar cell vacuolisation, which is believed to develop in response to acinar cell injury followed by acinar cell necrosis, inflammatory responses and tissue destruction. We and others have shown that endotoxemia can be a trigger for initiating experimental acute and chronic alcoholic pancreatitis.[1, 2], Lipopolysaccharide (LPS), a major cell wall component of gram-negative bacteria, directly affects acinar cells and may contribute to the pathophysiology of acute pancreatitis.[3] LPS is known to modulate pancreatic apoptosis and to activate pancreatic stellate cells, but the mechanisms determining early pancreatitis-associated injury with respect to alcohol exposure remain unclear.[1, 2] Chronic alcohol consumption has been shown to be associated with an elevated circulating endotoxin level in humans,[4] and animals.[5] Increased gut permeability and suppressed detoxification contributes to the elevated serum endotoxin level.[5] Therefore, LPS has important clinical relevance as a cofactor in triggering alcoholic pancreatitis. The degree of endotoxemia has been shown to be a predictor of the severity, systemic complications and mortality at admission of patients with acute pancreatitis.[6, 7] Pancreatic infection is the most common complication, with a high mortality rate in acute pancreatitis.[8] We have previously shown that chronic alcohol exposure demonstrated a decrease of inflammatory cells in the pancreatic tissue compared to controls. The anti-inflammatory effects of alcohol were confirmed by decreased expression of pro-inflammatory cytokines including TNFa, IL-1ß, IL-18, TGFß and MCP-1.[9] In addition alcohol significantly increased the activity of PPAR?, which is a known anti-inflammatory transcription factor, while pro-inflammatory factors including AP-2 and EGR-1 were significantly suppressed. NF?B binding showed a tendency towards a reduction.[9] Electron microscopy studies revealed enlarged and injured mitochondria and lysosomes, accompanied with peri-cellular fibrosis. Furthermore, alcohol exposure increased the activities of trypsin and cathepsin B, both known to be critical in initiating acinar cell injury and pancreatitis. Despite the known alcohol-mediated acinar cell and mitochondrial injury, the mitochondrial-mediated apoptotic pathway was attenuated. These data demonstrate that the rat pancreas exposed to alcohol maintains anti-inflammatory state by activating PPAR?. Intracellular mitochondrial and lysosomal damage after chronic alcohol exposure induces premature activation of digestive enzymes and establishment of peri-cellular fibrosis in the absence of inflammation.[9] Our newly obtained data showed that experimental acute alcoholic pancreatitis attenuated LPS-induced apoptosis stimulation and that LPS mediated a depletion of pancreatic Lamp-2 (a lysosomal protein that is required for the proper fusion of autophagosomes and lysosomes), which resulted in the suppression of cytoprotective autophagy signaling.[10] Accordingly, the combination of alcohol plus LPS correlated well with the accumulation of vacuoles (autophagosomes), accompanied by an attenuated autolysosomes formation, reduced ATP levels, and a switch from apoptotic to necrotic acinar cell death.[10] The modulation of autophagy may have therapeutic value, since severe necrotizing acute pancreatitis exhibits less apoptosis and more necrosis, while mild acute pancreatitis is associated with more apoptosis and less necrosis. This study showed, for the first time, the involvement and interconnection of apoptosis, autopahgy and necrosis in vivo. This in vitro study is in agreement with our in vivo report in which alcohol and LPS blocked apoptosis and autopahgy pathways and thereby promoted acinar cell death by necrosis. We also find Lamp-2 depletion in human pancreatitis tissue, which suggests a general mechanism for the initiation of AP.[10]% Reference 1. Vonlaufen, A., et al., Bacterial endotoxin: a trigger factor for alcoholic pancreatitis? Evidence from a novel, physiologically relevant animal model. Gastroenterology, 2007. 133(4): p. 1293-303. 2. Fortunato, F., et al., Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis? Am J Physiol Gastrointest Liver Physiol, 2006. 290(2): p. G232-41. 3. Vaccaro, M.I., et al., Lipopolysaccharide directly affects pancreatic acinar cells: implications on acute pancreatitis pathophysiology. Dig Dis Sci, 2000. 45(5): p. 915-26. 4. Schafer, C., et al., Concentrations of lipopolysaccharide-binding protein, bactericidal/permeability-increasing protein, soluble CD14 and plasma lipids in relation to endotoxaemia in patients with alcoholic liver disease. Alcohol Alcohol, 2002. 37(1): p. 81-6. 5. Bode, C. and J.C. Bode, Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol, 2003. 17(4): p. 575-92. 6. Parenti, D.M., W. Steinberg, and P. Kang, Infectious causes of acute pancreatitis. Pancreas, 1996. 13(4): p. 356-71. 7. Buttenschoen, K., et al., Endotoxin and antiendotoxin antibodies in patients with acute pancreatitis. Eur J Surg, 2000. 166(6): p. 459-66. 8. Lowham, A., J. Lavelle, and T. Leese, Mortality from acute pancreatitis. Late septic deaths can be avoided but some early deaths still occur. Int J Pancreatol, 1999. 25(2): p. 103-6. 9. Fortunato, F., et al., Immune-compromised state in the rat pancreas after chronic alcohol exposure: the role of peroxisome proliferator-activated receptor gamma. J Pathol, 2007. 213(4): p. 441-52. 10. Fortunato, F., et al., IMPAIRED AUTOLYSOSOME FORMATION CORRELATES WITH LAMP-2 DEPLETION: ROLE OF APOPTOSIS, AUTOPHAGY AND NECROSIS IN THE EARLY ONSET OF ALCOHOLIC PANCREATITIS. Revision submitted Gastroenterology, 2008.

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