Impaired autophagosome-lysosome fusion in the pathogenesis of pancreatitis.
In contrast to apoptosis, necrosis is generally viewed as a pro-inflammatory cell death mechanism. Accumulation of autophagosomes and massive acinar cell necrosis is observed in human acute pancreatitis, a severe and potentially lethal inflammatory condition. We have investigated the incidence of apoptosis, autophagy and necrosis affecting acinar cells in a rat model of acute pancreatitis induced by chronic alcohol intake and acute endotoxemia. We have observed that the combination of alcohol exposure and endotoxemia results in substantial accumulation of autophagosomes without an increase in autolysosomes, coupled to the depletion of LAMP-2, a lysosomal protein required for the proper fusion of autophagosomes with lysosomes. Alcohol plus endotoxemia favors the switch from apoptotic to necrotic cell death, as indicated by histopathological examination, reduced ATP levels, suppressed caspase activation, as well as the nuclear release of the proinflammatory factor HMGB1. Importantly, patients with alcoholic pancreatitis also exhibit local LAMP-2 depletion, recapitulating the results obtained in the animal model. We suggest that acinar cell vacuolization in pancreatitis is mediated by an endotoxemia-induced depletion of LAMP-2, which in turn facilitates the accumulation of autophagosomes due to the deficient formation of autolysosomes. Hence, we postulate that the depletion of lysosomal proteins may play a critical role in the pathogenesis of acute pancreatitis.
Fortunato
Franco
F
Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Germany. Franco.Fortunato@med.uni-heidelberg.de
Kroemer
Guido
G
D000818:Animals; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology*; D008561:Membrane Fusion; D008954:Models, Biological; D009336:Necrosis; D010195:Pancreatitis / Q000473:pathology*; D010588:Phagosomes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D051381:Rats
D052119:Lysosomal-Associated Membrane Protein 2