Autophagy and pancreatitis

Abstract

Acute pancreatitis is an inflammatory disease of the exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. Recent findings from experimental models and genetically altered mice summarized in this review reveal that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis and that one cause of autophagy impairment is defective function of lysosomes. We propose that the lysosomal/autophagic dysfunction is a key initiating event in pancreatitis and a converging point of multiple deranged pathways. There is strong evidence supporting this hypothesis. Investigation of autophagy in pancreatitis has just started, and many questions about the "upstream" mechanisms mediating the lysosomal/autophagic dysfunction and the "downstream" links to pancreatitis pathologies need to be explored. Answers to these questions should provide insight into novel molecular targets and therapeutic strategies for treatment of pancreatitis.

Fig. 1.

Schematic of autophagy progression. Autophagy starts with formation of membrane structures that sequester cytoplasmic organelles [e.g., mitochondria or zymogen granules (ZGs)], forming the double-membrane autophagosomes. Autophagosomes then fuse with lysosomes, thus becoming autolysosomes. LC3-II protein, a marker of autophagosomes; LAMP, integral lysosome-associated membrane protein; ER, endoplasmic reticulum.

Fig. 2.

Schematic illustrating 2 major mechanisms of defective autophagic flux. [Adapted from Klionsky et al. (54).]

Fig. 3.

Electron micrographs of pancreatic tissue from patients with acute pancreatitis. Note large autophagic vacuoles (VC) containing ZGs and fragments of rough endoplasmic reticulum (*, A) and zymogen content (arrows) immunoreactive for trypsinogen (B). [From Willemer et al. (111), with kind permission from Springer Science and Business Media.]

Fig. 4.

LC3-I to LC3-II conversion in rat and mouse models of acute pancreatitis and the ex vivo model of mouse acinar cells hyperstimulated with CCK-8. Arg, l-arginine; CDE, choline-deficient, ethionine-supplemented diet; Con, control; CR, caerulein; Sal, saline control.

Fig. 5.

Pancreatitis-like injury resulting from lysosomal/autophagic dysfunction in genetic models. A: hematoxylin-eosin-stained section of pancreas of N-acetylglucosamine-1-phosphotransferase-deficient (Gnptab^−/−) mouse. Note large cytoplasmic vacuoles in acinar cells containing partially degraded cargo. [From Vogel et al. (105), by permission from Sage Publications.] B: electron micrograph showing accumulation of large autophagic vacuoles (arrowheads) in pancreas of LAMP-2-deficient mice. [From Tanaka et al. (100), by permission from Macmillan Publishers Ltd.]

Fig. 6.

Schematic illustrating the hypothesis on a key initiating role of lysosomal/autophagic dysfunction in pancreatitis.