Abstract
Auto (self)-digestion of the pancreas by its own prematurely activated digestive proteases is thought to be an important event in the onset of acute pancreatitis. Although lysosomal cathepsin B is suggested to play a key role in intrapancreatic trypsinogen activation, it is not clear how trypsinogen is delivered to the lysosome. Autophagy is an intracellular bulk degradation system in which cytoplasmic components are directed to the lysosome/vacuole by a membrane-mediated process. To analyze whether autophagy delivers trypsinogen to the lysosome and whether this is related to the onset of acute pancreatitis, we produced a conditional knockout mouse lacking Atg5 (autophagy related) in pancreatic acinar cells. The severity of acute pancreatitis induced by cerulein was reduced in these mice. In addition, trypsin activation was greatly reduced in Atg5 deficient acinar cells. These data suggest that autophagy exerts a devastating effect in pancreatic acinar cells by activation of trypsinogen to trypsin. We propose that autophagy plays a major role in the pathogenesis of acute pancreatitis by delivering trypsinogen to the lysosome.
