Heme oxygenase-1 gene promoter polymorphism and acute pancreatitis

Abstract

s / Pancreatolog Zymophagy, a zymogen selective autophagy process, has been recently found to play a role in the exocrine pancreas and has been associated with pancreatitis. We investigated whether autophagosomes colocalize with active trypsin in experimental and human pancreatitis tissue specimens. The immunofluorescence technique revealed a significant increase in both trypsin and LC3, 3 and 24 hours after LPS in the early onset of experimental subclinical acute pancreatitis. The increase of trypsin and LC3wasmore pronounced in alcohol-fed rats but significantly less compared to control rats after LPS. We also found a significant increase in trypsin and LC3 expression in human acute/recurrent pancreatitis tissue samples but not in chronic pancreatitis or pancreatic control tissue. This increase was almost identical to the colocalization of Trypsin with LC3, indicating that LC3-positive autophagosomes contain trypsin. The colocalization of LC3 and trypsin was confirmed by puncture analysis, indicating a 10and 25-fold increase of zymophagosomes in acinar cells from acute/recurrent pancreatitis patients. LC3 and syncollin colocalization, however, showed a substantial loss in acute/recurrent and chronic pancreatitis samples, indicating that syncollin becomes degraded in pancreatitis, confirming previously reports. The zymophagosomal/ autophagosomal fusion with lysosomes is disrupted in pancreatitis, resulting in the accumulation of active trypsin in zymophagosomes. Our data showed that active trypsin becomes evident in zymophagosomes concurrently by the loss of syncollin. The accumulation of active trypsin in zymophagosomes may contribute to the initiation of acinar cell autodigestion and acute pancreatitis.