The pathogenic mechanisms underlying acute pancreatitis are not clear. Two key pathologic acinar cell responses of this disease are vacuole accumulation and trypsinogen activation. We show here that both result from defective autophagy, by comparing the autophagic responses in rodent models of acute pancreatitis to physiologic autophagy triggered by fasting. Pancreatitis-induced vacuoles in acinar cells were greater in number and much larger than those induced with fasting. Degradation of long-lived proteins, a measure of autophagic efficiency, was markedly inhibited in in vitro pancreatitis, while it was stimulated by acinar cell starvation. Further, processing of the lysosomal proteases cathepsin L (CatL) and CatB into their fully active, mature forms was reduced in pancreatitis, as were their activities in the lysosome-enriched subcellular fraction. These findings indicate that autophagy is retarded in pancreatitis due to deficient lysosomal degradation caused by impaired cathepsin processing. Trypsinogen activation occurred in pancreatitis but not with fasting and was prevented by inhibiting autophagy. A marker of trypsinogen activation partially localized to autophagic vacuoles, and pharmacologic inhibition of CatL increased the amount of active trypsin in acinar cells. The results suggest that retarded autophagy is associated with an imbalance between CatL, which degrades trypsinogen and trypsin, and CatB, which converts trypsinogen into trypsin, resulting in intra-acinar accumulation of active trypsin in pancreatitis. Thus, deficient lysosomal degradation may be a dominant mechanism for increased intra-acinar trypsin in pancreatitis.
Olga A. Mareninova, Kip Hermann, Samuel W. French, Mark S. O’Konski, Stephen J. Pandol, Paul Webster, Ann H. Erickson, Nobuhiko Katunuma, Fred S. Gorelick, Ilya Gukovsky, Anna S. Gukovskaya
Title and authors | Publication | Year |
---|---|---|
Lipotoxicity Causes Multisystem Organ Failure and Exacerbates Acute Pancreatitis in Obesity
S Navina, C Acharya, JP DeLany, LS Orlichenko, CJ Baty, SS Shiva, C Durgampudi, JM Karlsson, K Lee, KT Bae, A Furlan, J Behari, S Liu, T McHale, L Nichols, GI Papachristou, D Yadav, VP Singh |
Science Translational Medicine | 2011 |
Molecular mechanisms of pancreatic injury :
RP Sah, A Saluja |
Current Opinion in Gastroenterology | 2011 |
Intragenic duplication: a novel mutational mechanism in hereditary pancreatitis
MT Joergensen, A Geisz, K Brusgaard, OB de Muckadell, P Hegyi, AM Gerdes, M Sahin-Tóth |
Pancreas | 2011 |
Organellar dysfunction in the pathogenesis of pancreatitis
I Gukovsky, SJ Pandol, AS Gukovskaya |
Antioxidants & Redox Signaling | 2011 |
Trypsinogen activation in acute and chronic pancreatitis: is it a prerequisite?
RP Sah, AK Saluja |
Gut | 2011 |
Functions of Autophagy in Hepatic and Pancreatic Physiology and Disease
MJ Czaja |
Gastroenterology | 2011 |
The multiple roles of autophagy in cancer
MT Rosenfeldt, KM Ryan |
Carcinogenesis | 2011 |
Investigating the Pathobiology of Alcoholic Pancreatitis
SJ Pandol, A Lugea, OA Mareninova, D Smoot, FS Gorelick, AS Gukovskaya, I Gukovsky |
Alcoholism, clinical and experimental research | 2011 |
Genetic and Pharmacological Inhibition of the Ca2+ Influx Channel TRPC3 Protects Secretory Epithelia from Ca2+-Dependent Toxicity
MS Kim, KP Lee, D Yang, DM Shin, J Abramowitz, S Kiyonaka, L Birnbaumer, Y Mori, S Muallem |
Gastroenterology | 2011 |
Which Way to Die: the Regulation of Acinar Cell Death in Pancreatitis by Mitochondria, Calcium, and Reactive Oxygen Species
AS Gukovskaya, I Gukovsky |
Gastroenterology | 2011 |
Calcium and Reactive Oxygen Species in Acute Pancreatitis: Friend or Foe?
DM Booth, R Mukherjee, R Sutton, DN Criddle |
Antioxidants & Redox Signaling | 2011 |
Autophagy: a primer for the gastroenterologist/hepatologist.
Sokollik C, Ang M, Jones N |
Canadian journal of gastroenterology = Journal canadien de gastroenterologie | 2011 |