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Citations to this article

Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis
Olga A. Mareninova, … , Ilya Gukovsky, Anna S. Gukovskaya
Olga A. Mareninova, … , Ilya Gukovsky, Anna S. Gukovskaya
Published October 1, 2009
Citation Information: J Clin Invest. 2009;119(11):3340-3355. https://doi.org/10.1172/JCI38674.
View: Text | PDF | Corrigendum
Research Article Gastroenterology

Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis

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Abstract

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.

Authors

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

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Total citations by year

Year: 2025 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 2013 2012 2011 2010 2009 Total
Citations: 4 18 5 8 17 17 13 12 13 15 13 7 8 11 12 7 1 181
Citation information
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2011 (12)

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

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