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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 2015 (13)

Title and authors Publication Year
Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP
R Mukherjee, OA Mareninova, IV Odinokova, W Huang, J Murphy, M Chvanov, MA Javed, L Wen, DM Booth, MC Cane, M Awais, B Gavillet, RM Pruss, S Schaller, JD Molkentin, AV Tepikin, OH Petersen, SJ Pandol, I Gukovsky, DN Criddle, AS Gukovskaya, R Sutton, NI Unit, D Latawiec, D Rajamanoharan, E Mclaughlin, P Ghaneh, C Halloran, JP Neoptolemos, MG Raraty, SW French
Gut 2015
Lysosome-Associated Membrane Proteins (LAMP) Maintain Pancreatic Acinar Cell Homeostasis: LAMP-2–Deficient Mice Develop Pancreatitis
OA Mareninova, M Sendler, SR Malla, I Yakubov, SW French, E Tokhtaeva, O Vagin, V Oorschot, R Lüllmann-Rauch, J Blanz, D Dawson, J Klumperman, MM Lerch, J Mayerle, I Gukovsky, AS Gukovskaya
CMGH Cellular and Molecular Gastroenterology and Hepatology 2015
Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and Human Pancreatic Acinar Cells
SW Messenger, DD Thomas, MM Cooley, EK Jones, MA Falkowski, BK August, LA Fernandez, FS Gorelick, GE Groblewski
CMGH Cellular and Molecular Gastroenterology and Hepatology 2015
Redox signaling in acute pancreatitis
S Pérez, J Pereda, L Sabater, J Sastre
Redox Biology 2015
Cathepsin Inhibition-Induced Lysosomal Dysfunction Enhances Pancreatic Beta-Cell Apoptosis in High Glucose
M Jung, J Lee, HY Seo, JS Lim, EK Kim, SM Srinivasula
PloS one 2015
Impaired Autophagy Triggers Chronic Pancreatitis: Lessons From Pancreas-Specific Atg5 Knockout Mice
I Gukovsky, AS Gukovskaya
Gastroenterology 2015
Loss of Bace1 in Mice Does Not Alter the Severity of Caerulein Induced Pancreatitis
M Heindl, J Tuennemann, I Sommerer, J Mössner, A Hoffmeister, H Einwaechter
PloS one 2015
Framework for interpretation of trypsin-antitrypsin imbalance and genetic heterogeneity in pancreatitis
F Gao, Q Chen, Q Liu, S Chen, K Lin
Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association 2015
A Study on Subchronic Inhalation Toxicity of 1-Chloropropane
YH Chung, JH Han, YH Lee
Toxicological Research 2015
Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress
L Antonucci, JB Fagman, JY Kim, J Todoric, I Gukovsky, M Mackey, MH Ellisman, M Karin
Proceedings of the National Academy of Sciences 2015
Lysosome-Associated Membrane Protein-2: A Major Player in the Pathogenesis of Chronic Pancreatitis
G Perides
Cellular and Molecular Gastroenterology and Hepatology 2015
Blockade of Multidrug Resistance-Associated Proteins Aggravates Acute Pancreatitis and Blunts Atrial Natriuretic Factor’s Beneficial Effect in Rats: Role of MRP4 (ABCC4)
Ventimiglia MS, Najenson AC, Perazzo JC, Carozzo A, Vatta MS, Davio CA, Bianciotti LG
Molecular Medicine 2015
PTPRO-mediated autophagy prevents hepatosteatosis and tumorigenesis
Zhang W, Hou J, Wang X, Jiang R, Yin Y, Ji J, Deng L, Huang X, Wang K, Sun B
Oncotarget 2015

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