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

Mareninova, Olga A.; Hermann, Kip; French, Samuel W.; O’Konski, Mark S.; Pandol, Stephen J.; Webster, Paul; Erickson, Ann H.; Katunuma, Nobuhiko; Gorelick, Fred S.; Gukovsky, Ilya; Gukovskaya, Anna S.

doi:10.1172/jci69660

Cited by 136 publications

(153 citation statements)

References 69 publications

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“…These findings also stand in marked contrast to those reported in an earlier study in which Atg5 was ablated using Cre recombinase driven by the elastase promoter (13). In that study, no pancreatic injury was observed and the ATG5 deficiency was even claimed to ameliorate cerulein-induced pancreatic injury (13), a rather odd finding because cerulein-induced pancreatic injury entails inhibition of autophagic protein degradation (18). Notably, a more recent study demonstrated that Ptf1a-Cre-mediated Atg5 ablation does result in the development of pancreatitis (16), albeit not as severe as the pathology seen in Atg7 Δpan mice.…”

Section: Discussioncontrasting

confidence: 78%

“…Degradation of long-lived proteins, a major function of autophagy, is impaired during experimental pancreatitis, especially after administration of cerulein, which causes acinar cell vacuolization and excessive trypsinogen activation (18). Moreover, autophagic flux is reduced during pancreatitis due to defective cathepsinmediated processing of lysosomal proteases (18).…”

mentioning

confidence: 99%

“…Moreover, autophagic flux is reduced during pancreatitis due to defective cathepsinmediated processing of lysosomal proteases (18). Similarly, pancreasspecific ablation of inhibitor of IκB kinase (IKK)α results in acinar damage ranging from vacuole accumulation to chronic pancreatitis (15).…”

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confidence: 99%

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Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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203

182

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Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7 Δpan mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7 Δpan mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7 Δpan mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.T he pancreatic acinar cell is responsible for production and secretion of numerous digestive enzymes, including amylase, lipase, and various proteases. To cope with the high daily demand for these enzymes, the acinar cell possesses one of the highest protein biosynthetic rates of all cells, together with an extensive rough endoplasmic reticulum (RER) network (1). Due to its high protein synthetic rates, the acinar cell is prone to the accumulation of misfolded proteins and subsequent induction of ER stress (2, 3). ER stress was suggested to be involved in the pathogenesis of pancreatitis, a potentially fatal inflammatory disease of the exocrine pancreas (2, 4). By progressing from acute (sudden onset; duration <6 mo), to recurrent acute (>1 episode of acute pancreatitis), and chronic (duration >6 mo) disease (5), pancreatitis increases the risk of pancreatic ductal adenocarcinoma (PDAC), the fourth deadliest cancer worldwide, with a median survival of 6 mo (6). The molecular mechanisms mediating the progression of pancreatitis from acinar cell damage and inflammation to formation of pancreatic intraepithelial neoplasia (PanIN) and PDAC are not fully understood. Recent studies suggest that in addition to ER stress, insufficient autophagy also contributes to development of pancreatitis (7).Autophagy is an evolutionarily conserved, catabolic quality control process that maintains cellular homeostasis by degrading damaged organelles, misfolded protein aggregates, and foreign organisms (8). Autophagy is also important for generation of amino acids and other building blo...

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Section: Discussioncontrasting

confidence: 78%

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confidence: 99%

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Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Antonucci

Fagman

Kim

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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203

182

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“…One early feature of AP is the accumulation of large autophagic vacuoles in pancreatic acinar cells (67,68). Autophagic flux is impaired in AP, which mediates acinar cell vacuole formation, trypsinogen activation, cell death and the inflammatory response (for example, inflammasome activation) (67,69,70), suggesting a protective role of autophagy in AP.…”

Section: Autophagymentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

125

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The pancreas is a dual-purpose gland with exocrine and endocrine functions. The exocrine pancreas produces digestive proteases in inactive proenzyme form, namely zymogens. The pancreas is normally able to protect itself from zymogen activation by synthesis of protease inhibitors such as pancreatic secretory trypsin inhibitor and serine protease inhibitor (for example, SPINK1/Spink3). By contrast, pancreatic autodigestion and subsequent AP is initiated once these defenses are impaired. In studies of rodent models (for example, repetitive cerulein or L-arginine injections, choline-deficient ethionine supplementation [CDE] diet, perfusion of taurocholate into the biliary or pancreatic duct and surgical ligation or infusion of pancreatic duct models), some essential pathogenic AP events have been identified (see Figure 1) (15,16).The development of AP involves a complex cascade of events (17), which start with injury or disruption of the pan- Cell Death and DAMPs in Acute PancreatitisRui Kang, Michael T Lotze, Herbert J Zeh, Timothy R Billiar, and Daolin Tang Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP . Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP . DAMPs might be an attractive therapeutic target in AP.

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“…It has been found that pancreatitis stimulates autophagy induction and, at the same time, impairs late stages of autophagy (18). A defective autophagy could cause vacuole accumulation and trypsinogen activation, contributing to the development of pancreatitis (28).…”

Section: Hmgb1 Autophagy and Apoptosis In Pancreatic Cancermentioning

confidence: 99%

Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?

Cebrián

Bauden

Andersson

et al. 2016

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

Cited by 136 publications

References 69 publications

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

Cell Death and DAMPs in Acute Pancreatitis

Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?

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