Reducing Extracellular pH Sensitizes the Acinar Cell to Secretagogue-Induced Pancreatitis Responses in Rats

Bhoomagoud, Madhavi; Jung, Thomas; Atladóttir, Jórunn; Kolodecik, Thomas R.; Shugrue, Christine; Chaudhuri, Anamika; Thrower, Edwin C.; Gorelick, Fred S.

doi:10.1053/j.gastro.2009.05.041

Cited by 103 publications

(63 citation statements)

References 33 publications

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“…2 Inhibition of vATPase with the classic vATPase inhibitors bafilomycin-A1 and concanamycin-A not only inhibits CER-stimulated zymogen activation, 2 but also blocks the enhancing effect of an extracellular acid load in vitro. 23 Because the classic vATPase inhibitors bafilomycin and concanamycin have been shown to have nonspecific effects, [6][7][8][9] the current study was undertaken to confirm our previous results utilizing the novel class of vATPase inhibitors, the benzolactone enamides, which have a different mode of inhibition, as well as genetic manipulation using siRNA.…”

Section: Open Access Animal Physiology Downloaded From Https://wwwdosupporting

confidence: 59%

“…Our laboratory has shown that reducing extracellular or intracellular pH enhances secretagogue stimulated zymogen activation both in vitro and in vivo. 23 In addition, the lysosomal hydrolase cathepsin-B has been shown to activate trypsinogen 24,25 and this activation requires a low pH environment. 26 Furthermore, cathepsins have been shown to colocalize with digestive zymogens 27,28 and the zymogen activation compartment may be lysosomally derived and/or associated with the secretory pathway.…”

Section: Discussionmentioning

confidence: 99%

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Genetic and pharmacologic manipulation of vacuolar ATPase: Effects on zymogen activation in pancreatic acini

Kolodecik¹,

Gorelick²,

Thrower³

2009

OAAP

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Section: Open Access Animal Physiology Downloaded From Https://wwwdosupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacologic manipulation of vacuolar ATPase: Effects on zymogen activation in pancreatic acini

Kolodecik¹,

Gorelick²,

Thrower³

2009

OAAP

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“…This results in edema, vascular damage, hemorrhage and cell death (18,19). In addition to oxidative stress (20) and calcium overload (21), hypotension (22) and low acinar pH (23) contribute to these initiation processes. After initial production of active pancreatic enzymes, local cell death and systemic inflammation ensue.…”

Section: Introductionmentioning

confidence: 99%

Cell Death and DAMPs in Acute Pancreatitis

Kang

Lotze

Zeh

et al. 2014

Mol Med

124

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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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“…Intraluminal pH is also play a central role in normal pancreatic functions, since luminal acidosis may elevate the risk of AP [55,56]. Different etiological factors also can contribute to the development of AP such as excessive ethanol consumption, smoking, viral infections and also gallstones [57][58][59][60][61].…”

Section: Pancreasmentioning

confidence: 99%

Physiological and pathophysiological investigation of lacrimal and pancreatic ductal epithelial cells

Katona¹

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Reducing Extracellular pH Sensitizes the Acinar Cell to Secretagogue-Induced Pancreatitis Responses in Rats

Cited by 103 publications

References 33 publications

Genetic and pharmacologic manipulation of vacuolar ATPase: Effects on zymogen activation in pancreatic acini

Genetic and pharmacologic manipulation of vacuolar ATPase: Effects on zymogen activation in pancreatic acini

Cell Death and DAMPs in Acute Pancreatitis

Physiological and pathophysiological investigation of lacrimal and pancreatic ductal epithelial cells

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