scholarly journals EFFECTS OF CALCIUM ON ZYMOGEN ACTIVATION IN MOUSE PANCREATIC ACINAR CELLS

Pancreas ◽  
2005 ◽  
Vol 31 (4) ◽  
pp. 469
Author(s):  
R D Smith ◽  
M Raraty ◽  
D N Criddle ◽  
O V Gerasimenko ◽  
A V Tepikin ◽  
...  
Keyword(s):  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Zymogen Activation

scholarly journals Pancreatogenic Diabetes: Triggering Effects of Alcohol and HIV

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 108
Author(s):  
Moses New-Aaron ◽  
Murali Ganesan ◽  
Raghubendra Singh Dagur ◽  
Kusum K. Kharbanda ◽  
Larisa Y. Poluektova ◽  
...  
Keyword(s):  
Multiorgan Failure ◽  
Acinar Cells ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Alcoholic Pancreatitis ◽  
People Living With Hiv ◽  
Zymogen Activation ◽  
Pancreatogenic Diabetes ◽  
Hiv Entry ◽  
Living With Hiv

Multiorgan failure may not be completely resolved among people living with HIV despite HAART use. Although the chances of organ dysfunction may be relatively low, alcohol may potentiate HIV-induced toxic effects in the organs of alcohol-abusing, HIV-infected individuals. The pancreas is one of the most implicated organs, which is manifested as diabetes mellitus or pancreatic cancer. Both alcohol and HIV may trigger pancreatitis, but the combined effects have not been explored. The aim of this review is to explore the literature for understanding the mechanisms of HIV and alcohol-induced pancreatotoxicity. We found that while premature alcohol-inducing zymogen activation is a known trigger of alcoholic pancreatitis, HIV entry through C-C chemokine receptor type 5 (CCR5) into pancreatic acinar cells may also contribute to pancreatitis in people living with HIV (PLWH). HIV proteins induce oxidative and ER stresses, causing necrosis. Furthermore, infiltrative immune cells induce necrosis on HIV-containing acinar cells. When necrotic products interact with pancreatic stellate cells, they become activated, leading to the release of both inflammatory and profibrotic cytokines and resulting in pancreatitis. Effective therapeutic strategies should block CCR5 and ameliorate alcohol’s effects on acinar cells.

scholarly journals Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ali A. Aghdassi ◽  
Daniel S. John ◽  
Matthias Sendler ◽  
Christian Storck ◽  
Cindy van den Brandt ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Serine Protease ◽  
Acinar Cells ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Pancreatic Acinar Cells ◽  
Neutrophil Granulocyte ◽  
Zymogen Activation ◽  
Trypsinogen Activation ◽  
Extracellular Matrix Components

AbstractAcute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG−/− mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG−/− mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.

scholarly journals Pharmacological inhibition of PAR2 with the pepducin P2pal-18S protects mice against acute experimental biliary pancreatitis

2013 ◽  
Vol 304 (5) ◽  
pp. G516-G526 ◽  
Author(s):  
E. S. Michael ◽  
A. Kuliopulos ◽  
L. Covic ◽  
M. L. Steer ◽  
G. Perides
Keyword(s):  
Bile Acid ◽  
Acinar Cells ◽  
Experimental Pancreatitis ◽  
In Vivo Studies ◽  
Pancreatic Acinar Cells ◽  
Biliary Pancreatitis ◽  
Zymogen Activation ◽  
Injury Death ◽  
Acid Infusion ◽  
Concentration Changes

Pancreatic acinar cells express proteinase-activated receptor-2 (PAR2) that is activated by trypsin-like serine proteases and has been shown to exert model-specific effects on the severity of experimental pancreatitis, i.e., PAR2−/− mice are protected from experimental acute biliary pancreatitis but develop more severe secretagogue-induced pancreatitis. P2pal-18S is a novel pepducin lipopeptide that targets and inhibits PAR2. In studies monitoring PAR2-stimulated intracellular Ca2+ concentration changes, we show that P2pal-18S is a full PAR2 inhibitor in acinar cells. Our in vivo studies show that P2pal-18S significantly reduces the severity of experimental biliary pancreatitis induced by retrograde intraductal bile acid infusion, which mimics injury induced by endoscopic retrograde cholangiopancreatography (ERCP). This reduction in pancreatitis severity is observed when the pepducin is given before or 2 h after bile acid infusion but not when it is given 5 h after bile acid infusion. Conversely, P2pal-18S increases the severity of secretagogue-induced pancreatitis. In vitro studies indicate that P2pal-18S protects acinar cells against bile acid-induced injury/death, but it does not alter bile acid-induced intracellular zymogen activation. These studies are the first to report the effects of an effective PAR2 pharmacological inhibitor on pancreatic acinar cells and on the severity of experimental pancreatitis. They raise the possibility that a pepducin such as P2pal-18S might prove useful in the clinical management of patients at risk for developing severe biliary pancreatitis such as occurs following ERCP.

S1817 Protein Kinase D Modulates Secretagogue-Induced Zymogen Activation and Amylase Secretion in Rat Pancreatic Acinar Cells

2009 ◽  
Vol 136 (5) ◽  
pp. A-276
Author(s):  
Edwin C. Thrower ◽  
Jingzhen Yuan ◽  
Courtney Jones ◽  
Ashar Usmani ◽  
Meghan K. Kelly ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Protein Kinase D ◽  
Amylase Secretion ◽  
Zymogen Activation

scholarly journals Alcohols enhance caerulein-induced zymogen activation in pancreatic acinar cells

2002 ◽  
Vol 282 (3) ◽  
pp. G501-G507 ◽  
Author(s):  
Zhao Lu ◽  
Suresh Karne ◽  
Thomas Kolodecik ◽  
Fred S. Gorelick
Keyword(s):  
Acinar Cell ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Dependent Manner ◽  
Zymogen Activation ◽  
Concentration Dependent Manner ◽  
Pancreatic Acini ◽  
A Chain ◽  
Peak Value

Activation of zymogens within the pancreatic acinar cell is an early feature of acute pancreatitis. Supraphysiological concentrations of cholecystokinin (CCK) cause zymogen activation and pancreatitis. The effects of the CCK analog, caerulein, and alcohol on trypsin and chymotrypsin activation in isolated pancreatic acini were examined. Caerulein increased markers of zymogen activation in a time- and concentration-dependent manner. Notably, trypsin activity reached a peak value within 30 min, then diminished with time, whereas chymotrypsin activity increased with time. Ethanol (35 mM) sensitized the acinar cells to the effects of caerulein (10−10 to 10−7 M) on zymogen activation but had no effect alone. The effects of ethanol were concentration dependent. Alcohols with a chain length of ≥2 also sensitized the acinar cell to caerulein; the most potent was butanol. Branched alcohols (2-propanol and 2-butanol) were less potent than aliphatic alcohols (1-propanol and 1-butanol). The structure of an alcohol is related to its ability to sensitize acinar cells to the effects of caerulein on zymogen activation.

scholarly journals A novel protein kinase D inhibitor attenuates early events of experimental pancreatitis in isolated rat acini

2011 ◽  
Vol 300 (1) ◽  
pp. G120-G129 ◽  
Author(s):  
Edwin C. Thrower ◽  
Jingzhen Yuan ◽  
Ashar Usmani ◽  
Yannan Liu ◽  
Courtney Jones ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Protein Kinase ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Protein Kinase D ◽  
Amylase Secretion ◽  
Zymogen Activation ◽  
Isolated Rat ◽  
Novel Protein

Novel protein kinase C isoforms (PKC δ and ε) mediate early events in acute pancreatitis. Protein kinase D (PKD/PKD1) is a convergent point of PKC δ and ε in the signaling pathways triggered through CCK or cholinergic receptors and has been shown to activate the transcription factor NF-κB in acute pancreatitis. For the present study we hypothesized that a newly developed PKD/PKD1 inhibitor, CRT0066101, would prevent the initial events leading to pancreatitis. We pretreated isolated rat pancreatic acinar cells with CRT0066101 and a commercially available inhibitor Gö6976 (10 μM). This was followed by stimulation for 60 min with high concentrations of cholecystokinin (CCK, 0.1 μM), carbachol (CCh, 1 mM), or bombesin (10 μM) to induce initial events of pancreatitis. PKD/PKD1 phosphorylation and activity were measured as well as zymogen activation, amylase secretion, cell injury and NF-κB activation. CRT0066101 dose dependently inhibited secretagogue-induced PKD/PKD1 activation and autophosphorylation at Ser-916 with an IC50 ∼3.75–5 μM but had no effect on PKC-dependent phosphorylation of the PKD/PKD1 activation loop (Ser-744/748). Furthermore, CRT0066101 reduced secretagogue-induced zymogen activation and amylase secretion. Gö6976 reduced zymogen activation but not amylase secretion. Neither inhibitor affected basal zymogen activation or secretion. CRT0066101 did not affect secretagogue-induced cell injury or changes in cell morphology, but it reduced NF-κB activation by 75% of maximal for CCK- and CCh-stimulated acinar cells. In conclusion, CRT0066101 is a potent and specific PKD family inhibitor. Furthermore, PKD/PKD1 is a potential mediator of zymogen activation, amylase secretion, and NF-κB activation induced by a range of secretagogues in pancreatic acinar cells.

scholarly journals Genetic inhibition of protein kinase Cε attenuates necrosis in experimental pancreatitis

2014 ◽  
Vol 307 (5) ◽  
pp. G550-G563 ◽  
Author(s):  
Yannan Liu ◽  
Jingzhen Yuan ◽  
Tanya Tan ◽  
Wenzhuo Jia ◽  
Aurelia Lugea ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Inflammatory Responses ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Caspase Activation ◽  
Zymogen Activation ◽  
Cytochrome C Release ◽  
Interacting Protein ◽  
Regulated Necrosis

Understanding the regulation of death pathways, necrosis and apoptosis, in pancreatitis is important for developing therapies directed to the molecular pathogenesis of the disease. Protein kinase Cε (PKCε) has been previously shown to regulate inflammatory responses and zymogen activation in pancreatitis. Furthermore, we demonstrated that ethanol specifically activated PKCε in pancreatic acinar cells and that PKCε mediated the sensitizing effects of ethanol on inflammatory response in pancreatitis. Here we investigated the role of PKCε in the regulation of death pathways in pancreatitis. We found that genetic deletion of PKCε resulted in decreased necrosis and severity in the in vivo cerulein-induced pancreatitis and that inhibition of PKCε protected the acinar cells from CCK-8 hyperstimulation-induced necrosis and ATP reduction. These findings were associated with upregulation of mitochondrial Bak and Bcl-2/Bcl-xL, proapoptotic and prosurvival members in the Bcl-2 family, respectively, as well as increased mitochondrial cytochrome c release, caspase activation, and apoptosis in pancreatitis in PKCε knockout mice. We further confirmed that cerulein pancreatitis induced a dramatic mitochondrial translocation of PKCε, suggesting that PKCε regulated necrosis in pancreatitis via mechanisms involving mitochondria. Finally, we showed that PKCε deletion downregulated inhibitors of apoptosis proteins, c-IAP2, survivin, and c-FLIPs while promoting cleavage/inactivation of receptor-interacting protein kinase (RIP). Taken together, our findings provide evidence that PKCε activation during pancreatitis promotes necrosis through mechanisms involving mitochondrial proapoptotic and prosurvival Bcl-2 family proteins and upregulation of nonmitochondrial pathways that inhibit caspase activation and RIP cleavage/inactivation. Thus PKCε is a potential target for prevention and/or treatment of acute pancreatitis.

scholarly journals The novel protein kinase C isoforms -δ and -ε modulate caerulein-induced zymogen activation in pancreatic acinar cells

2008 ◽  
Vol 294 (6) ◽  
pp. G1344-G1353 ◽  
Author(s):  
Edwin C. Thrower ◽  
Sara Osgood ◽  
Christine A. Shugrue ◽  
Thomas R. Kolodecik ◽  
Anamika M. Chaudhuri ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Acinar Cell ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Cell Fractionation ◽  
Zymogen Activation ◽  
Cellular Models ◽  
Kinase C

Isoforms of protein kinase C (PKC) have been shown to modulate some cellular responses such as pathological secretion and generation of inflammatory mediators during acute pancreatitis (AP). We propose that PKC also participates in premature zymogen activation within the pancreatic acinar cell, a key event in the initiation of AP. This hypothesis was examined in in vivo and cellular models of caerulein-induced AP using PKC activators and inhibitors. Phorbol ester, 12- O-tetradecanoylphorbol-13-acetate (TPA, 200 nM), a known activator of PKC, enhanced zymogen activation at both 0.1 nM and 100 nM caerulein, concentrations which mimic physiological and supraphysiological effects of the hormone cholecystokinin, respectively, in preparations of pancreatic acinar cells. Isoform-specific PKC inhibitors for PKC-δ and PKC-ε reduced supraphysiological caerulein-induced zymogen activation. Using a cell-free reconstitution system, we showed that inhibition of PKC-δ and -ε, reduced zymogen activation in both zymogen granule-enriched and microsomal fractions. In dispersed acinar cells, 100 nM caerulein stimulation caused PKC-δ and -ε isoform translocation to microsomal membranes using cell fractionation and immunoblot analysis. PKC translocation was confirmed with in vivo studies and immunofluorescence microscopy in pancreatic tissues from rats treated with or without 100 nM caerulein. PKC-ε redistributed from an apical to a supranuclear region following caerulein administration. The signal for PKC-ε overlapped with granule membrane protein, GRAMP-92, an endosomal/lysosomal marker, in a supranuclear region where zymogen activation takes place. These results indicate that PKC-δ and -ε isoforms translocate to specific acinar cell compartments and modulate zymogen activation.

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