scholarly journals Comprehensive analysis of microRNA signature of mouse pancreatic acini: overexpression of miR-21-3p in acute pancreatitis

2016 ◽  
Vol 311 (5) ◽  
pp. G974-G980 ◽  
Author(s):  
Ajay Kumar Dixit ◽  
Anne E. Sarver ◽  
Zuobiao Yuan ◽  
John George ◽  
Usman Barlass ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Mouse Models ◽  
Expression Profile ◽  
Mirna Expression ◽  
Acinar Cells ◽  
Mirna Expression Profile ◽  
Comprehensive Analysis ◽  
Pancreatic Acinar Cells ◽  
Pancreatic Acini ◽  
Severity Of The Disease

In the current study, we have characterized the global miRNA expression profile in mouse pancreatic acinar cells and during acute pancreatitis using next-generation RNA sequencing. We identified 324 known and six novel miRNAs that are expressed in mouse pancreatic acinar cells. In the basal state, miR-148a-3p, miR-375-3p, miR-217-5p, and miR-200a-3p were among the most abundantly expressed, whereas miR-24-5p and miR-421-3p were the least abundant. Treatment of acinar cells with caerulein (100 nM) and taurolithocholic acid 3-sulfate [TLC-S (250 μM)] induced numerous changes in miRNA expression profile. In particular, we found significant overexpression of miR-21-3p in acini treated with caerulein and TLC-S. We further looked at the expression of miR-21-3p in caerulein, l-arginine, and caerulein + LPS-induced acute pancreatitis mouse models and found 12-, 21-, and 50-fold increased expression in the pancreas, respectively. In summary, this is the first comprehensive analysis of global miRNA expression profile of mouse pancreatic acinar cells in normal and disease conditions. Our analysis shows that miR-21-3p expression level correlates with the severity of the disease.

scholarly journals Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models

2015 ◽  
Vol 149 (2) ◽  
pp. 481-492.e7 ◽  
Author(s):  
Li Wen ◽  
Svetlana Voronina ◽  
Muhammad A. Javed ◽  
Muhammad Awais ◽  
Peter Szatmary ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Mouse Models ◽  
Acinar Cells ◽  
Cytosolic Calcium ◽  
Pancreatic Acinar Cells ◽  
Associated Injury

Substance P treatment stimulates chemokine synthesis in pancreatic acinar cells via the activation of NF-κB

2006 ◽  
Vol 291 (6) ◽  
pp. G1113-G1119 ◽  
Author(s):  
Raina Devi Ramnath ◽  
Madhav Bhatia
Keyword(s):  
Acute Pancreatitis ◽  
Substance P ◽  
Acinar Cell ◽  
Cell Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Chemokine Production ◽  
Pancreatic Acini ◽  
Monocyte Chemoattractant Protein 1

Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction and to the subsequent systemic inflammatory response, which may result in multiple organ dysfunction and death. Inflammatory mediators, including chemokines and substance P (SP), are known to play a crucial role in the pathogenesis of acute pancreatitis. It has been shown that pancreatic acinar cells produce the chemokine monocyte chemoattractant protein-1 (MCP-1) in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Similarly, SP levels in the pancreas and pancreatic acinar cell expression of neurokinin-1 receptor, the primary receptor for SP, are both increased during secretagogue-induced experimental pancreatitis. This study aims to examine the functional consequences of exposing mouse pancreatic acinar cells to SP and to determine whether it leads to proinflammatory signaling, such as production of chemokines. Exposure of mouse pancreatic acini to SP significantly increased synthesis of MCP-1, macrophage inflammatory protein-1α (MIP-1α), as well as MIP-2. Furthermore, SP also increased NF-κB activation. The stimulatory effect of SP was specific to chemokine synthesis through the NF-κB pathway, since the increase in chemokine production was completely attenuated when pancreatic acini were pretreated with the selective NF-κB inhibitor NF-κB essential modulator-binding domain peptide. This study shows that SP-induced chemokine synthesis in mouse pancreatic acinar cells is NF-κB dependent.

scholarly journals Src kinases play a novel dual role in acute pancreatitis affecting severity but no role in stimulated enzyme secretion

2016 ◽  
Vol 310 (11) ◽  
pp. G1015-G1027 ◽  
Author(s):  
Bernardo Nuche-Berenguer ◽  
Irene Ramos-Álvarez ◽  
R. T. Jensen
Keyword(s):  
Acute Pancreatitis ◽  
Map Kinases ◽  
Severe Disease ◽  
Acinar Cells ◽  
Dual Role ◽  
Enzyme Secretion ◽  
Pancreatic Acinar Cells ◽  
Enzyme Release ◽  
Amylase Release ◽  
Pancreatic Acini

In pancreatic acinar cells, the Src family of kinases (SFK) is involved in the activation of several signaling cascades that are implicated in mediating cellular processes (growth, cytoskeletal changes, apoptosis). However, the role of SFKs in various physiological responses such as enzyme secretion or in pathophysiological processes such as acute pancreatitis is either controversial, unknown, or incompletely understood. To address this, in this study, we investigated the role/mechanisms of SFKs in acute pancreatitis and enzyme release. Enzyme secretion was studied in rat dispersed pancreatic acini, in vitro acute-pancreatitis-like changes induced by supramaximal COOH-terminal octapeptide of cholecystokinin (CCK). SFK involvement assessed using the chemical SFK inhibitor (PP2) with its inactive control, 4-amino-7-phenylpyrazol[3,4-d]pyrimidine (PP3), under experimental conditions, markedly inhibiting SFK activation. In CCK-stimulated pancreatic acinar cells, activation occurred of trypsinogen, various MAP kinases (p42/44, JNK), transcription factors (signal transducer and activator of transcription-3, nuclear factor-κB, activator protein-1), caspases (3, 8, and 9) inducing apoptosis, LDH release reflective of necrosis, and various chemokines secreted (monocyte chemotactic protein-1, macrophage inflammatory protein-1α, regulated on activation, normal T cell expressed and secreted). All were inhibited by PP2, not by PP3, except caspase activation leading to apoptosis, which was increased, and trypsin activation, which was unaffected, as was CCK-induced amylase release. These results demonstrate SFK activation is playing a dual role in acute pancreatitis, inhibiting apoptosis and promoting necrosis as well as chemokine/cytokine release inducing inflammation, leading to more severe disease, as well as not affecting secretion. Thus, our studies indicate that SFK is a key mediator of inflammation and pancreatic acinar cell death in acute pancreatitis, suggesting it could be a potential therapeutic target in acute pancreatitis.

Pancreatic gene expression during the initiation of acute pancreatitis: identification of EGR-1 as a key regulator

2003 ◽  
Vol 14 (1) ◽  
pp. 59-72 ◽  
Author(s):  
Baoan Ji ◽  
Xue-qing Chen ◽  
David E. Misek ◽  
Rork Kuick ◽  
Samir Hanash ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Rt Pcr ◽  
Novel Genes ◽  
In Vivo Models ◽  
Severity Of The Disease ◽  
Deficient Mice

We hypothesized that genes expressed in pancreatic acinar cells during the initiation of acute pancreatitis determine the severity of the disease. Therefore, we utilized microarrays to identify those genes commonly induced in rat pancreatic acinar cells within 1–4 h in two in vivo models, caerulein and taurocholate administration. This strategy yielded 51 known genes representing a complex array of molecules, including those that are likely to either reduce or increase the severity of the disease. Novel genes identified in the current study included ATF3, BRF1, C/EBPβ, CGRP, EGR-1, ephrinA1, villin2, ferredoxin, latexin, lipocalin, MKP-1, NGFI-B, RhoA, tissue factor (TF), and syndecan. To validate these microarray results, the role of EGR-1 was further investigated using quantitative RT-PCR, Western blotting, and immunocytochemistry. EGR-1 expression occurred within acinar cells and correlated with the development of caerulein-induced acute pancreatitis in rats. Furthermore, the levels of the inflammation-related genes MCP-1, PAI, TF, IL-6, and ICAM-1 and the extent of lung inflammation were reduced during the initiation of caerulein-induced acute pancreatitis in EGR-1-deficient mice. Thus this study identified EGR-1 and several other novel genes likely to be important in the development and severity of acute pancreatitis.

Expression of NK-1 and NK-3 tachykinin receptors in pancreatic acinar cells after acute experimental pancreatitis in rats

2006 ◽  
Vol 291 (3) ◽  
pp. G518-G524 ◽  
Author(s):  
Maria Broccardo ◽  
Giorgio Linari ◽  
Simona Agostini ◽  
Giusi Amadoro ◽  
Francesco Carpino ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Substance P ◽  
Acinar Cells ◽  
Receptor Expression ◽  
Pancreatic Acinar Cells ◽  
Morphological Evidence ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Tachykinin Receptors ◽  
New Findings

Activation of neurokinin (NK)-1 receptors but not of NK-3 stimulates amylase release from isolated pancreatic acini of the rat. Immunofluorescence studies show that NK-1 receptors are more strongly expressed than NK-3 receptors on pancreatic acinar cells under basal conditions. No studies have examined the expression of the two NK receptor populations in pancreatic acini during pancreatitis in rats. We therefore investigated the relationships between expression of these two tachykinin receptors and experimental acute pancreatitis induced by stimulating pancreatic amylase with caerulein (CK) in rats. Hyperstimulation of the pancreas by CK caused an increase in plasma amylase and pancreatic water content and resulted in morphological evidence of cytoplasmic vacuolization. Immunofluorescence analysis revealed a similar percentage of NK-1 receptor antibody immunoreactive acinar cells in rats with pancreatitis and in normal rat tissue but a larger percentage of NK-3 receptor immunoreactive cells in acute pancreatitis than in normal pancreas. Western blot analysis of NK-1 and NK-3 receptor protein levels after CK-induced pancreatitis showed no change in NK-1 receptors but a stronger increase in NK-3 receptor expression in pancreatic acini compared with normal rats thus confirming the immunofluorescence data. These new findings support previous evidence that substance P-mediated functions within the pancreas go beyond sensory signal transduction contributing to neurogenic inflammation, and they suggest that substance P plays a role in regulating pancreatic exocrine secretion via acinar NK-1 receptors. The significant increase in NK-3 receptors during pancreatic stimulation suggests that NK-3 receptors also intervene in the pathogenesis of mild acute pancreatitis in rats.

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.

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