scholarly journals Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis

2019 ◽  
Vol 316 (1) ◽  
pp. G179-G186
Author(s):  
Haojie Huang ◽  
Jiaxiang Chen ◽  
Lisi Peng ◽  
Yao Yao ◽  
Defeng Deng ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transgenic Mice ◽  
Fibrous Tissue ◽  
Acinar Cells ◽  
Cyclooxygenase 2 ◽  
Therapeutic Interventions ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Transgenic Expression ◽  
Cox 2

Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.

scholarly journals Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas

2012 ◽  
Vol 302 (5) ◽  
pp. G535-G541 ◽  
Author(s):  
Joelle M.-J. Romac ◽  
Rafiq A. Shahid ◽  
Steve S. Choi ◽  
Gamze F. Karaca ◽  
Christoph B. Westphalen ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Trypsin Inhibitor ◽  
Acinar Cells ◽  
Cell Loss ◽  
Pancreatic Acinar Cells ◽  
Trypsin Inhibitor Activity ◽  
Myeloperoxidase Activity ◽  
Trypsin Activity ◽  
Pancreatic Secretory Trypsin Inhibitor ◽  
Transgenic Expression

IL-1β is believed to play a pathogenic role in the development of pancreatitis. Expression of human IL-1β in pancreatic acinar cells produces chronic pancreatitis, characterized by extensive intrapancreatic inflammation, atrophy, and fibrosis. To determine if activation of trypsinogen is important in the pathogenesis of chronic pancreatitis in this model, we crossed IL-1β transgenic [Tg( IL1β)] mice with mice expressing a trypsin inhibitor that is normally produced in rat pancreatic acinar cells [pancreatic secretory trypsin inhibitor (PTSI) I]. We previously demonstrated that transgenic expression of PSTI-I [Tg( Psti1)] increased pancreatic trypsin inhibitor activity by 190%. Tg( IL1β) mice were found to have marked pancreatic inflammation, characterized by histological changes, including acinar cell loss, inflammatory cell infiltration, and fibrosis, as well as elevated myeloperoxidase activity and elevated pancreatic trypsin activity, as early as 6 wk of age. In contrast to Tg( IL1β) mice, pancreatitis was significantly less severe in dual-transgenic [Tg( IL1β)-Tg( Psti1)] mice expressing IL-1β and PSTI-I in pancreatic acinar cells. These findings indicate that overexpression of PSTI-I reduces the severity of pancreatitis and that pancreatic trypsin activity contributes to the pathogenesis of an inflammatory model of chronic pancreatitis.

Cyclooxygenase-2 is required for activated pancreatic stellate cells to respond to proinflammatory cytokines

2007 ◽  
Vol 292 (1) ◽  
pp. C259-C268 ◽  
Author(s):  
Hiroyoshi Aoki ◽  
Hirohide Ohnishi ◽  
Kouji Hama ◽  
Satoshi Shinozaki ◽  
Hiroto Kita ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Inflammatory Responses ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Cyclooxygenase 2 ◽  
Dominant Negative ◽  
Pancreatic Stellate Cells ◽  
Cox 2 ◽  
Dependent Pathway ◽  
Tgf Β1

Cyclooxygenase-2 (COX-2) mediates various inflammatory responses and is expressed in pancreatic tissue from patients with chronic pancreatitis. To examine the role of COX-2 in chronic pancreatitis, we investigated its participation in regulating functions of pancreatic stellate cells (PSCs), using isolated rat PSCs. COX-2 was expressed in culture-activated PSCs but not in freshly isolated quiescent PSCs. TGF-β1, IL-1β, and IL-6 enhanced COX-2 expression in activated PSCs, concomitantly increasing the expression of α-smooth muscle actin (α-SMA), a parameter of PSC activation. The COX-2 inhibitor NS-398 blocked culture activation of freshly isolated quiescent PSCs. NS-398 also inhibited the enhancement of α-SMA expression by TGF-β1, IL-1β, and IL-6 in activated PSCs. These data indicate that COX-2 is required for the initiation and promotion of PSC activation. We further investigated the mechanism by which cytokines enhance COX-2 expression in PSCs. Adenovirus-mediated expression of dominant negative Smad2/3 inhibited the increase in expression of COX-2, α-SMA, and collagen-1 mediated by TGF-β1 in activated PSCs. Moreover, dominant negative Smad2/3 expression attenuated the expression of COX-2 and α-SMA enhanced by IL-1β and IL-6. Anti-TGF-β neutralizing antibody also attenuated the increase in COX-2 and α-SMA expression caused by IL-1β and IL-6. IL-6 as well as IL-1β enhanced TGF-β1 secretion from PSCs. These data indicate that Smad2/3-dependent pathway plays a central role in COX-2 induction by TGF-β1, IL-1β, and IL-6. Furthermore, IL-1β and IL-6 promote PSC activation by enhancing COX-2 expression indirectly through Smad2/3-dependent pathway by increasing TGF-β1 secretion from PSCs.

Prostaglandin E2 modulates TNF-α-induced MCP-1 synthesis in pancreatic acinar cells in a PKA-dependent manner

2007 ◽  
Vol 293 (6) ◽  
pp. G1196-G1204 ◽  
Author(s):  
Li-Kang Sun ◽  
Theresia Reding ◽  
Martha Bain ◽  
Mathias Heikenwalder ◽  
Daniel Bimmler ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Synergistic Effect ◽  
Tissue Injury ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Ar42j Cells ◽  
Tnf Α ◽  
Cox 2

Cyclooxygenase (COX)-2 is increased in human chronic pancreatitis. We recently demonstrated in a model of chronic pancreatitis (WBN/Kob rat) that inhibition of COX-2 activity reduces and delays pancreatic inflammation and fibrosis. Monocyte chemoattractant protein (MCP)-1 mRNA and PGE2 were significantly reduced, correlating with a decreased infiltration of macrophages. MCP-1 plays an important role in the recruitment of macrophages to the site of tissue injury. The aim of our study is to identify mechanisms by which macrophages and acinar cells maintain an inflammatory reaction. The expression profile of E prostanoid receptors EP1-4 and MCP-1 was analyzed by RT-PCR from pancreatic specimens and AR42J cells. MCP-1 secretion was detected by ELISA from rat pancreatic lobuli. We determined EP1-4 mRNA levels in WBN/Kob rats with chronic pancreatic inflammation. Individual isoforms were highly increased in rat pancreas, concurrent with MCP-1 mRNA expression. In supernatants of pancreatic lobuli and AR42J cells, MCP-1 was detectable by ELISA. In the presence of TNF-α, MCP-1 was upregulated. Coincubation with PGE2 enhanced the TNF-α-induced MCP-1 synthesis significantly. Similarly, TNF-α mRNA was synergistically upregulated by TNF-α and PGE2. Furthermore, the synergistic effect of TNF-α and PGE2 was abolished by inhibition of PKA but not of PKC. We conclude that EP receptors are upregulated during chronic pancreatic inflammation. PGE2 modulates the TNF-α-induced MCP-1 synthesis and secretion from acinar cells. This synergistic effect is controlled by PKA. This mechanism might explain the COX-2-dependent propagation of pancreatic inflammation.

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 Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

2014 ◽  
Vol 307 (9) ◽  
pp. G941-G949 ◽  
Author(s):  
Padmanabhan Srinivasan ◽  
Rubina Kapadia ◽  
Arundhati Biswas ◽  
Hamid M. Said
Keyword(s):  
Transgenic Mice ◽  
Chronic Exposure ◽  
Methylation Status ◽  
Acinar Cells ◽  
Alcohol Exposure ◽  
Significant Inhibition ◽  
Pancreatic Acinar Cells ◽  
Chronic Alcohol ◽  
Wild Type ◽  
Chronic Alcohol Exposure

Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5′-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na+ dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.

Activated Pancreatic Stellate Cells Promote Acinar Duct Metaplasia by Disrupting Mitochondrial Respiration and Releasing Reactive Oxygen Species

2021 ◽  
Vol 01 ◽  
Author(s):  
Hong Xiang ◽  
Fangyue Guo ◽  
Qi Zhou ◽  
Xufeng Tao ◽  
Deshi Dong
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Respiration ◽  
Reactive Oxygen ◽  
Acinar Cells ◽  
Stellate Cells ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Oxygen Species

Background: Chronic pancreatitis (CP) is a long-term risk factor for pancreatic ductal adenocarcinoma (PDAC), and both diseases share a common etiology. The activation of Pancreatic stellate cells (PaSCs) caused by inflammation of the chronic pancreas plays a pivotal role in the pathology of pancreatic fibrosis and the malignant phenotype of PDAC. However, the central role of activated PaSCs in acinar-to-ductal metaplasia (ADM) remains unknown. Objective: In the present study, we investigated the link between pancreatic fibrosis and ADM and the possible underlying mechanism. Methods: A caerulein-treated mouse CP model was established, and Masson trichrome histochemical stain and transmission electron microscope (TEM) were used to observe stromal fibrosis and cell ultrastructure, respectively. The expression of amylase and cytokeratin 19 (CK19), mitochondria respiration, and reactive oxygen species (ROS) were detected in vitro in the co-culture model of primary pancreatic acinar cells and PaSCs. Results: The activation of PaSCs and pancreatic fibrosis were accompanied by ADM in pancreatic parenchyma in caerulein-treated mice, which was verified by the co-cultivation experiment in vitro. Furthermore, we showed that activated PaSCs promote ADM by disrupting mitochondrial respiration and releasing ROS. The expression of inflammation-and ADM-related genes, including S100A8, S100A9, and CK19, was observed to be up-regulated in pancreatic acinar cells in the presence of activated PaSCs. The expression of S100A9 and CK19 proteins was also up-regulated in acinar cells co-cultured with activated PaSCs. Conclusion: The manipulation of mitochondrial respiration and ROS release is a promising preventive and/or therapeutic strategy for PDAC, and S100A9 is expected to be a therapeutic target to block the ADM process induced by the activation of PaSCs.

scholarly journals Increased Chromogranin A–Positive Hormone-Negative Cells in Chronic Pancreatitis

2018 ◽  
Vol 103 (6) ◽  
pp. 2126-2135 ◽  
Author(s):  
Abu Saleh Md Moin ◽  
Megan Cory ◽  
Jennifer Choi ◽  
Allison Ong ◽  
Sangeeta Dhawan ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Chromogranin A ◽  
Endocrine Cells ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Cell Regeneration ◽  
Inflammation Marker ◽  
Β Cells ◽  
Cell Frequency ◽  
Endogenous Expression

Abstract Context Chronic pancreatitis (CP) is characterized by inflammation, fibrosis, and a loss of pancreatic acinar cells, which can result in exocrine and eventually endocrine deficiency. Pancreatitis has been reported to induce formation of new endocrine cells (neogenesis) in mice. Our recent data have implicated chromogranin A–positive hormone-negative (CPHN) cells as potential evidence of neogenesis in humans. Objective We sought to establish if CPHN cells were more abundant in CP in humans. Design, Setting, and Participants We investigated the frequency and distribution of CPHN cells and the expression of the chemokine C-X-C motif ligand 10 (CXCL10) and its receptor chemokine C-X-C motif receptor 3 in pancreas of nondiabetic subjects with CP. Results CPHN cell frequency in islets was increased sevenfold in CP [2.1% ± 0.67% vs 0.35% ± 0.09% CPHN cells in islets, CP vs nonpancreatitis (NP), P < 0.01], as were the CPHN cells found as scattered cells in the exocrine areas (17.4 ± 2.9 vs 4.2 ± 0.6, CP vs NP, P < 0.001). Polyhormonal endocrine cells were also increased in CP (2.7 ± 1.2 vs 0.1 ± 0.04, CP vs NP, % of polyhormonal cells of total endocrine cells, P < 0.01), as was expression of CXCL10 in α and β cells. Conclusion There is increased islet endogenous expression of the inflammation marker CXCL10 in islets in the setting of nondiabetic CP and an increase in polyhormonal (insulin-glucagon expressing) cells. The increase in CPHN cells in CP, often in a lobular distribution, may indicate foci of attempted endocrine cell regeneration.

Metallothionein is a component of exocrine pancreas secretion: implications for zinc homeostasis

1996 ◽  
Vol 271 (4) ◽  
pp. C1103-C1110 ◽  
Author(s):  
R. C. De Lisle ◽  
M. P. Sarras ◽  
J. Hidalgo ◽  
G. K. Andrews
Keyword(s):  
Transgenic Mice ◽  
Pancreatic Juice ◽  
Secretory Pathway ◽  
Physiological Role ◽  
Acinar Cells ◽  
Transgenic Animals ◽  
Light Level ◽  
Zinc Homeostasis ◽  
Pancreatic Acinar Cells ◽  
Pancreatic Ducts

Using transgenic mice that overexpress metallothionein-I (MT-I) and zinc-induced normal and transgenic animals, we have explored the localization of MT in the pancreas. Light-level immunocytochemistry demonstrated MT in acinar cells but not islet cells. Immunolabeling also revealed the presence of MT in pancreatic ducts, suggesting that it is released from acinar cells. Ultrastructural immunolocalization showed that MT was cytoplasmic, and no MT immunoreactivity was detected in lumens of the vesicular secretory pathway. Secreted pancreatic juice was collected from pilocarpine-stimulated mice and assayed for MT by a 109Cd-labeled hemoglobin-exchange assay and by radioimmunoassay. Both methods revealed high (> 1,000 ng/ml) levels of MT in the stimulated secretion. The level of MT in pancreatic juice from transgenic mice was only slightly (2-fold) increased despite dramatic overexpression of MT-I in the pancreas (> 20-fold). In contrast, zinc induction of MT significantly increased MT by 5- to 10-fold in the pancreatic juice, in normal and transgenic mice. These data indicate that MT is released from pancreatic acinar cells but not by the classical vesicular secretory pathway. In addition, MT levels in pancreatic juice are regulated by zinc, suggesting a physiological role of the pancreas in metal homeostasis.

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