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.

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 Icariin Promote Stem Cells Regeneration and Repair Acinar Cells in L-arginine / Radiation -Inducing Chronic Pancreatitis in Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 155932582097081
Author(s):  
Enas M. Moustafa ◽  
Fatma S. M. Moawed ◽  
Gehan R. Abdel-Hamid
Keyword(s):  
Chronic Pancreatitis ◽  
Hedgehog Signaling ◽  
Histopathological Examination ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Myeloperoxidase Activity ◽  
Significant Amelioration ◽  
Gli 1 ◽  
Patched 1

Objective: Chronic Pancreatitis (CP) is a multifactorial disease. It was characterized by severe inflammation and acinar cell destruction. Thus, the present study was initiated to evaluating the ability of bone marrow-based mesenchymal stem cell (MSCs) combined with Icariin to restore and regenerate acinar cells in the pancreas of rats suffering chronic pancreatitis. Methods: Chronic pancreatitis was induced in rats via both L-arginine plus radiation, repeated L-arginine injection (2.5g/Kg body-weight, 1, 4,7,10,13,16,19 days), then, on day 21, rats were exposed to a single dose of gamma-radiation (6 Gy), which exacerbate injury of pancreatic acinar cells. One day after irradiation, rats were treated with either MSCs (1 × 107 /rat, once, tail vein injection) labeled PKH26 fluorescent linker dye and/or Icariin (100 mg/Kg, daily, orally) for 8 weeks. Results: Icariin promotes MSCs proliferation boosting its productivity in vitro. MSCs, and/or icariin treatments has regulated molecular factors TGF-β/PDGF and promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cell in the tissue, and confirmed by histopathological examination. Moreover, a significant decrease in IL-8 and TNF-α cytokines with significant amelioration of myeloperoxidase activity were noted. As well as, reduction in MCP-1 and collagen type-1 levels along with Hedgehog signaling down-regulating expression in such cells, Patched-1, Smoothened, and GLi-1. Conclusion: The potent bioactive therapeutic Icariin combined with MSCs induces a significantly greater improvement, compared to each therapy alone.

scholarly journals Transgenic expression of pancreatic secretory trypsin inhibitor-1 rescues SPINK3-deficient mice and restores a normal pancreatic phenotype

2010 ◽  
Vol 298 (4) ◽  
pp. G518-G524 ◽  
Author(s):  
Joelle M.-J. Romac ◽  
Masaki Ohmuraya ◽  
Cathy Bittner ◽  
M. Faraz Majeed ◽  
Steven R. Vigna ◽  
...  
Keyword(s):  
Trypsin Inhibitor ◽  
Survival Rates ◽  
Acinar Cells ◽  
Threshold Level ◽  
Protective Role ◽  
Trypsin Inhibitors ◽  
Pancreatic Acinar Cells ◽  
Wild Type ◽  
Transgenic Expression ◽  
Pancreatic Trypsin Inhibitor

Endogenous trypsin inhibitors are synthesized, stored, and secreted by pancreatic acinar cells. It is believed that they play a protective role in the pancreas by inhibiting trypsin within the cell should trypsinogen become prematurely activated. Rodent trypsin inhibitors are highly homologous to human serine protease inhibitor Kazal-type 1 (SPINK1). The mouse has one pancreatic trypsin inhibitor known as SPINK3, and the rat has two trypsin inhibitors commonly known as pancreatic secretory trypsin inhibitors I and II (PSTI-I and -II). Rat PSTI-I is a 61-amino acid protein that shares 65% sequence identity with mouse SPINK3. It was recently demonstrated that mice with genetic deletion of the Spink3 gene ( Spink3−/− ) do not survive beyond 15 days and lack normal pancreata because of pancreatic autophagy. We have shown that targeted transgenic expression of the rat Psti1 gene to acinar cells in mice [ TgN(Psti1)] protects mice against caerulein-induced pancreatitis. To determine whether the autophagic phenotype and lethality in Spink3−/− mice were due to lack of pancreatic trypsin inhibitor, we conducted breeding studies with Spink3+/− heterozygous mice and TgN(Psti1) mice. We observed that, whereas Spink3+/+, Spink3+/−, and Spink3−/− /TgN(Psti1) mice had similar survival rates, no Spink3−/− mice survived longer than 1 wk. The level of expression of SPINK3 protein in acini was reduced in heterozygote mice compared with wild-type mice. Furthermore, endogenous trypsin inhibitor capacity was reduced in the pancreas of heterozygote mice compared with wild-type or knockout mice rescued with the rat Psti1 gene. Surprisingly, the lesser amount of SPINK3 present in the pancreata of heterozygote mice did not predispose animals to increased susceptibility to caerulein-induced acute pancreatitis. We propose that a threshold level of expression is sufficient to protect against pancreatitis.

Effect of Low-Molecular Weight Trypsin Inhibitor, Nafamostat Mesilate, on Trypsin Activity Using the Pancreatic Acinar Cells

Pancreas ◽  
2009 ◽  
Vol 38 (5) ◽  
pp. 595-597 ◽  
Author(s):  
Daisuke Hashimoto ◽  
Masaki Ohmuraya ◽  
Jun Wang ◽  
Ken-ichi Yamamura ◽  
Masahiko Hirota ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Trypsin Inhibitor ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Low Molecular Weight ◽  
Nafamostat Mesilate ◽  
Trypsin Activity

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.

Enhanced Trypsin Activity in Pancreatic Acinar Cells Deficient for Serine Protease Inhibitor Kazal Type 3

Pancreas ◽  
2006 ◽  
Vol 33 (1) ◽  
pp. 104-106 ◽  
Author(s):  
Masaki Ohmuraya ◽  
Masahiko Hirota ◽  
Kimi Araki ◽  
Hideo Baba ◽  
Ken-ichi Yamamura
Keyword(s):  
Protease Inhibitor ◽  
Serine Protease ◽  
Acinar Cells ◽  
Serine Protease Inhibitor ◽  
Pancreatic Acinar Cells ◽  
Trypsin Activity ◽  
Type 3
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