p53-Dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas

2000 ◽  
Vol 279 (4) ◽  
pp. G827-G836 ◽  
Author(s):  
Charles R. Scoggins ◽  
Ingrid M. Meszoely ◽  
Michihiko Wada ◽  
Anna L. Means ◽  
Liying Yang ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Apoptosis ◽  
Target Genes ◽  
P53 Protein ◽  
Acinar Cells ◽  
Epithelial Proliferation ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation ◽  
The Relationship ◽  
P53 Target Genes

The mechanisms linking acinar cell apoptosis and ductal epithelial proliferation remain unknown. To determine the relationship between these events, pancreatic duct ligation (PDL) was performed on p53(+/+) and p53(−/−) mice. In mice bearing a wild-type p53 allele, PDL resulted in upregulation of p53 protein in both acinar cells and proliferating duct-like epithelium. In contrast, upregulation of Bcl-2 occurred only in duct-like epithelium. Both p21WAF1/CIP1 and Bax were also upregulated in duct-ligated lobes. After PDL in p53(+/+) mice, acinar cells underwent widespread apoptosis, while duct-like epithelium underwent proliferative expansion. In the absence of p53, upregulation of p53 target genes and acinar cell apoptosis did not occur. The absence of acinar cell apoptosis in p53(−/−) mice also eliminated the proliferative response to duct ligation. These data demonstrate that PDL-induced acinar cell apoptosis is a p53-dependent event and suggest a direct link between acinar cell apoptosis and proliferation of duct-like epithelium in duct-ligated pancreas.

Effects of pancreatic duct ligation on pancreatic response to bombesin

2006 ◽  
Vol 290 (4) ◽  
pp. G633-G639 ◽  
Author(s):  
Taiichi Otani ◽  
Akira Matsukura ◽  
Takeshi Takamoto ◽  
Yasuji Seyama ◽  
Yasuhito Shimizu ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Acinar Cell ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Zymogen Activation ◽  
Trypsinogen Activation ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation ◽  
Trypsinogen Activation Peptide

To examine mechanisms that might be related to biliary pancreatitis, we examined the effects of pancreatic duct ligation (PDL) with pancreatic stimulation in vivo. PDL alone caused no increase in pancreatic levels of trypsinogen activation peptide (TAP), trypsin, or chymotrypsin and did not initiate pancreatitis. Although bombesin caused zymogen activation within the pancreas, the increases were slight and it did not cause pancreatitis. However, the combination of PDL with bombesin resulted in prominent increases in pancreatic TAP, trypsin, chymotrypsin, and the appearance of TAP in acinar cells and caused pancreatitis. Disruption of the apical actin network in the acinar cell was observed when PDL was combined with bombesin but not with PDL or bombesin alone. These studies suggest that when PDL is combined with pancreatic acinar cell stimulation, it can promote zymogen activation, the retention of active enzymes in acinar cells, and the development of acute pancreatitis.

scholarly journals Acinar cell-specific knockout of the PTHrP gene decreases the proinflammatory and profibrotic responses in pancreatitis

2014 ◽  
Vol 307 (5) ◽  
pp. G533-G549 ◽  
Author(s):  
Vandanajay Bhatia ◽  
Cristiana Rastellini ◽  
Song Han ◽  
Judith F. Aronson ◽  
George H. Greeley ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Acinar Cell ◽  
Cell Function ◽  
Stellate Cell ◽  
Acinar Cells ◽  
Amylase Secretion ◽  
Matrix Deposition ◽  
Pancreatic Duct Ligation ◽  
Parathyroid Hormone Related Protein ◽  
Duct Ligation

Pancreatitis is a necroinflammatory disease with acute and chronic manifestations. Accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic pancreatitis (CP). Pancreatic parathyroid hormone-related protein (PTHrP) levels are elevated in a mouse model of cerulein-induced AP. Here, we show elevated PTHrP levels in mouse models of pancreatitis induced by chronic cerulein administration and pancreatic duct ligation. Because acinar cells play a major role in the pathophysiology of pancreatitis, mice with acinar cell-specific targeted disruption of the Pthrp gene ( PTHrP Δacinar) were generated to assess the role of acinar cell-secreted PTHrP in pancreatitis. These mice were generated using Cre-LoxP technology and the acinar cell-specific elastase promoter. PTHrP Δacinar exerted protective effects in cerulein and pancreatic duct ligation models, evident as decreased edema, histological damage, amylase secretion, pancreatic stellate cell (PSC) activation, and extracellular matrix deposition. Treating acinar cells in vitro with cerulein increased IL-6 expression and NF-κB activity; these effects were attenuated in PTHrP Δacinar cells, as were the cerulein- and carbachol-induced elevations in amylase secretion. The cerulein-induced upregulation of procollagen I expression was lost in PSCs from PTHrP Δacinar mice. PTHrP immunostaining was elevated in human CP sections. The cerulein-induced upregulation of IL-6 and ICAM-1 (human acinar cells) and procollagen I (human PSCs) was suppressed by pretreatment with the PTH1R antagonist, PTHrP ( 7 – 34 ). These findings establish PTHrP as a novel mediator of inflammation and fibrosis associated with CP. Acinar cell-secreted PTHrP modulates acinar cell function via its effects on proinflammatory cytokine release and functions via a paracrine pathway to activate PSCs.

scholarly journals CaMK II Inhibition Attenuates ROS Dependent Necroptosis in Acinar Cells and Protects against Acute Pancreatitis in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Qingtian Zhu ◽  
Lu Hao ◽  
Qinhao Shen ◽  
Jiajia Pan ◽  
Weili Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Protective Effect ◽  
Acinar Cell ◽  
Acinar Cells ◽  
Serum Levels ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation ◽  
Prevention And Treatment

As a calcium-regulated protein, CaMK II is closely related to cell death, and it participates in the development of pathological processes such as reperfusion injury, myocardial infarction, and oligodendrocyte death. The function of CaMK II activation in acute pancreatitis (AP) remains unclear. In our study, we confirmed that the expression of p-CaMK II was increased significantly and consistently in injured pancreatic tissues after caerulein-induced AP. Then, we found that KN93, an inhibitor of CaMK II, could mitigate the histopathological manifestations in pancreatic tissues, reduce serum levels of enzymology, and decrease oxidative stress products. Accordingly, we elucidated the effect of KN93 in vitro and found that KN93 had a protective effect on the pancreatic acinar cell necroptosis pathway by inhibiting the production of ROS and decreasing the expression of RIP3 and p-MLKL. In addition, we identified the protective effect of KN93 on AP through another mouse model induced by pancreatic duct ligation (PDL). Together, these data demonstrated that CaMK II participates in the development of AP and that inhibiting CaMK II activation could protect against AP by reducing acinar cell necroptosis, which may provide a new idea target for the prevention and treatment of AP in the clinic.

Cytokine Expression and Induction of Acinar Cell Apoptosis after Pancreatic Duct Ligation in Mice

1999 ◽  
Vol 19 (6) ◽  
pp. 637-644 ◽  
Author(s):  
Hiroaki Yasuda ◽  
Keisho Kataoka ◽  
Hiroshi Ichimura ◽  
Mayuko Mitsuyoshi ◽  
Tohko Iida ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Acinar Cell ◽  
Cell Apoptosis ◽  
Cytokine Expression ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation

Fas and fas ligand system as a mediator of pancreatic acinar cell apoptosis after pancreatic duct ligation

1998 ◽  
Vol 114 ◽  
pp. A511
Author(s):  
H. Yasuda ◽  
K. Kataoka ◽  
M. Moriguchi ◽  
K. Kashima ◽  
H. Ichimura ◽  
...  
Keyword(s):  
Pancreatic Duct ◽  
Acinar Cell ◽  
Cell Apoptosis ◽  
Fas Ligand ◽  
Pancreatic Acinar Cell ◽  
Ligand System ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation

Crambene induces pancreatic acinar cell apoptosis via the activation of mitochondrial pathway

2006 ◽  
Vol 291 (1) ◽  
pp. G95-G101 ◽  
Author(s):  
Yang Cao ◽  
Sharmila Adhikari ◽  
Abel Damien Ang ◽  
Marie Véronique Clément ◽  
Matthew Wallig ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Annexin V ◽  
Acinar Cells ◽  
Mitochondrial Pathway ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Pancreatic Acini

We investigated the apoptotic pathway activated by crambene (1-cyano-2-hydroxy-3-butene), a plant nitrile, on pancreatic acinar cells. As evidenced by annexin V-FITC staining, crambene treatment for 3 h induced the apoptosis but not necrosis of pancreatic acini. Caspase-3, -8, and -9 activities in acini treated with crambene were significantly higher than in untreated acini. Treatment with caspase-3, -8, and -9 inhibitors inhibited annexin V staining, as well as caspase-3 activity, pointing to an important role of these caspases in crambene-induced acinar cell apoptosis. The mitochondrial membrane potential was collapsed, and cytochrome c was released from the mitochondria in crambene-treated acini. Neither TNF-α nor Fas ligand levels were changed in pancreatic acinar cells after crambene treatment. These results provide evidence for the induction of pancreatic acinar cell apoptosis in vitro by crambene and suggest the involvement of mitochondrial pathway in pancreatic acinar cell apoptosis.

Apoptosis is the dominant form of acinar cell death after pancreatic duct ligation in rats

1995 ◽  
Vol 108 (4) ◽  
pp. A399
Author(s):  
M. Wada ◽  
R. Doi ◽  
R. Hosotani ◽  
J. Lee ◽  
M. Imamura
Keyword(s):  
Cell Death ◽  
Pancreatic Duct ◽  
Acinar Cell ◽  
Dominant Form ◽  
Pancreatic Duct Ligation ◽  
Duct Ligation

scholarly journals Functional Analysis of p53 Binding under Differential Stresses

2006 ◽  
Vol 26 (19) ◽  
pp. 7030-7045 ◽  
Author(s):  
Adam J. Krieg ◽  
Ester M. Hammond ◽  
Amato J. Giaccia
Keyword(s):  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Cpg Island ◽  
P53 Protein ◽  
Pcr Analysis ◽  
Glutathione Peroxidase 1 ◽  
Specific Pcr ◽  
Subsequent Effect ◽  
P53 Target Genes ◽  
Hct116 Cells

ABSTRACT Hypoxia and DNA damage stabilize the p53 protein, but the subsequent effect that each stress has on transcriptional regulation of known p53 target genes is variable. We have used chromatin immunoprecipitation followed by CpG island (CGI) microarray hybridization to identify promoters bound by p53 under both DNA-damaging and non-DNA-damaging conditions in HCT116 cells. Using gene-specific PCR analysis, we have verified an association with CGIs of the highest enrichment (>2.5-fold) (REV3L, XPMC2H, HNRPUL1, TOR1AIP1, glutathione peroxidase 1, and SCFD2), with CGIs of intermediate enrichment (>2.2-fold) (COX7A2L, SYVN1, and JAG2), and with CGIs of low enrichment (>2.0-fold) (MYC and PCNA). We found little difference in promoter binding when p53 is stabilized by these two distinctly different stresses. However, expression of these genes varies a great deal: while a few genes exhibit classical induction with adriamycin, the majority of the genes are unchanged or are mildly repressed by either hypoxia or adriamycin. Further analysis using p53 mutated in the core DNA binding domain revealed that the interaction of p53 with CGIs may be occurring through both sequence-dependent and -independent mechanisms. Taken together, these experiments describe the identification of novel p53 target genes and the subsequent discovery of distinctly different expression phenomena for p53 target genes under different stress scenarios.

scholarly journals Identical regional mechanisms of intracellular free Ca2+ concentration increase during polarized agonist-evoked Ca2+ response in pancreatic acinar cells

1994 ◽  
Vol 304 (1) ◽  
pp. 313-316 ◽  
Author(s):  
E C Toescu ◽  
D V Gallacher ◽  
O H Petersen
Keyword(s):  
Acinar Cell ◽  
Dynamic Properties ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Initial Increase ◽  
Concentration Increase ◽  
Agonist Stimulation ◽  
Basal Pole ◽  
The Relationship ◽  
Identical Fashion

The initial increase of intracellular free Ca2+ concentration ([Ca2+]i) following agonist stimulation is spatially restricted to one pole of the cell, from where a wave of [Ca2+]i spreads across the cytosol. In the present study we have investigated the dynamic properties of the agonist-activated Ca(2+)-release mechanisms in different regions of the acinar cell and show that, during maximal agonist stimulation, the rate of [Ca2+]i increase at the secretory pole is identical with that recorded at the basal pole. Furthermore, the relationship between [Ca2+]i and the apparent rate of [Ca2+]i increase is similar in both regions of the cell. The data show that whereas the sensitivity to the Ca(2+)-releasing agent is different in different regions of the cell, the process of [Ca2+]i increase, once triggered, will proceed in an identical fashion, irrespective of the area of the cell.

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