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.

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

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.

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 Upregulation of dynamin II expression during the acquisition of a mature pancreatic acinar cell phenotype.

1996 ◽  
Vol 44 (12) ◽  
pp. 1373-1378 ◽  
Author(s):  
T A Cook ◽  
K J Mesa ◽  
B A Gebelein ◽  
R A Urrutia
Keyword(s):  
Acinar Cell ◽  
Growth Factor Receptor ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Cell Phenotype ◽  
Receptor Mediated Endocytosis ◽  
Ar42j Cells

Members of the dynamin superfamily are GTPases which have been shown to support receptor-mediated endocytosis in vivo and bind to growth factor receptor-associated proteins in vitro. In acinar cells of the pancreas, receptor-mediated endocytosis is very important for the recycling of membranes after secretory granule release. Therefore, characterization of the molecular machinery responsible for this process is critical for a better understanding of this phenomenon. In this study we sought to determine the expression pattern of the endocytic GTPase dynamin II during pancreatic acinar cell differentiation in developing rat embryos and in dexamethasone-treated AR42J cells using Western blot, Northern blot, and immunocytochemical analyses. During pancreatic development, dynamin immunoreactivity is almost undetectable until day E17 but undergoes significant upregulation in acinar cells starting at E18. In addition, the levels of dynamin mRNA and protein in AR42J cells increase approximately threefold during dexamethasone-induced acinar differentiation. The increase in dynamin levels that occurs in both embryonic pancreatic cells and dexamethasone-treated AR42J cells correlates with the establishment of a more differentiated acinar phenotype. Therefore, these results suggest a potential role for dynamin in supporting receptor-mediated endocytosis in mature pancreatic acinar cells.

scholarly journals MECOM permits pancreatic acinar cell dedifferentiation avoiding cell death under stress conditions

2020 ◽  
Author(s):  
Elyne Backx ◽  
Elke Wauters ◽  
Jonathan Baldan ◽  
Mathias Van Bulck ◽  
Ellis Michiels ◽  
...  
Keyword(s):  
Cell Death ◽  
Acinar Cell ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Stress Conditions ◽  
Loss Of Function ◽  
Cell Dedifferentiation ◽  
Duct Cells

ABSTRACTMaintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar cells dedifferentiate, predispose for cancer formation in the pancreas. Dedifferentiated acinar cells acquire a large panel of duct cell specific markers. However, it remains unclear to what extent dedifferentiated acini differ from native duct cells and which genes are uniquely regulating acinar cell dedifferentiation. Moreover, most studies have been performed in mouse since the availability of human cells is scarce.Here, we applied a non-genetic lineage tracing method in our culture model of human pancreatic exocrine cells that allowed cell-type specific gene expression profiling by RNA sequencing. Subsequent to this discovery analysis, one transcription factor that was unique for dedifferentiated acinar cells was functionally characterized using in vitro and in vivo genetic loss-of-function experimental models.RNA sequencing analysis showed that human dedifferentiated acinar cells expressed genes in ‘Pathways of cancer’ with prominence of the transcription factor MECOM (EVI-1) that was absent from duct cells. During mouse embryonic development, pre-acinar cells transiently expressed MECOM and MECOM was re-expressed in experimental in vivo models of acute and chronic pancreatitis in vivo, conditions in which acinar cells dedifferentiate. MECOM expression correlated with and was directly regulated by SOX9. MECOM loss-of-function in mouse acinar cells in vitro and in vivo impaired cell adhesion resulting in more prominent acinar cell death and suppressed acinar cell dedifferentiation by limiting ERK signaling.In conclusion, we transcriptionally profiled the two major human pancreatic exocrine cell types, acinar and duct cells, during experimental stress conditions. We provide insights that in dedifferentiated acinar cells, cancer pathways are upregulated in which MECOM is a critical regulator that suppresses acinar cell death by permitting cellular dedifferentiation.

scholarly journals Pharmacological and genetic inhibition of calcineurin protects against carbachol-induced pathological zymogen activation and acinar cell injury

2012 ◽  
Vol 302 (8) ◽  
pp. G898-G905 ◽  
Author(s):  
Kamaldeen A. Muili ◽  
Mahwish Ahmad ◽  
Abrahim I. Orabi ◽  
Syeda M. Mahmood ◽  
Ahsan U. Shah ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Cell Injury ◽  
Acinar Cells ◽  
High Amplitude ◽  
Pancreatic Acinar Cell ◽  
Critical Event ◽  
Amylase Secretion ◽  
Zymogen Activation ◽  
Inhibitory Peptide ◽  
A Subunit

Acute pancreatitis is a major health burden for which there are currently no targeted therapies. Premature activation of digestive proenzymes, or zymogens, within the pancreatic acinar cell is an early and critical event in this disease. A high-amplitude, sustained rise in acinar cell Ca2+ is required for zymogen activation. We previously showed in a cholecystokinin-induced pancreatitis model that a potential target of this aberrant Ca2+ signaling is the Ca2+-activated phosphatase calcineurin (Cn). However, in this study, we examined the role of Cn on both zymogen activation and injury, in the clinically relevant condition of neurogenic stimulation (by giving the acetylcholine analog carbachol) using three different Cn inhibitors or Cn-deficient acinar cells. In freshly isolated mouse acinar cells, pretreatment with FK506, calcineurin inhibitory peptide (CiP), or cyclosporine (CsA) blocked intra-acinar zymogen activation ( n = 3; P < 0.05). The Cn inhibitors also reduced leakage of lactate dehydrogenase (LDH) by 79%, 62%, and 63%, respectively ( n = 3; P < 0.05). Of the various Cn isoforms, the β-isoform of the catalytic A subunit (CnAβ) was strongly expressed in mouse acinar cells. For this reason, we obtained acinar cells from CnAβ-deficient mice (CnAβ−/−) and observed an 84% and 50% reduction in trypsin and chymotrypsin activation, respectively, compared with wild-type controls ( n = 3; P < 0.05). LDH release in the CnAβ-deficient cells was reduced by 50% ( n = 2; P < 0.05). The CnAβ-deficient cells were also protected against zymogen activation and cell injury induced by the cholecystokinin analog caerulein. Importantly, amylase secretion was generally not affected by either the Cn inhibitors or Cn deficiency. These data provide both pharmacological and genetic evidence that implicates Cn in intra-acinar zymogen activation and cell injury during pancreatitis.

scholarly journals Protease activation during in vivo pancreatitis is dependent on calcineurin activation

2009 ◽  
Vol 297 (5) ◽  
pp. G967-G973 ◽  
Author(s):  
Ahsan U. Shah ◽  
Amna Sarwar ◽  
Abrahim I. Orabi ◽  
Samir Gautam ◽  
Wayne M. Grant ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Serum Amylase ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Critical Event ◽  
Myeloperoxidase Activity ◽  
Important Target ◽  
Protease Activation ◽  
Cell Vacuolization

The premature activation of digestive proenzymes, specifically proteases, within the pancreatic acinar cell is an early and critical event during acute pancreatitis. Our previous studies demonstrate that this activation requires a distinct pathological rise in cytosolic Ca2+. Furthermore, we have shown that a target of aberrant Ca2+ in acinar cells is the Ca2+/calmodulin-dependent phosphatase calcineurin (PP2B). In this study, we hypothesized that PP2B mediates in vivo protease activation and pancreatitis severity. To test this, pancreatitis was induced in mice over 8 h by administering hourly intraperitoneal injections of the cholecystokinin analog caerulein (50 μg/kg). Treatment with the PP2B inhibitor FK506 at 1 and 8 h after pancreatitis induction reduced trypsin activities by greater than 50% ( P < 0.005). Serum amylase and IL-6 was reduced by 86 and 84% relative to baseline ( P < 0.0005) at 8 h, respectively. Histological severity of pancreatitis, graded on the basis of pancreatic edema, acinar cell vacuolization, inflammation, and apoptosis, was reduced early in the course of pancreatitis. Myeloperoxidase activity from both pancreas and lung was reduced by 93 and 83% relative to baseline, respectively ( P < 0.05). These data suggest that PP2B is an important target of the aberrant acinar cell Ca2+ rise associated with pathological protease activation and pancreatitis.

In vivo rat pancreatic acinar cell function during supramaximal stimulation with caerulein

1985 ◽  
Vol 249 (6) ◽  
pp. G702-G710 ◽  
Author(s):  
A. Saluja ◽  
I. Saito ◽  
M. Saluja ◽  
M. J. Houlihan ◽  
R. E. Powers ◽  
...  
Keyword(s):  
Acinar Cell ◽  
Intracellular Transport ◽  
Cell Function ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Zymogen Granule ◽  
Zymogen Granules ◽  
Morphological Studies ◽  
Supramaximal Stimulation

Infusion of a supramaximal dose of caerulein results in acute interstitial pancreatitis in rats. We report studies of in vivo pancreatic acinar cell function during the initial 3.5 h of supramaximal stimulation with caerulein (5 micrograms X kg-1 X h-1). Amino acid [( 3H]phenylalanine) uptake was not altered, and there was no change in the rate or extent of protein synthesis or in intracellular transport of in vivo pulse-labeled proteins from microsome to zymogen granule-enriched fractions. However, the discharge of labeled protein was markedly inhibited. Radioautographic studies indicated that the pulse-labeled proteins retained in the gland were not located extracellularly but had accumulated within acinar cells, with a preferential distribution at the cell apex (presumably in zymogen granules) and in large vacuoles that form within the cell during hyperstimulation. Supramaximal stimulation with caerulein also caused increasing amounts of amylase and labeled proteins to be recovered in the postmicrosomal fraction. These findings suggest that supramaximal stimulation causes digestive enzymes to become localized in organelles that are fragile and subject to disruption during tissue homogenization. These organelles may be the vacuoles noted in morphological studies and believed to represent immature condensing vacuoles and/or crinophagic vacuoles.

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