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PubMed1993

Caerulein and gastrin(2-17 ds) regulate differently synthesis of secretory enzymes, mRNA levels and cell proliferation in pancreatic acinar cells (AR4-2J).

In order to characterize the biological functions coupled to cholecystokinin (CCK) A and B receptors, the effects of gastrin(2-17 ds) and caerulein were compared. An isolated cell model, the pancreatic acinar cell line AR4-2J, was used and the experiments were carried out in serum-free media. Caerulein was found to evoke no mitogenic effects either alone or in the presence of the CCK antagonists L364,718 and CR1409. Gastrin(2-17 ds) increased cell proliferation by 2-fold with an IC50 of 150 pM, corresponding to the occupancy of the CCK B receptors. CR1409, at concentrations that fully occupied CCK B receptors, inhibited the gastrin(2-17 ds) effects. Caerulein enhanced chymotrypsinogen biosynthesis by 100% and the corresponding mRNA level by 75%; amylase biosynthesis and mRNA level were enhanced by 40% only. Half-maximal increases in chymotrypsin activity and mRNA level were recorded in response to caerulein at concentrations of 100 pM and 50 pM respectively. Gastrin(2-17 ds) at 100 nM enhanced chymotrypsinogen biosynthesis by 26% and its mRNA level by 35%; these responses were lower than those evoked by 0.1 nM caerulein. Furthermore, CR1409 completely inhibited caerulein- and gastrin(2-17 ds)-stimulated chymotrypsinogen synthesis, with similar IC50 (4 microM). These results suggest that both peptides induced the synthesis of the secretory enzyme after occupancy of CCK A receptors.

Amylases↗
PubMed2004

Recurrent pancreatitis due to a cystic pancreatic tumor: a rare presentation of acinar cell carcinoma.

CONTEXT: Acinar cell carcinoma is an uncommon malignancy of the pancreas. It has characteristic histomorphology, immunohistochemistry profile, and clinicopathological behavior. CASE REPORT: We report a rare case of recurrent pancreatitis secondary to acinar cell carcinoma of the pancreas. We describe the endoscopic ultrasound characteristic, treatment and the surgical outcome. CONCLUSIONS: Acinar cell carcinoma should be considered in the differential diagnosis of cystic pancreatic tumors presenting with recurrent pancreatitis.

Aged↗
PubMed2000

Gabapentin-induced mitogenic activity in rat pancreatic acinar cells.

Gabapentin induces pancreatic acinar cell tumors in rats through unknown, yet apparently nongenotoxic mechanisms. The primary objective of this study was to determine whether gabapentin acts as a tumor promoter by stimulating acinar cell proliferation in rat pancreas. To this end, indices of pancreatic growth, including increased pancreatic weight, stimulation of acinar cell proliferation, and/or enhanced expression of immediate-early oncogenes were monitored in rats given gabapentin in the diet at 2 g/kg/day for up to 12 months. Rats fed raw soy flour (RSF), a known inducer of pancreatic acinar cell tumors through cholecystokinin-mediated mitogenic stimulation, were used throughout as positive controls. In addition, recent data suggests that gabapentin binds to the alpha(2)delta subunit of a voltage-gated, L-type calcium channel. Because signaling pathways for proliferative processes in pancreatic acinar cells involve intracellular calcium mobilization, the effects of gabapentin on intracellular calcium mobilization ([Ca(2+)](i)) and (3)H-thymidine incorporation were investigated in pancreatic acinar cells isolated from normal rat pancreas and in the AR42J rat pancreatic tumor cell line. As indicated by BrdU labeling indices, acinar cell proliferation increased 3-fold by Day 3 of RSF treatment and remained slightly greater than controls throughout the experiment. Pancreatic weights of RSF-fed rats were 32 to 56% greater than controls throughout the experiment. In contrast, gabapentin had no effect on pancreatic weight or acinar cell labeling index, and therefore had no apparent effect on pancreatic growth. In isolated pancreatic acinar cells, however, gabapentin induced mobilization of intracellular calcium and caused a slight increase in (3)H-thymidine incorporation. The data suggest that gabapentin may possess low level mitogenic activity, which is not easily detectable in in vivo assays.

Acetates↗
PubMed2000

A hypothesis: SNARE-ing the mechanisms of regulated exocytosis and pathologic membrane fusions in the pancreatic acinar cell.

The pancreatic acinar cell has been a classic model to study regulated exocytosis occurring at the apical plasma membrane. The acinar cell is also an excellent model with which to study pathologic membrane fusion events, including aberrant zymogen granule fusion with the lysosome and basolateral exocytosis, which are the earliest cellular events of acute pancreatitis. However, despite much effort, little is known about the precise mechanisms that mediate these physiologic and pathologic membrane fusion events until recently. Over the past 5 years, there has been a major advance in the fundamental understanding of vesicle fusion based on the SNARE hypothesis. A basic tenet of the SNARE hypothesis is that the minimal machinery for membrane fusion is a cognate set of v- and t-SNAREs on opposing membranes. A corollary to this hypothesis is that these SNARE proteins are prevented from spontaneous assembly by clamping proteins. Here, the recent developments in the identification of cognate v- and t-SNAREs and clamping proteins are reviewed, which are strategically located to mediate these physiologic exocytic and pathologic fusion events in the pancreatic acinar cell.

Animals↗
PubMed2005

Lineage tracing and characterization of insulin-secreting cells generated from adult pancreatic acinar cells.

Although several studies have suggested that insulin-secreting cells can be generated in vitro from cells residing in adult exocrine pancreas, neither the origin of these cells nor their precise insulin secretory properties was obtained. We show here that insulin-secreting cells can be derived from adult mouse pancreatic exocrine cells by suspension culture in the presence of EGF and nicotinamide. The frequency of insulin-positive cells was only 0.01% in the initial preparation and increased to approximately 5% in the culture conditions. Analysis by the Cre/loxP-based direct cell lineage tracing system indicates that these newly made cells originate from amylase/elastase-expressing pancreatic acinar cells. Insulin secretion is stimulated by glucose, sulfonylurea, and carbachol, and potentiation by glucagon-like peptide-1 also occurs. Insulin-containing secretory granules are present in these cells. In addition, we found that the enzymatic dissociation of pancreatic acini itself leads to activation of EGF signaling, and that inhibition of EGF receptor kinase blocks the transdifferentiation. These data demonstrate that pancreatic acinar cells can transdifferentiate into insulin-secreting cells with secretory properties similar to those of native pancreatic beta cells, and that activation of EGF signaling is required in such transdifferentiation.

Animals↗
PubMed1990

Pancreatic acinar cells in culture: expression of acinar and ductal antigens in a growth-related manner.

In the current study two monoclonal antibodies (mAb) were used to investigate the expression of adult acinar and duct cell-specific antigens and their relationship with cell growth in primary acinar cell cultures. We have previously found that adult mouse pancreatic acinar cells divide in primary culture. Furthermore, during growth the cells lose their differentiated morphology and exhibit decreased expression of secretory proteins, followed by some degree of morphological redifferentiation after reaching confluency. A mAb specific in the adult pancreas for acinar cells (mAb Acinar-1) and another specific in the adult pancreas for duct cells (mAb Duct-1) were generated using such cultures as the immunogen. The starting material for the cultures consisted of predominantly Acinar-1 positive cells which incorporated [3H]thymidine, as determined by autoradiography and immunofluorescence labeling. However, expression of the acinar antigen persisted for only the first 3 to 7 days in culture. By contrast, expression of the duct antigen was rare until after 5 days in culture and was highest at day 9, the peak of cell growth. Dual label immunofluorescence showed that during the growth phase fewer cells expressed the acinar antigen, most expressed the duct antigen, and occasional cells expressed both antigens. After reaching confluency, the growth rate declined from days 15 to 21, and the cells progressively regained the acinar antigen with a concomitant loss of the duct antigen. mAb labeling was morphometrically quantitated and showed that more than 97% of the labeled area was Acinar-1 positive at 3 days, which decreased to approximately 16% at day 9, and then returned to over 97% by day 21 of culture. Ultrastructural immunolabeling showed that Acinar-1 positive cells at 21 days had well organized rough endoplasmic reticulum and small apical vesicles, while Duct-1 positive cells were undifferentiated in appearance (day 9) or had numerous mitochondria (day 21). Thus, changes in cell-specific antigens were paralleled by cell type associated morphological characteristics and indicate that adult acinar cells can retrodifferentiate to a more duct-like cell while retaining the potential to express an acinar-specific antigen.

Animals↗
PubMed2003

Expression differences in mitochondrial and secretory chaperonin 60 (Cpn60) in pancreatic acinar cells.

In pancreatic acinar cells, chaperonin Cpn60 is present in all the cellular compartments involved in protein secretion as well as in mitochondria. To better understand the role Cpn60 plays in pancreatic secretion, we have evaluated its changes under experimental conditions known to alter pancreatic secretion. Quantitative protein A-gold immunocytochemistry was used to reveal Cpn60 in pancreatic acinar cells. Cpn60 immunolabelings in cellular compartments involved in secretion were found to decrease in acute pancreatitis as well as upon stimulation of secretion and in starvation conditions. A major increase in Cpn60 was recorded in diabetic condition. This was normalized by insulin treatment. Although in certain situations changes in secretory enzymes and in Cpn60 correlate well, in others, nonparallel secretion seemed to take place. In contrast, expression of mitochondrial Cpn60 in acinar cells appeared to remain stable in all conditions except starvation, where its levels decreased. Expression of Cpn60 in the secretory pathway and in mitochondria thus appears to behave differently, and Cpn60 in the secretory pathway must be important for quality control and integrity of secretion.

Animals↗
PubMed2002

Primary culture of porcine pancreatic acinar cells.

INTRODUCTION: The methodology of acinar cell culture has become of primary importance in the research of pancreatic physiology and pharmacology. AIM: To develop a method for primary culture of porcine pancreatic acinar cells. METHODOLOGY: Dispersed pancreatic acinar cells were made by RPMI-1640 medium containing collagenase III. After purification, the isolated acinar cells were cultured in RPMI-1640 medium with 2.5% fetal bovine serum. The morphologic characteristics of acinar cells were described. (3)H-thymidine incorporation of acinar cells and activity of amylase or lipase were determined during the culture. RESULTS: There were no remarkable morphologic changes in the pancreatic acinar cells during the 20-day culture. The acini showed the tendency of gathering but did not attach to the walls of the culture disks. Incorporation of (3)H-thymidine in acinar cells in the primary culture was well kept. The secretion of amylase or lipase from acini decreased with the time of culture. CONCLUSIONS: In the primary culture of acinar cells from porcine pancreas developed in this study, the acinar cells retained normal morphology and ability of growth but not secretion of amylase or lipase. The method would be beneficial for further experiments on acini of porcine pancreas.

Amylases↗
PubMed2002

Secretion and cell volume regulation by salivary acinar cells from mice lacking expression of the Clcn3 Cl- channel gene.

Salivary gland acinar cells shrink when Cl(-) currents are activated following cell swelling induced by exposure to a hypotonic solution or in response to calcium-mobilizing agonists. The molecular identity of the Cl(-) channel(s) in salivary cells involved in these processes is unknown, although ClC-3 has been implicated in several tissues as a cell-volume-sensitive Cl(-) channel. We found that cells isolated from mice with targeted disruption of the Clcn3 gene undergo regulatory volume decrease in a fashion similar to cells from wild-type littermates. Consistent with a normal regulatory volume decrease response, the magnitude and the kinetics of the swell-activated Cl(-) currents in cells from ClC-3-deficient mice were equivalent to those from wild-type mice. It has also been suggested that ClC-3 is activated by Ca(2+)-calmodulin-dependent protein kinase II; however, the magnitude of the Ca(2+)-dependent Cl(-) current was unchanged in the Clcn3(-/-) animals. In addition, we observed that ClC-3 appeared to be highly expressed in the smooth muscle cells of glandular blood vessels, suggesting a potential role for this channel in saliva production by regulating blood flow, yet the volume and ionic compositions of in vivo stimulated saliva from wild-type and null mutant animals were comparable. Finally, in some cells ClC-3 is an intracellular channel that is thought to be involved in vesicular acidification and secretion. Nevertheless, the protein content of saliva was unchanged in Clcn3(-/-) mice. Our results demonstrate that the ClC-3 Cl(-) channel is not a major regulator of acinar cell volume, nor is it essential for determining the secretion rate and composition of saliva.

Animals↗
PubMed1998

Optical measurement of stimulus-evoked membrane dynamics in single pancreatic acinar cells.

Stimulation of pancreatic acinar cells induces the release of digestive enzymes via the exocytotic fusion of zymogen granules and activates postfusion granule membrane retrieval and receptor cycling. In the present study, changes in membrane surface area of rat single pancreatic acinar cells were monitored by cell membrane capacitance (Cm) measurements and by the membrane fluorescent dye FM1-43. When measured with the Cm method, agonist treatment evoked a graded, transient increase in acinar cell surface area averaging 3. 5%. In contrast, a 13% increase in surface area was estimated using FM1-43, corresponding to the fusion of 48 zymogen granules at a rate of 0.5 s-1. After removal of FM1-43 from the surface-accessible membrane, a residual fluorescence signal was shown by confocal microscopy to be localized in endosome-like structures and confined to the apical regions of acinar cells. The development of an optical method for monitoring the membrane turnover of single acinar cells, in combination with measurements of Cm changes, reveals coincidence of exocytotic and endocytotic activity in acinar cells after hormonal stimulation.

Animals↗
PubMed1989

Effects of cholecystokinin and carbamylcholine on Paneth cell secretion in mice: a comparison with pancreatic acinar cells.

To confirm whether the Paneth cells of mice (ICR, male, 10-12 weeks old) have the same secretory response to hormonal and cholinergic stimulation as do pancreatic acinar cells, ultrastructural changes of Paneth cells and pancreatic acinar cells 1 hr after administration of various doses of cholecystokinin (octapeptide, CCK-8) and carbamylcholine were morphometrically assessed. After maximal (1.5 micrograms/kg intraperitoneally [i.p.]) and supramaximal (15 micrograms/kg, i.p.) stimulation by CCK-8, pancreatic acinar cells showed, respectively, degranulation or disturbance of secretion (e.g., an increase in lysosome-like bodies, aggregation of zymogen granules). The Paneth cells, however, were almost unchanged in the parameters examined. After carbamylcholine injection (1,000 micrograms/kg, subcutaneously [s.c.]), both pancreatic acinar cells and Paneth cells showed degranulation. Paneth cells sometimes developed large vacuoles, probably formed after massive exocytosis; such vacuoles were not observed in pancreatic acinar cells. It is suggested that Paneth cells and pancreatic acinar cells have different secretory responses. Paneth cell secretion, which possibly plays a role in controlling the intestinal bacterial milieu, may be stimulated by cholinergic rather than hormonal mechanisms.

Animals↗
PubMed1990

Novel islet, duct, and acinar cell markers defined by monoclonal autoantibodies from prediabetic BB rats.

Novel islet cell, duct cell, and acinar cell markers have been identified by monoclonal autoantibodies (Maab) derived from prediabetic BB rats. Spleen cells from two rats that both developed diabetes after splenectomy were fused with mouse myeloma cells. A cellular immunoradiometric assay for differential reactivity toward the surface of two closely related, insulin- and non-insulin-producing rat islet tumor cell lines was used to select and clone several IgM-producing hybridomas. The supernatants were finally characterized by two-color immunofluorescence with islet hormone antisera on frozen sections of human, monkey, and rat pancreas. Maab EB52 stained PP cells, but also few A cells on rat pancreas. Maab CA812 identified a subpopulation of islet D cells on rat, human and monkey pancreas. Although the CA812-reactive antigen and somatostatin were coexpressed in most D cells in adult rat pancreas, only a few islet D cells were stained in the newborn pancreas. The CA812-reactive antigen was not detected in somatostatin-producing cells in the duct epithelium. Maab H37 and IF5 selectively stained acinar cells in rat, human, and monkey pancreas, whereas Maab DA39 identified the rat ductal epithelium including the scattered endocrine cells of the ducts. In summary, B lymphocytes producing autoantibodies to pancreatic endocrine, exocrine, and ductal markers are present in prediabetic BB rats and can be detected by use of transformed pluripotent islet cells as target. Such B lymphocytes can be immortalized to produce monoclonal antibodies to study their role in insulin-dependent diabetes mellitus pathogenesis and to clarify the development of the pancreas.

Animals↗
PubMed1985

Activation of N-nitrosobis(2-oxopropyl)amine and N-nitroso(2-hydroxypropyl)-(2-oxopropyl)amine to mutagens for V79 cells by isolated hamster and rat pancreatic acinar cells.

A pancreatic acinar cell-mediated mutagenicity assay was developed as an in vitro model system to study the metabolism of N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amino (HPOP) into forms mutagenic for Chinese hamster V79 cells. Mutations at the hypoxanthine:guanine phosphoribosyltransferase locus and the Na/K ATPase locus were scored by resistance to 6-thioguanine and ouabain, respectively. The ability of both Syrian golden hamster and Fischer rat pancreatic acinar cells to convert BOP and HPOP to mutagens for V79 cells was investigated in order to examine the basis for species specificity. Acinar cells of both species were capable of activating BOP and HPOP to mutagens for V79 cells in a dose-dependent manner. In the 6-thioguanine resistance assay, rat acinar cells induced higher mutation frequencies than hamster acinar cells with both BOP and HPOP. In the ouabain resistance assay, both cell types induced equivalent levels of mutation with the respective nitrosamines. BOP was a considerably more potent mutagen than HPOP after activation by either cell type. This is consistent with the known in vivo specificity of BOP versus HPOP in the hamster pancreas and suggests that BOP may be activated to mutagenic metabolites by a pathway(s) independent from its enzymatic reduction to HPOP. The comparable abilities of rat and hamster acinar cells to convert BOP or HPOP to mutagenic forms imply that pancreatic metabolic activation alone cannot explain the difference in organotropism of BOP and HPOP in the two species.

Animals↗
PubMedDate not supplied

Regeneration of beta-cells and neogenesis from small ducts or acinar cells promote recovery of endocrine pancreatic function in alloxan-treated rats.

BACKGROUND: We previously showed by using biochemical parameters that male Sprague-Dawley rats receiving a single intraperitoneal (i.p.) administration of alloxan (120 mg/kg body weight) with no further treatment recovered endocrine pancreatic function after 12 days. METHODS: Male Sprague-Dawley rats received an i.p. injection of alloxan (120 mg/kg body wt), were killed at 3, 6, 9, or 12 days (n=7), and their capacity to recover endocrine function was evaluated by means of a) biochemical parameters, which included glucose, triglyceride, and total cholesterol measurements and b) nuclear incorporation of 5'-bromodeoxyuridine (BrdU) by beta and acinar cells as well as presence of neogenesis from either ductal or acinar cells using double-staining BrdU-insulin immunohistochemical technique. RESULTS: Three days after receiving a single i.p. administration of alloxan, rats showed increase in serum glucose, triglyceride, and total cholesterol concentrations, reaching levels of 542.4+/-63.1, 907.6+/-154.9, and 106.0+/-2.7 mg/dL (mean+/-standard deviation [SD]), respectively. At this time, increase in beta-cell replication was also observed, although this reached maximum by day 6 (p <0.001). Replication was also present in acinar cells, but these cells showed their maximum at day 3 (p <0.001) and subsequently decreased, as did beta-cells, almost steadily to normal values by day 12. Neogenesis of beta-cells was observed mainly as transdifferentiation from acinar cells at day 3 and from ductal cells at day 6, after which it tended to be normal. CONCLUSIONS: Male Sprague-Dawley rats receiving a single i.p. alloxan dose tended to normalize their endocrine function by day 12 after alloxan administration. This process included both regeneration and neogenesis of pancreatic beta-cells from either ductal or acinar cells.

Alloxan↗
PubMed1986

Do B cells and peri-insular acinar cells of canine pancreas have nerves in common?

Synapses providing simultaneous contact with insulin-producing B cells and acinar cells have been found at the margins of islets of Langerhans in the dog. Blood vessels have also been observed in the vicinity of such synapses. The frequently described correlation between insulin and protein secretion might be a result of the simultaneous influence of these nerve endings on both enzyme- and hormone-producing cells.

Animals↗
PubMed1994

[Mechanisms for cell damage in acute pancreatitis using isolated acinar cells].

Due to the complexity of interacting organ systems, in vivo the interpretation of results obtained from whole-animal experiments of acute pancreatitis remains difficult. To enlighten cause-and-effect-relationships, functional isolated parts of the pancreas are applied increasingly in research into the pathogenesis of the disease, therefore. By means of a collagenase digestion technique, intact acinar cells from normal as well as from pretreated rat pancreas could reproducibly be obtained in high yield. Animals were pretreated in situ by induction of either mesenteric ischemia/reperfusion, juice edema, or acute pancreatitis (AP). Pancreatic acinar cells isolated from these pretreated rats consumed oxygen at comparable rates under resting conditions throughout all experimental groups. A reduced stress capacity of cell respiration as well as a preterm decline in short-term culture was observed in the cells of the AP group, however. These results demonstrate that the induction of AP has found its reflection within the acinar cells themselves. Interestingly, these effects were not clouded by the isolation procedure. The manner of in-situ pretreatment of the respective animal proved to be decisive for later viability of isolated acinar cells in short-term culture. Uncoupling of oxidative phosphorylation by 2,4-dinitrophenol (DNP) lead to an accelerated decline of the acinar cells in all groups. The intactness of cellular energy metabolism seems to play a crucial role in maintaining cellular integrity, therefore. In additional experiments in vitro, the intracellularly mediated cell damage by DNP was compared with one induced from the extracellular environment of isolated cells by antibodies directed against cell surface antigens plus complement.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1998

Diurnal pattern of rat pancreatic acinar cell replication.

Fully differentiated pancreatic acinar cells can enter the cell cycle under appropriate conditions in the rat. The aim of this study was to analyse the diurnal pattern of acinar cell proliferation as a function of food intake and the release of cholecystokinin (CCK), because the peptide hormone CCK is a major physiological regulator of rat pancreatic acinar cell replication. Pancreatic acinar cell replication was quantitated using an antibody against the S-phase marker proliferating cell nuclear antigen (PCNA). In addition, acinar cells in S-phase were detected after injecting bromodeoxyuridine (BrdU) and subsequent immunohistochemical staining of BrdU-positive nuclei. Rat pancreata were analysed during the day under standard diet conditions, as well as after various schedules of fasting and refeeding and after the application of the CCK receptor antagonist L-364,718. Between 6 a.m. and 6 p.m., the PCNA labeling index was 4.4+/-0.9%, while between 9 p.m. and 3 a.m. the PCNA labeling index was elevated and reached peak values of 11.4% (mean value: 7.8+/-2.5%) around midnight. BrdU-positive cells also doubled around midnight, compared to the 9:00 a.m. value. In fasted rats, acinar cell proliferation was completely suppressed and this suppression could be overcome by injection of the CCK analog cerulein. In addition, the CCK antagonist L-364,718 led to the same results as fasting. Here we show for the first time that there is a diurnal pattern of pancreatic acinar cell proliferation in rats, which is dependent on food intake and is mediated by CCK.

Animals↗
PubMed1985

Amylase secretion from isolated pure acinar cells.

Isolation of pure acinar cells of the rat pancreas was achieved employing counterflow sedimentation filtration technique (CSFT). The preparation of purified acinar cells contained an occasional red blood cell (RBC, 200:1) with total absence of endocrine and duct cells. A significant stimulation of amylase secretion from isolated pure acinar cells was produced by octapeptide of cholecystokinin (CCK8) and insulin produced potentiation of the effect of CCK8. Synthetic glucagon inhibited basal and CCK8 stimulated amylase secretion. Non-synthetic purified glucagon stimulated amylase secretion and potentiated the effect of CCK8. Vasoactive intestinal polypeptide (VIP) did not stimulate amylase secretion but potentiated the effect of CCK8. No leakage of lactic dehydrogenase (LDH) was detected from the cells in any of the secretion studies. Thus a highly purified preparation of isolated pure acinar cells of rat pancreas could be obtained with excellent morphologic and functional integrity.

Amylases↗