Effect of sodium thiosulfate on viable areas of the pancreas in experimental pancreatitis

Experimental pancreatitis in white rats is marked by stromal edema, dystrophic changes of acinar cells, with intracellular edema in an intact part of the pancreas. Subsequently the acinar cells undergo intracellular regeneration and hypertrophy, which is accompanied by intensive incorporation of 14C-leucin into glandular proteins. Sodium thiosulfate prevents the development of stromal edema and intracellular edema of the acinar cells and retards the development of acinar cell hypertrophy. The drug produces an inhibitory action on 14C-leucin incorporation into pancreatic proteins.     

Pancreatic acinar cell necrosis with intact storage of digestive enzymes in selenomethionine treated rats

Morphological and biochemical changes were observed in the pancreas and serum of rats after the intraperitoneal administration of selenomethionine, sodium selenite and methionine. Selenomethionine caused rapidly developing acinar cell necrosis. The first pathological changes were mitochondrial swelling and flocculent densities, and dilatation of cisternae of the endoplasmic reticulum. Zymogen granules appeared disrupted only in disintegrated acinar cells. Signs of autodigestive pancreatic inflammation with fat necrosis, elevation of pancreatic phospholipase A2 and serum amylase activities, as well as pulmonary oedema were present. Sodium selenite caused similar histologic changes to those produced by selenomethionine, but no changes were seen after methionine administration. Destruction of pancreatic acinar cells by an intraductal oleic acid injection that resulted in exocrine atrophy did not prevent systemic selenomethionine toxicity. Our results show that selenomethionine causes pancreatic acinar cell necrosis and that intracellular transport and storage of digestive enzymes is not primarily altered by this chemical.     

JAK and STAT proteins are expressed and activated by IFN-gamma in rat pancreatic acinar cells

The development of acute pancreatitis (AP) is triggered by acinar events, but the subsequent extra-acinar events, particularly a distinct immune response, appear to determine its severity. Cytokines modulate this immune response and are derived not only from immunocytes but also from pancreatic acinar cells. We studied whether pancreatic acinar cells were also capable of responding to cytokines. The JAK/STAT-pathway represents the main effector for many cytokines. Therefore, expression and regulation of JAK and STAT proteins were investigated in rat pancreatic acinar cells. Western blotting showed expression of JAK1, JAK2, Tyk2, and STAT1, STAT2, STAT3, STAT5, STAT6. In addition, STAT1 was reversibly tyrosine-phosphorylated upon the procedure of acinar cell isolation. In contrast, STAT3-phosphorylation occurred spontaneously after pancreas removal and was not reversible within 8 h. STAT1 phosphorylation was also observed upon treatment with IFN-gamma but not upon EGF, TNF-alpha or IL-6, and inhibited by the JAK2-inhibitor AG-490. Immunohistochemistry revealed cytoplasmic expression of unphosphorylated STAT1 in untreated acinar cells and nuclear translocation of phosphorylated STAT1 following IFN-gamma-treatment. Interestingly, although CCK leads to the activation of multiple stress pathways in pancreatic acinar cells, we found no influence of CCK on phosphorylation of STAT1, STAT3, or STAT5 in the pancreas. In conclusion, our data provide further evidence that pancreatic acinar cells are able to interact with immune cells. Besides stimulating immune cells via cytokine secretion, acinar cells are in turn capable of responding to IFN-gamma via JAK2 and STAT1 which may have an impact on the development of AP.     

Morphofunctional analysis of zinc-accumulating capacity of digestive system organs]

The distribution of zinc and related changes have been studied in zinc--loaded chick pancreas, ileum and liver at the ultrastructural level by sulphide--silver method. White Leghorn chicks fed a high zinc diets (50, 500, 1000, 2000 and 4000 mgZn/kg diet) for 6 weeks, were killed at intervals; portions of their organs were fixed for light and electron microscopy; other samples were analyzed for zinc by AA spectrophotometry. A drastic increase of zinc level in chick pancreas fed 2000 mg Zn/kg diet (as ZnCl2) was associated with acinar cell degeneration. Apoptosis was the predominant form of acinar cell deletion. This study provides support for a previously proposed theory that cell injury stimulates passive zinc accumulation.     

Effects of hypothyroidism on the ultrastructure of rat pancreatic acinar cells: a stereological analysis.

The morphological and stereological characteristics of the exocrine pancreas subcellular organelles from healthy and thyroidectomized rats have been studied. The acinar tissue from hypothyroid rats showed an interstitial edema and evidence of degenerative processes. Stereological parameters of zymogen granules were significantly reduced in thyroidectomized rats. The hypothyroidism induced degenerative changes in the pancreatic acinar cells as well as a decrease in the number and size of the zymogen granules. These modifications probably cause functional alterations.     

Morphometry and elemental analysis of rat exocrine pancreas following administration of trypsin inhibitor

The morphological responses of the exocrine pancreas of the adult male rat to soybean trypsin inhibitor (STI) were studied by ultrastructural morphometry and electron probe X-ray microanalysis. STI administered orally in drinking water for 14 days resulted in a 72% increase in the wet weight of the pancreas. This enlargement was due, largely, to an increase in acinar cell mass. Volume increases in the acinar cell mass and extra-acinar cell compartment were 72 and 30%, respectively. The estimated total number of acinar cells in the mean exocrine pancreas was 500 million in the control and 630 million in the experimental group, representing an increase of 27%. Acinar cell volume was 1,790 microns 3 for the control and 2,457 microns 3 for the STI group. The pronounced morphometric changes of the organelles in the STI group were: the mean nucleolar volume increased by 56%; the volume of zymogen granular mass per cell increased by 93%; the volume of the Golgi complex and the condensing vacuoles per cell increased by 52 and 100%, respectively, whereas the membrane area of the Golgi complex and the condensing vacuoles increased by 98 and 47%, respectively. Spectral analysis of seven elements (Na, Mg, P, S, Cl, K and Ca) showed significant changes for nuclei, zymogen granules and mitochondria following STI: nuclei showed Na, P, K increased; zymogen granules showed Na, P, S, K increased, Cl decreased; mitochondrial particles showed Mg, P, Cl, Ca increased, and the mitochondrial matrix showed S decreased. The persistent uptake of STI probably resulted in a continual release of a trophic hormone acting on pancreatic tissue components, consequently causing hyperplasia and hypertrophy of the exocrine pancreas to accommodate a heightened demand for synthesis of exportable proteins.     

Early indicators of exocrine pancreas carcinogenesis produced by non-genotoxic agents

In the past 40 years the incidence of pancreatic cancer in many Western countries had increased. Since no single factor responsible for the development of pancreatic cancer has been identified, it is believed that non-genotoxic factors may play an important role in the pathogenesis of this highly fatal form of cancer. Focal abnormalities of acinar cells, referred to as atypical acinar cell foci or nodules, occur spontaneously in rats and some other species. Their incidence increases with age from zero at birth to about 75% in 2-year-old rats. These spontaneous lesions have a phenotype that cannot be distinguished from the putative, atypical preneoplastic, acinar cell foci induced in rat pancreas by the carcinogen azaserine. Unsaturated fat (corn oil) has been found to increase the incidence of atypical acinar cell nodules and adenomas in the pancreas of non-carcinogen-treated rats without influencing the weight of the pancreas. Furthermore, unsaturated fat has a specific promoting effect on the growth potential of atypical acinar cell foci and nodules induced in rat pancreas by azaserine, resulting in an increase in the number and size of these lesions. Rats fed raw soya flour or trypsin inhibitors develop an enlarged pancreas as a result of hypertrophy and hyperplasia. They also develop acidophilic atypical acinar cell foci and nodules, adenomas and adenocarcinomas after being fed full-fat raw soya flour for 2 years. It may be concluded from the observations in rat pancreas that non-genotoxic compounds or conditions that enhance pancreatic growth may be classified as non-genotoxic pancreatic tumour promoters. The observations with corn oil, however, indicate that there may be non-genotoxic compounds that specifically enhance growth of spontaneous initiated atypical acinar cell foci without causing hyperplasia of the pancreas. The possible mechanisms whereby unsaturated fat and trypsin inhibitors exert their effects on exocrine pancreatic carcinogenesis are discussed.     

Comparative studies of the action of long duration alcohol drinking on rat pancreatic exocrine cells

The influence of a long term ingestion of ethanol on the rat exocrine pancreas has been studied by electron microscopy. The comparison of micrographs from alcoholic and non alcoholic pancreas allowed us to compare the different organelles of acinar pancreatic cells. These data have been submitted to factorial analysis of correspondences. The ultrastructural modifications revealed out by this analysis are in good agreement with the hypothesis of an adaptation of exocrine cells to a chronic hyperfunctional state.     

Lack of pancreatic [3H]estradiol-binding activity in cystic fibrosis

A major characteristic of cystic fibrosis (CF) is the progressive degeneration of acinar cells in the pancreas. It is now well established that the normal pancreas contains an abundant amount of an [3H]estradiol-binding protein. Although the physiological function of this protein is unknown, available evidence suggests that it modulates resting secretion from acinar cells. Analysis of pancreatic autopsy samples from 13 patients who had CF demonstrated a high degree of correlation between loss of acinar cells and loss of [3H]estradiol-binding activity. Autopsy samples taken from individuals unaffected by CF contained large amounts of the [3H]estradiol-binding protein that were significantly correlated with the tissue content of amylase. This biological model demonstrates that the [3H]estradiol-binding protein in pancreas is localized primarily within acinar cells. Based on the presumed regulatory role this protein has on pancreatic secretion, an hypothesis is offered to account for acinar cell degeneration in individuals suffering from cystic fibrosis.     

Development of pancreatic acini in embryos of the grass snake Natrix natrix (Lepidosauria,Serpentes)

This study report about the differentiation of pancreatic acinar tissue in grass snake, Natrix natrix, embryos using light microscopy, transmission electron microscopy, and immuno-gold labeling. Differentiation of acinar cells in the embryonic pancreas of the grass snake is similar to that of other amniotes. Pancreatic acini occurred for the first time at Stage VIII, which is the midpoint of embryonic development. Two pattern of acinar cell differentiation were observed. The first involved formation of zymogen granules followed by cell migration from ducts. In the second, one zymogen granule was formed at the end of acinar cell differentiation. During embryonic development in the pancreatic acini of N. natrix, five types of zymogen granules were established, which correlated with the degree of their maturation and condensation. Within differentiating acini of the studied species, three types of cells were present: acinar, centroacinar, and endocrine cells. The origin of acinar cells as well as centroacinar cells in the pancreas of the studied species was the pancreatic ducts, which is similar as in other vertebrates. In the differentiating pancreatic acini of N. natrix, intermediate cells were not present. It may be related to the lack of transdifferentiation activity of acinar cells in the studied species. Amylase activity of exocrine pancreas was detected only at the end of embryonic development, which may be related to animal feeding after hatching from external sources that are rich in carbohydrates and presence of digestive enzymes in the egg yolk. Mitotic division of acinar cells was the main mechanism of expansion of acinar tissue during pancreas differentiation in the grass snake embryos.     

Transdifferentiation of tadpole pancreatic acinar cells to duct cells mediated by Notch and stromelysin-3

The tadpole pancreas has differentiated acinar cells but an underdeveloped ductal system. At the climax of metamorphosis thyroid hormone (TH) induces the tadpole acinar cells to dedifferentiate to a progenitor state. After metamorphosis is complete the exocrine pancreas redifferentiates in the growing frog forming a typical vertebrate pancreas including a complex ductal system. A micro array analysis found that TH up regulates stromelysin 3 (ST3, matrix metalloproteinase 11) in the exocrine pancreas at metamorphic climax. Transgenic tadpoles were prepared with an elastase promoter driving either the ST3 gene or the constitutively active form of Notch (IC). Expression of the transgenes was controlled by the tetracycline system. A few days after either of these transgenes is activated by doxycycline the pancreatic acinar cells turn into duct-like cells. This transdetermination occurs without cell division since both acinar and ductal markers can be visualized transiently in the same cell. We propose that remodeling of the tadpole acinar cells is initiated when ST3 is up regulated by TH. Stromelysin-3 then cleaves and activates Notch.     

Alcohol and Acute Pancreatitis

Alcohol abuse is associated with the development of both acute and chronic pancreatitis. The majority of patients who abuse alcohol will not develop pancreatitis; the reasons for different susceptibilities to alcohol are unknown. Most patients who present with acute alcoholic pancreatitits will have underlying chronic disease, but up to a third will have no evidence of chronic pancreatitis. Alcohol has a number of acute effects on the pancreas that are potentially toxic. These include increasing pancreatic duct pressure, decreasing pancreatic blood flow, generating free radicals, and stimulating pathologic zymogen activation within the pancreatic acinar cell.     

荒漠沙蜥冬眠前与冬眠中期肝脏、胰腺、脂肪体超微结构的比较

对荒漠沙蜥（Phrynocephalus przewalskii）冬眠前及冬眠中期的肝脏、胰腺和脂肪体的超微结构进行了比较观察。结果表明,荒漠沙蜥肝脏、胰腺和脂肪体中的糖原颗粒、脂滴、内质网、线粒体等细胞结构有明显变化。冬眠中期胰腺腺泡细胞线粒体中出现致密颗粒,核周间隙增宽,核中出现无定形体。文中对上述结果的生理意义进行了讨论。     

Pancreatic damage induced by injecting a large dose of arginine

Male Wistar rats were injected intraperitoneally with a large dose of arginine (500 mg/100 g body weight) and were sacrificed 24, 48 and 72 h later. Pancreatic tissue was examined by electron microscopy to study the resulting process of degeneration. Degeneration started with disorganization of the rough endoplasmic reticulum into whorls with a concomitant decrease in the numbers of zymogen granules. The main changes in acinar cells after 24 h were partial distension of the endoplasmic reticulum, whorls of agranular membranes encircling zymogen granules and perinuclear vacuoles. At this time large sequestered areas in the cytoplasm contained disarranged rough endoplasmic reticulum and degraded zymogen granules. The mitochondria showed only slight changes. After 48 h, dissociation and necrosis of acinar cells were noted. Subsequently, the necrotic cells were replaced by interstitial tissue composed of leucocytes and fibroblasts. It was concluded that a large dose of arginine is toxic to the rat pancreas when injected intraperitoneally. The early morphological changes of the acinar cells may be related to metabolic alterations associated with the endoplasmic reticulum. The disorganization of the endoplasmic reticulum and the reduced number of zymogen granules may indicate disturbance of protein synthesis. The focal sequestration and degradation of the cytoplasm seemed to represent changes of the acinar cells associated with removal of damaged organelles.     

Ultrastructural changes in the rat exocrine pancreas after jejunoileal bypass

The influence of a 90% jejunoileal bypass on the rat exocrine pancreas was studied by morphometrical procedures. In sham-operated animals exocrine acinar cells accounted for 80.3% of the pancreas volume. These cells are composed of 9.9% nuclei, 8.4% mitochondria, 12.2% zymogen granules, 0.3% lipid droplets and 69.2% of a compartment ("ERGLS") composed of endoplasmic reticulum, ribosomes, Golgi areas, lysosomes and the cytoplasmic ground substance. Intestinal bypass did not change the volume density of exocrine cells nor that of nuclei in the cells during the three postoperative months. The means nuclear diameter was approximately the same in both groups. However, the volume density of secretory granules diminished by 50%. This was accompanied by a decrease in mean granular diameter, but not in their numerical density. The volume density of lipid droplets increased 10 fold, that of mitochondria increased slightly from the 15th postoperative day but significantly from the 45th day. The remaining cellular compartment composed of "ERGLS" was not modified by intestinal bypass. These findings suggest that a 90% jejunoileal bypass induces major changes in the composition of pancreatic acinar cells but not in their size.     

Expression of a dominant-negative mutant TGF-beta type II receptor in transgenic mice reveals essential roles for TGF-beta in regulation of growth and differentiation in the exocrine pancreas.

Using a dominant-negative mutant receptor (DNR) approach in transgenic mice, we have functionally inactivated transforming growth factor-beta (TGF-beta) signaling in select epithelial cells. The dominant-negative mutant type II TGF-beta receptor blocked signaling by all three TGF-beta isoforms in primary hepatocyte and pancreatic acinar cell cultures generated from transgenic mice, as demonstrated by the loss of growth inhibitory and gene induction responses. However, it had no effect on signaling by activin, the closest TGF-beta family member. DNR transgenic mice showed increased proliferation of pancreatic acinar cells and severely perturbed acinar differentiation. These results indicate that TGF-beta negatively controls growth of acinar cells and is essential for the maintenance of a differentiated acinar phenotype in the exocrine pancreas in vivo. In contrast, such abnormalities were not observed in the liver. Additional abnormalities in the pancreas included fibrosis, neoangiogenesis and mild macrophage infiltration, and these were associated with a marked up-regulation of TGF-beta expression in transgenic acinar cells. This transgenic model of targeted functional inactivation of TGF-beta signaling provides insights into mechanisms whereby loss of TGF-beta responsiveness might promote the carcinogenic process, both through direct effects on cell proliferation, and indirectly through up-regulation of TGF-betas with associated paracrine effects on stromal compartments.     

Induction of pancreatic acinar pathology via inhalation of nicotine.

This study was conducted to determine the effects of nicotine inhalation on the onset, progression, and sequential development of pancreatic lesions. Male Sprague-Dawley rats in groups of five were exposed to saline or nicotine aerosol twice daily for 15, 30, 45, and 60 min for 21 days. After sacrifice, blood samples were analyzed for plasma levels of nicotine, glucose, gastrin, and cholecystokinin. Pancreatic tissues were examined for pathological lesions. While there were no significant differences in plasma levels of glucose, gastrin, and cholecystokinin in all groups, there was a steady increase in plasma levels of nicotine with increased exposures to nicotine. Histopathological examination of pancreatic tissue revealed definitive pancreatic injuries that also appeared to be directly correlated with increased duration of nicotine exposure. The pathological changes of the pancreas were confined only to acinar cells of the exocrine pancreas. Two main types of cellular changes were observed: cellular swelling/vacuolation and nuclear condensation/cellular pyknosis. Both of these changes indicated tissue injuries in the pancreas. Transformation of the glandular acini to solid masses of epithelial cells was also observed. The results from our present study strongly suggest that the exocrine pancreas is very sensitive and susceptible to nicotine toxicity. Our data further indicate that early morphological changes in the pancreas induced by nicotine may occur without functional or metabolic alterations; however, such changes could occur at a later stage, when tissue and cellular changes become more extensive.