Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0149521 (chronic pancreatitis)
 7,199 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alcohol may affect the integrity of the pancreatic parenchyma, as seen in alcoholic pancreatitis, some cases of chronic alcoholism without clinical pancreatitis, and experimental studies. The composition of pancreatic juice may reflect some of these changes. One type of parenchymal alteration is the loss of differentiative features of acinar cells, so that they take on the characteristics of ductular cells. Concomitant fibrosis completes the formation of the tubular complexes found in association with alcoholic chronic pancreatitis. Sustained alcohol intake may produce the accumulation of lipid droplets in parenchymal cells, some of which may be shown to be within the rough endoplasmic reticulum of acinar cells. Epithelial cells may undergo mucous metaplasia. The epithelial-basal lamina barrier frequently is breached in the area of intraluminal aggregates, with or without obvious inflammation in the immediate area. Loss of barrier function may lead to interaction among components of the external compartment (lumen) and the internal compartment (stroma). Increased levels of blood proteins and glycosaminoglycans in the juice, enzyme activation, fibrin formation, and complement activation are potential consequences of barrier loss. Increased lactoferrin levels could result in part from the activity and degranulation of polymorphonuclear leukocytes.
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PMID:Alcohol and the integrity of the pancreas. 385 12

By light and electron microscopic immunocytochemistry the distribution is described of human pancreatic elastase 1 (E1) during ontogenesis, in adults, in cases of acute and chronic pancreatitis, acute pancreatic ischaemia as well as pancreatic tumours. E1-positive cells were first detected in ductal sprouts in the 14th gestational week. Complete acini expressing E1 could be found from the 17th to the 20th week of gestation onwards. Scattered distinct E1-positive epithelia could be found in the ducts of fetal and adult pancreas. By immunoelectron microscopy, E1 was localized in rough endoplasmic reticulum, condensing vacuoles, zymogen granules of acinar epithelia and in acinar lumina. E1 appeared to be distributed homogeneously in zymogen granules. As specific markers of acinar cells, both monoclonal antibodies under study identified heterotopic pancreatic acini in peribiliar glands of the liver and also helped to visualize different damage patterns in pancreatitis. The acinar epithelia surrounding acute lipolytic necroses initially reacted more intensely with the E1-antibodies than undamaged pancreatic tissue. In acute ischaemia, acinar cells which are dissociated from intercalated ducts lost their immunocytochemical reactivity for E1. Pancreatic parenchyma involved in advanced acute pancreatitis as well as in chronic inflammation was detected only weakly by both E1-antibodies. However, atrophic lobules in post-inflammatory scars were stained more intensely by the E1-antibodies than normal parenchyma. Pancreatic tumours (adenomas, adenocarcinomas, solid-cystic tumours and islet cell tumours) were not labelled by these antibodies.
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PMID:Immunocytochemical localization of elastase 1 in human pancreas. 763 50

Male rats were injected daily ip (350 mg/100 g body weight) with L-arginine from 1 to 4 weeks. Weekly changes were assessed by glucose tolerance, pancreatic insulin, histology, immunohistochemistry, ultrastructure, and quantification of insulin mRNA by in situ hybridization. Following Week 1, light microscopy revealed areas of focal acinar cell degeneration and incipient disaggregation of exocrine cytoarchitecture. Ultrastructural changes revealed initial attenuation in endoplasmic reticulum and condensation and clumping of nuclear chromatin. Some mitochondria appeared swollen and the plasma membrane showed areas of focal disintegration. Islets appeared normal, although pancreatic insulin levels were lower than controls as was the quantified signal for insulin mRNA. At the end of Week 2, acinar necrosis was evident throughout most pancreatic lobules. Increasing numbers of acinar cells underwent progressive degeneration with further loss of plasma membrane integrity, the appearance of autophagic vacuoles, increased cytoplasmic debris, and mitochondrial disruption. At Week 4, only isolated single acinar cells remained within a fibrous connective tissue matrix contiguous with ducts, blood vessels, intrapancreatic nerves, and islets. Immunohistochemistry of islets and nerves revealed normal endocrine and neural components. Although nonfasted, arginine-treated rats were normoglycemic and no further significant changes in pancreatic insulin and mRNA were found between Weeks 2 and 4, some impairment of glucose tolerance was present throughout the 4-week period. Data support the hypothesis that excess arginine selectively destroys acinar cells. It is suggested that necrosis arises from attenuation in nucleoprotein synthesis which may result from amino acid imbalance and/or toxicity. Excess arginine-treated animals may serve as a model for the study of acute and chronic pancreatitis.
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PMID:Pancreatic changes elicited by chronic administration of excess L-arginine. 807 May 43

Epithelial neutrophil-activating protein 78 (ENA-78) is a member of the CXC chemokines and acts as a potent chemoattractant and activator of neutrophil function. On stimulation in vitro, ENA-78 is highly expressed in many cell types. ENA-78 protein levels are strongly elevated in synovial fluid and blood of patients with rheumatoid arthritis. By in situ hybridization and immunofluorescence staining, ENA-78 has been recognized as a major CXC chemokine expressed in epithelial cells of the intestinal mucosa of patients with Crohn's disease, ulcerative colitis, and acute appendicitis. A high expression of ENA-78 and interleukin-8 (IL-8) was also observed in the exocrine tissue of patients with chronic pancreatitis (CP). It is interesting to note that expression of IP-10, MIP-1alpha, and MCP-1 is high in healthy pancreatic tissue but low in tissue of patients with CP, suggesting a mutually exclusive expression of the ELR-CXC vs. non-ELR-CXC/CC chemokines. High-resolution studies of intracellular chemokines has revealed specific immunoreactivity for ENA-78 associated with the endoplasmic reticulum of many cell types. In contrast, GROalpha immunoreactivity was exclusively localized in the nucleus. Despite their common effects on neutrophil functions, the differential intracellular localization of ENA-78 and GROalpha suggests additional roles for these two chemokines in normal cell biology.
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PMID:Regulation and function of the CXC chemokine ENA-78 in monocytes and its role in disease. 936 15

The purpose of this study was to investigate the morphological changes in the islets observed in a new chronic pancreatitis model with diabetes induced by repetition of cerulein injection plus water-immersion stress in rats. The rats of this model were treated with water-immersion stress for 5 h and two intraperitoneal injections of 20 micrograms/kg body weight of cerulein once a week for 16 weeks. In the stress and cerulein group, 62% of the islets exhibited infiltration of mononucleated cells, and/or peri- and intrainsular fibrosis. On immunohistochemical study, some islets showed reduced density of the insulin immunoreactivity. The glucagon-producing cells decreased in number. With electron microscopy, various endocrine changes were observed, mainly in the B cells. The changes included scattered debris damage with reduction of secretary granules, and vesiculation of the endoplasmic reticulum. Numerous fibroblasts clustered around the islets, and proliferating collagen fibers invaded the islets. The microvascular changes consisted of bleeding and damage to the endothels. In the pancreas treated with stress alone or cerulein alone, significant endocrine damage was not observed. In conclusion, chronic repetitive treatment with stress and cerulein, together with poor islet circulation due to fibrosis and vascular changes, resulted in the endocrine cellular damage.
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PMID:Morphological study of pancreatic endocrine in an experimental chronic pancreatitis with diabetes induced by stress and cerulein. 1044 84

AIM:To investigate the etiologic association of pancreas divisum (PD) with chronic pancreatitis and to clarify its pathogenesis.METHODS:A PD canine model was established in 32 dogs. The dogs were randomly divvided into 4 groups(n =8). Group I: The communicating branch between the dorsal and ventral pancreatic ducts was partly ligated Group IIa: The communicating branch was amputated and completely ligated Group IIb: The dorsal duct was amputated and ligated at 2mm distance to the minor papilla. Group III: A sham operation without any amputation or ligation was performed. Before and after operation, the activities of serum phospholipase A2 (PLA2) and amylase (Ams) were assayed and the basal pressures of the ducts were measured when secretin was injected. Pancreatic ductograhpy and the pathologic examination were made.RESULYS:The activities of serum PLA2 and ams in Group I,II a, and IIb were sigificantly increased 5-80 days after operation. At sacrifice, the basal pressures of the ventral duct were significantly wiaher 30min-60min after provocation in Group I, IIa and IIb. The pressures of the dorsal duct were significantly increased in Group IIb but no difference in Group I and IIa. Under light microscopy the fibrosis of interlobus and periducts, the destruction of acini and infiltratiob of inflammatory cell in dorsal and ventral pancreas were found in Group IIb. But in Group I and IIa, this findings were pesent only in ventral pancreas. The electron microscopy showed that in ventral pancreas of Group I and IIa and the dorsal and ventral pancreas of Group IIb, the rough endoplasmic reticulum of the acinar cells showed granules-scaling, fusion and dilatation. The zymogen granules decreased and the mitochondria was swollen.CONCLUSION:PD is oue of etiologic factors in chronic pancreatitis. The pathogenesis is the functional obstruction of the minor papilla at the peak stage of secretion.
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PMID:An experimental study in etiologic effect of pancreas divisum on chronic pancreatitis and its pathogenesis. 1181 64

Relations between hyperlipidemia and chronic pancreatitis remain unclear. Microcirculatory disturbances and oxidative stress are involved in pathogeneses of a high numbers of diseases. The objective of this study was to induce hyperlipidemia in rats by long-term high-fat diet intake, then investigate the biochemical, microcirculatory, and histological alterations in blood and pancreatic tissues of these animals, and discuss their potential significances. Pancreatic blood flow was detected by intravital microscope; malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured in pancreatic tissues for assessment of oxidative stress and alpha-smooth muscle actin (alpha-SMA) expression was determined by immunohistochemical staining and RT-PCR. The results showed that the velocity of pancreatic microvascular blood flow of rats with hyperlipidemia decreased significantly as compared to control value (p = 0.008). Pancreatic MDA content increased whereas SOD activity decreased in these rats (p = 0.022; p = 0.039, respectively). Histologically, microvesicles in acinar and islet cells, dilated rough endoplasmic reticulum, swollen mitochondrion and modified vascular endothelial cells were observed under light microscope and transmission electron microscope. In addition, alpha-SMA expression was up-regulated significantly (p < 0.05). These results suggest that long-term high-fat diet can induce chronic pancreatic injuries which could be considered as "nonalcoholic fatty pancreatic disease", and pancreatic microcirculatory disturbances and oxidative stress may play an important part in the underlying pathogenesis.
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PMID:Long-term high-fat diet induces pancreatic injuries via pancreatic microcirculatory disturbances and oxidative stress in rats with hyperlipidemia. 1681 51

We investigated the biochemical properties and cellular expression of the c.346C>T (p.R116C) human cationic trypsinogen (PRSS1) mutant, which we identified in a German family with autosomal dominant hereditary pancreatitis. This mutation leads to an unpaired Cys residue with the potential to interfere with protein folding via incorrect disulfide bond formation. Recombinantly expressed p.R116C trypsinogen exhibited a tendency for misfolding in vitro. Biochemical analysis of the correctly folded, purified p.R116C mutant revealed unchanged activation and degradation characteristics compared to wild type trypsinogen. Secretion of mutant p.R116C from transfected 293T cells was reduced to approximately 20% of wild type. A similar secretion defect was observed with another rare PRSS1 variant, p.C139S, whereas mutants p.A16V, p.N29I, p.N29T, p.E79K, p.R122C, and p.R122H were secreted normally. All mutants were detected in cell extracts at comparable levels but a large portion of mutant p.R116C was present in an insoluble, protease-sensitive form. Consistent with intracellular retention of misfolded trypsinogen, the endoplasmic reticulum (ER) stress markers immunoglobulin-binding protein (BiP) and the spliced form of the X-box binding protein-1 (XBP1s) were elevated in cells expressing mutant p.R116C. The results indicate that mutation-induced misfolding and intracellular retention of human cationic trypsinogen causes hereditary pancreatitis in carriers of the p.R116C mutation. ER stress triggered by trypsinogen misfolding represents a new potential disease mechanism for chronic pancreatitis.
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PMID:Hereditary pancreatitis caused by mutation-induced misfolding of human cationic trypsinogen: a novel disease mechanism. 1919 23

As a molecular chaperone, GRP94 is the most abundant glycoprotein in the endoplasmic reticulum, playing an important role in maintaining cellular homeostasis. Here, we investigated the expression and the role of GRP94 in regulating cell growth and apoptosis in pancreatic cancer cells. GRP94 mRNA levels were analyzed by QRT-PCR. Immunohistochemistry was performed to localize GRP94 in tissues of the normal pancreas (n=20), chronic pancreatitis (n=20) and pancreatic ductal adenocarcinoma (n=44). Silencing of GRP94 expression was carried out by transfection with specific siRNA oligonucleotides. Apoptosis was induced by treatment with actinomycin D. Compared to normal pancreatic tissues, median mRNA levels of GRP94 were 1.5- and 3.7-fold (p<0.05) lower in chronic pancreatitis and pancreatic cancer tissues, respectively. GRP94 protein was strongly expressed in normal acinar cells and moderately expressed in normal ductal cells. GRP94 expression was lost in 48% of the cancer cases. Moderate or strong staining in cancer cells was observed in 32 and 20% of pancreatic cancer tissues, respectively. Silencing GRP94 by siRNA increased apoptosis of pancreatic cancer cells in vitro. Patients with higher than the median expression have a tendency for a worsened survival. When the small number of patients with the highest expression (n=3) were compared with the rest of the group (n=41), the survival difference was significantly worse (5 vs. 18 months, respectively, p=0.006). Down-regulation of GRP94 decreases apoptosis resistance in pancreatic cancer cells. Clinically, patients with high GRP94 expression show a tendency for a worsened survival.
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PMID:Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells. 1972 18

Calcium sensing receptor (CaSR) mutations implicated in familial hypocalciuric hypercalcemia, pancreatitis and idiopathic epilepsy syndrome map to an extended arginine-rich region in the proximal carboxyl terminus. Arginine-rich motifs mediate endoplasmic reticulum retention and/or retrieval of multisubunit proteins so we asked whether these mutations, R886P, R896H or R898Q, altered CaSR targeting to the plasma membrane. Targeting was enhanced by all three mutations, and Ca(2+)-stimulated ERK1/2 phosphorylation was increased for R896H and R898Q. To define the role of the extended arginine-rich region in CaSR trafficking, we independently determined the contributions of R890/R891 and/or R896/K897/R898 motifs by mutation to alanine. Disruption of the motif(s) significantly increased surface expression and function relative to wt CaSR. The arginine-rich region is flanked by phosphorylation sites at S892 (protein kinase C) and S899 (protein kinase A). The phosphorylation state of S899 regulated recognition of the arginine-rich region; S899D showed increased surface localization. CaSR assembles in the endoplasmic reticulum as a covalent disulfide-linked dimer and we determined whether retention requires the presence of arginine-rich regions in both subunits. A single arginine-rich region within the dimer was sufficient to confer intracellular retention comparable to wt CaSR. We have identified an extended arginine-rich region in the proximal carboxyl terminus of CaSR (residues R890 - R898) which fosters intracellular retention of CaSR and is regulated by phosphorylation. Mutation(s) identified in chronic pancreatitis and idiopathic epilepsy syndrome therefore increase plasma membrane targeting of CaSR, likely contributing to the altered Ca(2+) signaling characteristic of these diseases.
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PMID:Calcium sensing receptor mutations implicated in pancreatitis and idiopathic epilepsy syndrome disrupt an arginine-rich retention motif. 2079 21


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