UMLS:C0030305 - FACTA Search

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Query: UMLS:C0030305 (pancreatitis)
16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The subcellular distribution of the lysosomal enzymes cathepsin B and D in the pancreas was evaluated in rats infused with saline (control) or a maximal (0.25 microgram . kg-1 . h-1) or a supramaximally stimulating dose (5 micrograms . kg-1 . h-1) of the secretagogue caerulein. The latter results in acute edematous pancreatitis, inhibition of digestive enzyme secretion, and the localization of digestive zymogens in organelles whose fragility has been increased by caerulein infusion [A. Saluja et al. Am. J. Physiol. 249 (gastrointest. Liver Physiol. 12): G702-G710, 1985]. Samples from control animals were found to have 29.9 +/- 1.8% of the cathepsin B activity in the pellet centrifuged at 1,300 g for 15 min (containing primarily zymogen granules) and 54.7 +/- 2.5% in the pellet centrifuged at 12,000 g for 12 min (containing primarily lysosomes and mitochondria). After supramaximal stimulation with caerulein for 3.5 h the pellet centrifuged at 1,300 g for 15 min had 55.1 +/- 2.5%, and the pellet centrifuged at 12,000 g for 12 min had 30.6 +/- 2.0% of cathepsin B activity. This redistribution was time dependent, noted within 1 h of starting caerulein infusion, and maximal after 2.5 h of infusion. Electron microscopic immunolabeling studies revealed localization of cathepsin D in discrete organelles that, in the samples from animals infused with a supramaximally stimulating dose of caerulein, were larger, more abundant, and more concentrated in the pellet centrifuged at 1,300 g for 15 min than in the controls. During infusion with supramaximal doses of caerulein, the cathepsin B-containing organelles were found to become progressively more fragile.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Subcellular redistribution of lysosomal enzymes during caerulein-induced pancreatitis. 282 25

Rats infused with a dose of the secretagogue caerulein that is in excess of that which stimulates a maximal rate of pancreatic digestive enzyme secretion develop acute edematous pancreatitis. We have previously noted that infusion of this dose of caerulein (5 micrograms . kg-1 . h-1) induces the appearance of large heterogeneous vacuoles in acinar cell, blockade of exocytosis, and intracellular accumulation of digestive zymogens [O. Watanabe et al. Am. J. Physiol. 246 (Gastrointest. Liver Physiol. 9): G457-G467, 1984 and A. Saluja et al. Am. J. Physiol. 249 (Gastrointest. Liver Physiol. 12): G702-G710, 1985]. The current studies were performed to further elucidate these phenomena at the electron microscopic level of resolution and employed the techniques of pulse labeling, radioautography, and immunolocalization. Rats were infused with caerulein (5 micrograms . kg-1 . h-1) for 1 h, given a pulse of [3H]phenylalanine, and killed at selected times during the subsequent 5- to 180-min postpulse period during which caerulein infusion was continued. Transport from the endoplasmic reticulum to the Golgi cisternae was not altered by supramaximal stimulation, but transport through post-Golgi elements was altered. In particular, the maturation of condensing vacuoles into zymogen granules was found to be impaired. This led to the accumulation of partially condensed vacuoles and to the development of the large vacuoles containing newly synthesized digestive zymogens as well as the lysosomal hydrolase cathepsin D. The source of the latter could be impaired sorting of lysosomal and digestive enzymes and/or fusion of vacuoles with lysosomes. At the later times after pulse labeling, mature zymogen granules were also found to fuse with these large cathepsin D-containing vacuoles by a process analogous to crinophagy. Thus these studies indicate that the large heterogeneous vacuoles that appear during supramaximal secretagogue stimulation and that contain admixed digestive zymogens and lysosomal hydrolases arise by at least two mechanisms, impaired condensing vacuole maturation and crinophagy.
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PMID:Intracellular transport of pancreatic zymogens during caerulein supramaximal stimulation. 366 11

Prostaglandins have been noted to have a "protective" effect against gastrointestinal mucosal injury induced by a wide variety of agents although possible protective effects of prostaglandins on injury to other tissues have not been reported. We have tested the effect of prostaglandin E2 (PGE2) on acute experimental pancreatitis induced by feeding young female mice a choline-deficient ethionine-supplemented (CDE) diet for 24 hr. Administration of 0.05--0.20 microgram PGE2/g body wt 1 hr before and 4 hr after institution of the CDE diet lowered the mortality rate of diet-induced pancreatitis from 56% to 31%. Larger and smaller doses of PGE2 were without effect. Administration of PGE2 (0.10 microgram/g body weight) diminished the rise in in-vitro LDH discharge and the increase in "free" Cathepsin D activity which occur during diet-induced pancreatitis. Similarly, PGE2 (0.10 microgram/g body wt) diminished the magnitude of the increase in in-vitro protein discharge and the elevated concentrations of trypsinogen and chymotrypsinogen in pancreas fragments taken from mice given the CDE diet. These findings indicate the PGE2 has a protective effect against CDE diet-induced acute experimental pancreatitis. The Cathespin D and LDH changes noted during CDE diet-induced pancreatitis suggest that this diet may decrease membrane integrity and thus allow these enzymes to leak out of the lysosomes and acinar cell, respectively, during pancreatitis. Although the basis for the protective effect of PGE2 remains unclear, our observations suggest that the prostaglandin may act to reduce the alteration in membrane integrity which occurs during CDE-diet induced pancreatitis.
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PMID:Protective effects of PGE2 on diet-induced acute pancreatitis in mice. 615 72

The effects of hormonal or cholinergic stimulation on survival and on activities of lysosomal enzymes and amylase in pancreatic tissue and ascites were studied in rats with induced pancreatitis. Pancreatitis per se caused an increase of the activities of cathepsin D, N-acetyl-beta-D-glucosaminidase and amylase, and a decrease of acid phosphatase in pancreatic tissue. Pancreatic protein concentration was not influenced. In pancreatitic rats administration of cerulein or carbachol markedly decreased survival rate. Cerulein increased the activities of cathepsin D and amylase in ascites and cathepsin D and acid phosphatase in pancreatic tissue. Carbachol increased the activities of cathepsin D and amylase in ascites and acid phosphatase in pancreatic tissue. Both cerulein and carbachol decreased the activity of amylase in pancreatic tissue. Administration of secretin or the anticholinergic drug Pro-Banthine did not influence survival rate or the activities of lysosomal enzymes and amylase in ascites. In pancreatic tissue the activity of acid phosphatase was slightly increased by secretin or Pro-Banthine. In conclusion, the results show a nonparallel alteration of lysosomal enzyme activities in pancreatic tissue in rats with pancreatitis. Cerulein and cholinergic stimulation decreased survival rate and brought about a marked increase of cathepsin D activity in ascites and, in the case of cerulein, also in pancreatic tissue. The implication of lysosomes and especially the catheptic proteases in the pathogenesis and outcome of acute pancreatitis deserves further attention.
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PMID:Hormonal and cholinergic effects on amylase and lysosomal enzyme activities in pancreatic tissue and ascites of rats with acute experimental pancreatitis. 619 36

Rats infused with a supramaximally stimulating dose of the cholecystokinin-pancreozymin analogue caerulein develop acute interstitial pancreatitis (M. Lampel and H.F. Kern. Virchows Arch. A 373: 97-117, 1977). We have studied the early (30-180 min) morphological changes in pancreatic acinar cells induced by infusing caerulein (2.5 micrograms X kg-1 X h-1). The techniques of thin-section electron microscopy, freeze fracture, and enzyme and immunocytochemistry were employed. Shortly (30 min) after the onset of caerulein infusion, large vacuoles appeared in the Golgi area. After longer periods of infusion, these vacuoles further enlarged (probably by fusion with other such vacuoles as well as autophagic vacuoles) and became more widely distributed in the cytoplasm. These large vacuoles were found to be acid phosphatase positive and to be labeled by antibodies directed against digestive zymogens as well as the lysosomal enzyme cathepsin D. These observations indicate that the large vacuoles contain both digestive zymogens and lysosomal hydrolases. During caerulein infusion, morphological evidence of exocytosis at the luminal plasmalemma was reduced or absent, and evidence of basolateral exocytosis was not noted. These studies suggest that secretagogue hyperstimulation with caerulein interferes with the processes involved in condensing vacuole maturation, which normally lead to the separation of digestive zymogens and lysosomal hydrolases. As a result, both types of enzymes remain within the same compartment. This may lead to the intracellular activation of digestive enzymes by lysosomal hydrolases and be an important step in the development of acute pancreatitis.
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PMID:Supramaximal caerulein stimulation and ultrastructure of rat pancreatic acinar cell: early morphological changes during development of experimental pancreatitis. 672 Aug 95

Pancreatic cancer is a rapidly fatal disease, and there is an urgent need for early detection markers and novel therapeutic targets. The current study has used a proteomic approach of two-dimensional (2D) gel electrophoresis and mass spectrometry (MS) to identify differentially expressed proteins in six cases of pancreatic adenocarcinoma, two normal adjacent tissues, seven cases of pancreatitis, and six normal pancreatic tissues. Protein extracts of individual sample and pooled samples of each type of tissues were separated on 2D gels using two different pH ranges. Differentially expressed protein spots were in-gel digested and identified by MS. Forty proteins were identified, of which five [i.e., alpha-amylase; copper zinc superoxide dismutase; protein disulfide isomerase, pancreatic; tropomyosin 2 (TM2); and galectin-1] had been associated previously with pancreatic disease in gene expression studies. The identified proteins include antioxidant enzymes, chaperones and/or chaperone-like proteins, calcium-binding proteins, proteases, signal transduction proteins, and extracellular matrix proteins. Among these proteins, annexin A4, cyclophilin A, cathepsin D, galectin-1, 14-3-3zeta, alpha-enolase, peroxiredoxin I, TM2, and S100A8 were specifically overexpressed in tumors compared with normal and pancreatitis tissues. Differential expression of some of the identified proteins was further confirmed by Western blot analyses and/or immunohistochemical analysis. These results show the value of a proteomic approach in identifying potential markers for early diagnosis and therapeutic manipulation. The newly identified proteins in pancreatic tumors may eventually serve as diagnostic markers or therapeutic targets.
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PMID:Protein expression profiles in pancreatic adenocarcinoma compared with normal pancreatic tissue and tissue affected by pancreatitis as detected by two-dimensional gel electrophoresis and mass spectrometry. 1560 67

Cell-death programs executed in the pancreas under pathological conditions remain largely undetermined, although the severity of experimental pancreatitis has been found to depend on the ratio of apoptosis to necrosis. We have defined mechanisms by which apoptosis is induced in pancreatic acinar cells by the oxidant stressor menadione. Real-time monitoring of initiator caspase activity showed that caspase-9 (66% of cells) and caspase-8 (15% of cells) were activated within 30 min of menadione administration, but no activation of caspase-2, -10, or -12 was detected. Interestingly, when caspase-9 activation was inhibited, activation of caspase-8 was increased. Half-maximum activation (t(0.5)) of caspase-9 occurred within approximately 2 min and was identified at or in close proximity to mitochondria, whereas t(0.5) for caspase-8 occurred within approximately 26 min of menadione application and was distributed homogeneously throughout cells. Caspase-9 but not caspase-8 activation was blocked completely by the calcium chelator BAPTA or bongkrekic acid, an inhibitor of the mitochondrial permeability transition pore. In contrast, caspase-8 but not caspase-9 activation was blocked by the destruction of lysosomes (preincubation with Gly-Phe beta-naphthylamide, a cathepsin C substrate), loss of lysosomal acidity (bafilomycin A1), or inhibition of cathepsin L or D. Using pepstatin A-BODIPY FL conjugate, we confirmed translocation of cathepsin D out of lysosomes in response to menadione. We conclude that the oxidative stressor menadione induces two independent apoptotic pathways within pancreatic acinar cells: the classical mitochondrial calcium-dependent pathway that is initiated rapidly in the majority of cells, and a slower, caspase-8-mediated pathway that depends on the lysosomal activities of cathepsins and is used when the caspase-9 pathway is disabled.
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PMID:Caspase-8-mediated apoptosis induced by oxidative stress is independent of the intrinsic pathway and dependent on cathepsins. 1743 Dec 16

Cathepsin D (CD) is the major lysosomal aspartic protease and is widely distributed in the cells of various mammalian tissues. CD participates in various physiological events such as regulation of programmed cell death, activation of enzymatic precursors, and metabolic degradation of intracellular proteins through macroautophagy. To investigate the role of CD in pancreatic acinar cells, which constitute the exocrine pancreas, we generated and examined mice specifically deficient for CD in pancreatic acinar cells. CD deficient mice showed normal pancreatic development and autophagic activity, although LC3-II, which is a marker of the autophagosome, accumulates in both physiological and pancreatitis conditions. Moreover, CD deficiency leads to accumulation of matured cathepsin B (CB) and cathepsin L (CL) which are members of the cysteine protease family. We therefore conclude that CD in pancreatic acinar cells is implicated in CB and CL degradation but not in autophagic activity.
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PMID:Cathepsin D in pancreatic acinar cells is implicated in cathepsin B and L degradation, but not in autophagic activity. 2668 26

Acute pancreatitis is a complex disorder involving both premature intracellular protease activation and inflammatory cell invasion. An initiating event is the intracellular activation of trypsinogen by cathepsin B (CTSB), which can be induced directly via G protein-coupled receptors on acinar cells or through inflammatory cells. Here, we studied CTSB regulation by another lysosomal hydrolase, cathepsin D (CTSD), using mice with a complete (CTSD^-/-) or pancreas-specific conditional CTSD knockout (KO) (CTSD^f/f/p48^Cre/+). We induced acute pancreatitis by repeated caerulein injections and isolated acinar and bone marrow cells for ex vivo studies. Supramaximal caerulein stimulation induced subcellular redistribution of CTSD from the lysosomal to the zymogen-containing subcellular compartment of acinar cells and activation of CTSD, CTSB, and trypsinogen. Of note, the CTSD KO greatly reduced CTSB and trypsinogen activation in acinar cells, and CTSD directly activated CTSB but not trypsinogen in vitro During pancreatitis in pancreas-specific CTSD^f/f/p48^Cre/+ animals, markers of severity were reduced only at 1 h, whereas in the complete KO, this effect also included the late disease phase (8 h), indicating an important effect of extra-acinar CTSD on course of the disease. CTSD^-/- leukocytes exhibited reduced cytokine release after lipopolysaccharide (LPS) stimulation, and CTSD KO also reduced caspase-3 activation and apoptosis in acinar cells stimulated with the intestinal hormone cholecystokinin. In summary, CTSD is expressed in pancreatic acinar and inflammatory cells, undergoes subcellular redistribution and activation during experimental pancreatitis, and regulates disease severity by potently activating CTSB. Its impact is only minimal and transient in the early, acinar cell-dependent phase of pancreatitis and much greater in the later, inflammatory cell-dependent phase of the disease.
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PMID:Cathepsin D regulates cathepsin B activation and disease severity predominantly in inflammatory cells during experimental pancreatitis. 2922 80

Pancreatitis is a common, sometimes fatal, disease of exocrine pancreas, initiated by damaged acinar cells. Recent studies implicate disordered macroautophagy/autophagy in pancreatitis pathogenesis. ATG8/LC3 protein is critical for autophagosome formation and a widely used marker of autophagic vacuoles. Transgenic GFP-LC3 mice are a valuable tool to investigate autophagy ; however, comparison of homeostatic and disease responses between GFP-LC3 and wild-type (WT) mice has not been done. We examined the effects of GFP-LC3 expression on autophagy, acinar cell function, and experimental pancreatitis. Unexpectedly, GFP-LC3 expression markedly increased endogenous LC3-II level in pancreas, caused by downregulation of ATG4B, the protease that deconjugates/delipidates LC3-II. By contrast, GFP-LC3 expression had lesser or no effect on autophagy in liver, lung and spleen. Autophagic flux analysis showed that autophagosome formation in GFP-LC3 acinar cells increased 3-fold but was not fully counterbalanced by increased autophagic degradation. Acinar cell (ex vivo) pancreatitis inhibited autophagic flux in WT and essentially blocked it in GFP-LC3 cells. In vivo pancreatitis caused autophagy impairment in WT mice, manifest by upregulation of LC3-II and SQSTM1/p62, increased number and size of autophagic vacuoles, and decreased level of TFEB, all of which were exacerbated in GFP-LC3 mice. GFP-LC3 expression affected key pancreatitis responses; most dramatically, it worsened increases in serum AMY (amylase), a diagnostic marker of acute pancreatitis, in several mouse models. The results emphasize physiological importance of autophagy for acinar cell function, demonstrate organ-specific effects of GFP-LC3 expression, and indicate that application of GFP-LC3 mice in disease models should be done with caution.Abbreviations: AP: acute pancreatitis; Arg-AP: L-arginine-induced acute pancreatitis; ATG: autophagy-related (protein); AVs: autophagic vacuoles; CCK: cholecystokinin-8; CDE: choline-deficient, D,L-ethionine supplemented diet; CER: caerulein (ortholog of CCK); CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; ER: endoplasmic reticulum; LAMP: lysosomal-associated membrane protein; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; TEM: transmission electron microscopy; TFEB: transcription factor EB; ZG: zymogen granule(s).
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PMID:Transgenic expression of GFP-LC3 perturbs autophagy in exocrine pancreas and acute pancreatitis responses in mice. 3194 16

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