Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030305 (pancreatitis)
 16,014 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This in vivo and in vitro study demonstrates the protective effects of a new synthetic protease inhibitor--nafamostat mesilate, FUT-175--on increased cellular and lysosomal fragility within acinar cells during the early stage of cerulein-induced acute pancreatitis in rats. FUT-175 prevented hyperamylasemia, pancreatic edema, congestion owing to amylase, and lactic dehydrogenase (LDH) discharge from acini as well as cathepsin-B leakage from lysosomes dose-dependently in doses of 1-10 mg/kg.h. These results suggest that FUT-175 can protect against pancreatitis at subcellular levels in lysosomes and cellular or organelle membranes. Proteases may well play the important role in the pathogenesis of acute pancreatitis, and such a low molecular protease inhibitor may be useful clinically in the treatment of acute pancreatitis.
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PMID:Protective effect of nafamostat mesilate on cellular and lysosomal fragility of acinar cells in rat cerulein pancreatitis. 128 Dec 4

The complex events by which digestive enzyme zymogens and lysosomal hydrolases are segregated from each other and differentially transported to their respective membrane-bound intracellular organelles in the pancreas have been noted to be disturbed during the early stages of several models of experimental pancreatitis. As a result, lysosomal hydrolases such as cathepsin B are redistributed to the subcellular zymogen granule-rich fraction and lysosomal hydrolases as well as digestive enzyme zymogens are colocalized within large cytoplasmic vacuoles. The current study was designed to create an in vitro system that would reproduce this redistribution phenomenon. Our results indicate that cathepsin B redistribution occurs when rat pancreatic fragments are incubated with a supramaximally stimulating concentration of the cholecystokinin analogue caerulein along with plasma from an animal subjected to in vivo supramaximal caerulein stimulation. Neither the plasma nor a supramaximally stimulating concentration of caerulein, alone, is sufficient to induce in vitro cathepsin B redistribution. The ability of the plasma to induce in vitro cathepsin redistribution is dependent upon its content of a 10,000-30,000-D protein and is lost by exposure to protease inhibitors. In vitro cathepsin B redistribution also occurs when rat pancreatic fragments are incubated with plasma obtained from opossums with hemorrhagic necrotizing pancreatitis caused by bile/pancreatic duct ligation.
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PMID:A plasma protease which is expressed during supramaximal stimulation causes in vitro subcellular redistribution of lysosomal enzymes in rat exocrine pancreas. 201 May 41

The study was performed to compare an usual method of induction of acute experimental pancreatitis with a simplified, easier and faster induction through a subcutaneous and intravenous injection of cerulein, with good reproducibility as compared to the literature. Four groups were studied. In the group I, continuous three hour intravenous injection of 15 micrograms/Kg of cerulein, was given. Group II was a control group with saline infusion. Group III received a subcutaneous injection of 20 micrograms/Kg and an intravenous injection of 20 micrograms/Kg of cerulein one hour later. Group IV was the control group with saline. The results of biochemical measurements, such as tecidual trypsinogen, chimotrypsinogen, proelastase, cathepsin and serum amylase, showed no difference between the two methods. Histologic study revealed edematous pancreatitis in group I and III, with moderate acinar necrose in group III. These results suggest that the proposed simplified method induces enough acute and edematous pancreatitis to allow studies in physiopathology and therapeutics.
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PMID:[Simplified model of induction of experimental acute pancreatitis with a supra-maximal dose of cerulein]. 753 38

The intracellular distribution and action of a new synthetic protease inhibitor, E3123, were studied in cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by a 4-h iv infusion of a supramaximal dose of cerulein, and was treated by prophylactic (pretreatment) or therapeutic (posttreatment) continuous administration of E3123. Pancreatic edema and hyperamylasemia were ameriolated only by prophylactic treatment. A subcellular fractionation study showed that the activities of cathepsin-B and trypsin in the zymogen granule-enriched fraction of the cerulein-pancreatitis group were remarkably increased. Both prophylactic and therapeutic treatment significantly prevented the elevation of these enzyme activities. These effects were accompanied by amelioration of pancreatic histopathological features, including intracellular vacuolization and fat necrosis. A microscopic autoradiographic study using 3H-labeled E3123 showed diffuse intracellular distribution of E3123, and the radioactivity of 3H-E3123 in the posttreatment group was three times greater than that in the pretreatment group. This study provides the first experimental evidence that, even when administered therapeutically, exogenous protease inhibitors are transported into pancreatic acinar cells, thereby reducing the severity of early intracellular alterations in cerulein-induced acute pancreatitis.
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PMID:Intracellular action of an exogenous low-molecular-weight synthetic protease inhibitor, E3123, in cerulein-induced acute pancreatitis in rats. 807 70

A premature and intracellular activation of digestive zymogens is thought to be responsible for the onset of pancreatitis. Because trypsin has a critical role in initiating the activation cascade of digestive enzymes in the gut, it has been assumed that trypsin also initiates intracellular zymogen activation in the pancreas. We have tested this hypothesis in isolated acini and lobules from rat pancreas. Intracellular trypsinogen activation was induced by supramaximal secretagogue stimulation and measured using either specific trypsin substrates or immunoreactivity of the trypsinogen activation peptide (TAP). To prevent a trypsin-induced trypsinogen activation, we used the cell-permeant, highly specific, and reversible inhibitor Nalpha-(2-naphthylsulfonyl)-3-amidinophenylalanine-carboxymethylpiperazide (S124), and to prevent cathepsin-induced trypsinogen activation, we used the cysteine protease inhibitor E-64d. Incubation of acini or lobules in the presence of S124 completely prevented the generation of trypsin activity in response to supramaximal caerulein but had no effect whatsoever on the generation of TAP. Conversely, when trypsin activity was recovered at the end of the experiment by either washout of S124 from acini or extensive dilution of lobule homogenates, it was up to 400% higher than after caerulein alone and corresponded, in molar terms, to the generation of TAP. Both trypsin activity and TAP release were inhibited in parallel by E-64d. We conclude that caerulein-induced trypsinogen activation in the pancreas is caused by an E-64d-inhibitable mechanism such as cathepsin-induced trypsinogen activation, and neither involves nor requires intracellular trypsin activity. Specific trypsin inhibition, on the other hand, prevents 80% of trypsin inactivation or autodegradation in the pancreas.
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PMID:Trypsin activity is not involved in premature, intrapancreatic trypsinogen activation. 1180 59

Polish accomplishments in clinical and experimental pancreatology concern acute (AP) and chronic (CP) pancreatitis. Special notice was drawn in Polish studies on hemostasis disorders in acute experimental pancreatitis (AEP), and resulting clinical implications (possibility of thrombotic-embolic complications leading to hemorrhagic defects associated with coagulation factors consumption). Studies on lysosomal hydrolases role in AEP pathogenesis were discussed. In those studies notice was drawn to initiating role of zymogen activation by lysosomal hydrolases, especially beta-glucuronidase, with smaller activity of acid phosphatase and cathepsin in this process. It was stated, that also lysosomal enzymes are released from macrophages obtained from bronchoalveolar lavage fluid in AEP. It was revealed that prostacyclin (PGI(2)) shows stabilizing effect on lysosomes in liver and kidneys in AEP. Platelets activating factor antagonist inhibits pulmonary lysosomal hydrolases activity in such conditions. Polish studies concerning reactive forms of oxygen role in AEP pathogenesis are one of the first in Europe. Oxidative-antioxidative balance was disturbed in acute pancreatitis course and associated multiorgan changes both under experimental conditions and in humans. Oxidative stress as an early prognostic symptom in AP in humans was also emphasized, showing correlation of oxidative stress indicators with phospholipase A serum activity and polymorphonuclear elastase in plasma of patients with different degree of this disease. In a range of clinical studies special attention should be given to studies concerning lipid disorders as an AP etiological factor in humans. Clear decrease in lipoprotein lipase activity in AP in humans was determined. Polish studies concerning importance of sphincterectomy in acute gallstone derivative pancreatitis (AGP) were presented. Polish researchers accomplishments in chronic alcoholic pancreatitis (CAP) etiopathogenesis were discussed.
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PMID:Pancreas; pancreatitis--Polish accomplishments. 1507 70

Pancreatic cancer is a serious disease with poor patient outcome, often as a consequence of late diagnosis in advanced stages. This is in large part due to the lack of diagnostic tools for early detection. To address this deficiency, we have investigated novel molecular near-infrared fluorescent (NIRF) in vivo imaging techniques in clinically relevant mouse models of pancreatic cancer. Genome wide gene expression profiling was used to identify cathepsin cystein proteases and matrix metalloproteinases (MMP) as targets for NIRF imaging. Appropriate protease activatable probes were evaluated for detection of early-stage pancreatic cancer in mice with orthotopically implanted pancreatic cancer cell lines. Mice with pancreatitis served as controls. Whole body in vivo NIRF imaging using activatable cathepsin sensitive probes specifically detected pancreatic tumors as small as 1-2 mm diameter. Imaging of MMP activity demonstrated high specificity for MMP positive tumors. Intravital flexible confocal fluorescence lasermicroscopy of protease activity enabled specific detection of pancreatic tumors at the cellular level. Importantly, topical application of NIRF-probes markedly reduced background without altering signal intensity. Taken together, macroscopic and confocal lasermicroscopic molecular in vivo imaging of protease activity is highly sensitive, specific and allows discrimination between normal pancreatic tissue, inflammation and pancreatic cancer. Translation of this approach to the clinic could significantly improve endoscopic and laparoscopic detection of early-stage pancreatic cancer.
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PMID:Highly sensitive detection of early-stage pancreatic cancer by multimodal near-infrared molecular imaging in living mice. 1870 39

The pathogenic mechanisms underlying acute pancreatitis are not clear. Two key pathologic acinar cell responses of this disease are vacuole accumulation and trypsinogen activation. We show here that both result from defective autophagy, by comparing the autophagic responses in rodent models of acute pancreatitis to physiologic autophagy triggered by fasting. Pancreatitis-induced vacuoles in acinar cells were greater in number and much larger than those induced with fasting. Degradation of long-lived proteins, a measure of autophagic efficiency, was markedly inhibited in in vitro pancreatitis, while it was stimulated by acinar cell starvation. Further, processing of the lysosomal proteases cathepsin L (CatL) and CatB into their fully active, mature forms was reduced in pancreatitis, as were their activities in the lysosome-enriched subcellular fraction. These findings indicate that autophagy is retarded in pancreatitis due to deficient lysosomal degradation caused by impaired cathepsin processing. Trypsinogen activation occurred in pancreatitis but not with fasting and was prevented by inhibiting autophagy. A marker of trypsinogen activation partially localized to autophagic vacuoles, and pharmacologic inhibition of CatL increased the amount of active trypsin in acinar cells. The results suggest that retarded autophagy is associated with an imbalance between CatL, which degrades trypsinogen and trypsin, and CatB, which converts trypsinogen into trypsin, resulting in intra-acinar accumulation of active trypsin in pancreatitis. Thus, deficient lysosomal degradation may be a dominant mechanism for increased intra-acinar trypsin in pancreatitis.
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PMID:Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. 1980 11

Two key pathologic acinar cell responses of acute pancreatitis are vacuole accumulation and trypsinogen activation. Degradation of long-lived proteins, a measure of autophagic efficiency, is markedly inhibited in pancreatitis. Further, processing of the lysosomal proteases cathepsin L (CatL) and CatB into their fully active, mature forms is reduced in pancreatitis, as are their activities in the lysosome-enriched subcellular fraction. These findings indicate that autophagy is retarded in pancreatitis due to deficient lysosomal degradation caused by impaired cathepsin processing. Trypsinogen activation occurred in pancreatitis and is prevented by inhibiting autophagy. A marker of trypsinogen activation partially localized to autophagic vacuoles, and pharmacologic inhibition of CatL increased the amount of active trypsin in acinar cells. The results suggest that retarded autophagy is associated with an imbalance between CatL, which degrades trypsinogen and trypsin, and CatB, which converts trypsinogen into trypsin, resulting in intra-acinar accumulation of active trypsin in pancreatitis. Thus, deficient lysosomal degradation may be a dominant mechanism for increased intra-acinar trypsin in pancreatitis. Proinflammatory cytokines and oxidative stress play a pivotal role in the early pathophysiological events of the disease. Cytokines such as interleukin 1beta and tumor necrosis factor alpha initiate and propagate almost all consequences of the systemic inflammatory response syndrome. On the other hand, depletion of pancreatic glutathione is an early hallmark of acute pancreatitis and reactive oxygen species are also associated with the inflammatory process. Changes in thiol homeostasis and redox signaling decisively contribute to amplification of the inflammatory cascade through mitogen activated protein kinase (MAP kinase) pathways.
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PMID:Pathophysiology of acute and infected pancreatitis. 2018 Jul 51

Cathepsins regulate premature trypsinogen activation within acinar cells, a key initial step in pancreatitis. The identity, origin, and causative roles of activated cathepsins in pancreatic inflammation and pain are not defined. By using a near infrared-labeled activity-based probe (GB123) that covalently modifies active cathepsins, we localized and identified activated cathepsins in mice with cerulein-induced pancreatitis and in pancreatic juice from patients with chronic pancreatitis. We used inhibitors of activated cathepsins to define their causative role in pancreatic inflammation and pain. After GB123 administration to mice with pancreatitis, reflectance and confocal imaging showed significant accumulation of the probe in inflamed pancreas compared with controls, particularly in acinar cells and macrophages, and in spinal cord microglia and neurons. Biochemical analysis of pancreatic extracts identified them as cathepsins B, L, and S (Cat-B, Cat-L, and Cat-S, respectively). These active cathepsins were also identified in pancreatic juice from patients with chronic pancreatitis undergoing an endoscopic procedure for the treatment of pain, indicating cathepsin secretion. The cathepsin inhibitor K11777 suppressed cerulein-induced activation of Cat-B, Cat-L, and Cat-S in the pancreas and ameliorated pancreatic inflammation, nocifensive behavior, and activation of spinal nociceptive neurons. Thus pancreatitis is associated with an increase in the active forms of the proteases Cat-B, Cat-L, and Cat-S in pancreatic acinar cells and macrophages, and in spinal neurons and microglial cells. Inhibition of cathepsin activation ameliorated pancreatic inflammation and pain. Activity-based probes permit identification of proteases that are predictive biomarkers of disease progression and response to therapy and may be useful noninvasive tools for the detection of pancreatic inflammation.
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PMID:Active cathepsins B, L, and S in murine and human pancreatitis. 2289 21


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