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)

We previously reported that serum hepatocyte growth factor (HGF) levels are elevated in patients with acute pancreatitis and that pancreatitis-associated ascitic fluid (PAAF) contains cytotoxic factor(s) inducing apoptosis on Madin-Darby canine kidney (MDCK) cells. In this study, plasma HGF levels and HGF tissue distribution were investigated in rats with experimental acute pancreatitis, and the effects of HGF on the cytotoxic activity and apoptosis-inducing activity of PAAF also were examined. Plasma HGF levels were elevated in rats with two experimental pancreatitis models of different grades of severity. The degree of its elevation was correlated with the severity and the organ dysfunctions. In rats with severe pancreatitis, HGF protein and messenger RNA (mRNA) levels significantly increased in liver, kidney, and lung, which were injured organs. When anti-HGF neutralizing antibody was administered in severe pancreatitis, liver dysfunction worsened, and apoptotic cells increased in kidney. Recombinant HGF inhibited the cytocidal activity of PAAF on MDCK cells in a dose-dependent manner. Moreover, recombinant HGF prevented the apoptotic cell death (DNA fragmentation, nuclear fragmentation, and caspase-3 activation) induced by PAAF. These results suggest that HGF is produced in injured organs and may function as an organotrophic and antiapoptotic factor against the organ injuries in acute pancreatitis.
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PMID:Hepatocyte growth factor increases in injured organs and functions as an organotrophic factor in rats with experimental acute pancreatitis. 1063 Mar 88

The purpose of this study was to determine if alcohol consumption and endotoxin injection change the rate of apoptosis in the pancreas. Rats were fed a Lieber-DeCarli diet for 14 weeks. At 14 weeks, the animals were injected with lipopolysaccharide (LPS) or saline and killed. The pancreata were resected and snap frozen. Apoptosis was detected by TUNEL assay. Caspase-3 activity, Bcl-2 (protein), and Fas ligand (mRNA) were assayed in pancreas extracts and alpha-amylase in plasma. Alcohol feeding significantly decreased alpha-amylase and caspase-3 activity, and significantly increased Bcl-2. LPS injection increased caspase-3 activity and decreased Bcl-2. Fas ligand mRNA was increased only in alcohol-fed, LPS-injected rats. TUNEL labeling was significantly increased only in alcohol-fed, LPS-injected rats. These data show that (a) long-term alcohol feeding suppresses apoptosis in the pancreas; (b) LPS increases the rate of apoptosis in the pancreas; (c) caspase-3 activity and Bcl-2 expression change in opposite directions; (d) TUNEL positivity and Fas ligand expression are increased, and Bcl-2 is decreased in ethanol-fed + LPS-injected rats. These results suggest that prolonged alcohol consumption may sensitize acinar cells to endotoxin-induced injury and raise the possibility that a similar mechanism may cause pancreatitis in human alcoholics.
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PMID:Alcohol feeding and lipopolysaccharide injection modulate apoptotic effectors in the rat pancreas in vivo. 1097 12

Apoptosis and necrosis are critical parameters of pancreatitis, the mechanisms of which remain unknown. Many characteristics of pancreatitis can be studied in vitro in pancreatic acini treated with high doses of cholecystokinin (CCK). We show here that CCK stimulates apoptosis and death signaling pathways in rat pancreatic acinar cells, including caspase activation, cytochrome c release, and mitochondrial depolarization. The mitochondrial dysfunction is mediated by upstream caspases (possibly caspase-8) and, in turn, leads to activation of caspase-3. CCK causes mitochondrial alterations through both permeability transition pore-dependent (cytochrome c release) and permeability transition pore-independent (mitochondrial depolarization) mechanisms. Caspase activation and mitochondrial alterations also occur in untreated pancreatic acinar cells; however, the underlying mechanisms are different. In particular, caspases protect untreated acinar cells from mitochondrial damage. We found that caspases not only mediate apoptosis but also regulate other parameters of CCK-induced acinar cell injury that are characteristic of pancreatitis; in particular, caspases negatively regulate necrosis and trypsin activation in acinar cells. The results suggest that the observed signaling pathways regulate parenchymal cell injury and death in CCK-induced pancreatitis. Protection against necrosis and trypsin activation by caspases can explain why the severity of pancreatitis in experimental models correlates inversely with the extent of apoptosis.
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PMID:Cholecystokinin induces caspase activation and mitochondrial dysfunction in pancreatic acinar cells. Roles in cell injury processes of pancreatitis. 1196 11

We have demonstrated that pancreatitis-associated ascitic fluid contributes to hepatocyte injury during acute pancreatitis; a phenomenon independent of ascites' enzymatic content and Kupffer cell-derived cytokines. Our aim is to characterize the mechanisms of pancreatitis-associated ascitic fluid induced hepatocyte death. NIH mice were injected intraperitoneally with pathogen-free pancreatitis-associated ascitic fluid. Twenty-four hours later, serum AST, ALT, LDH, and hepatocyte apoptosis (TUNEL) were measured. Human hepatocytes (CCL-13) were treated with pancreatitis-associated ascitic fluid +/-SB203580 or caspase-3 inhibitor-II. Mitochondrial membrane integrity was determined by DiOC6 staining. Apoptosis was measured by TUNEL staining and flow cytometry after dual labeling with Annexin-V/7-AAD. Data are mean +/- SEM of triplicates. Pancreatitis-associated ascitic fluid increased serum AST, ALT, LDH, and apoptotic cells in the mouse liver (all P < 0.03 vs. sham). In CCL-13 cells, pancreatitis-associated ascitic fluid induced a time and dose-dependent increase in apoptosis, in addition to p38-MAPK phosphorylation (P = 0.02 vs. control), caspase-3 cleavage (P < 0.03 vs. control) and decreased DiOC6 mitochondrial staining (P < 0.01 vs. control). Both caspase-3 inhibitor-II and SB203580 decreased apoptosis, but the former had no effect on DiOC6 staining. Pancreatitis-associated ascitic fluid induces liver injury and hepatocyte apoptosis by activating p38-MAPK and caspase-3 dependent pro-apoptotic pathways.
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PMID:Liver injury during acute pancreatitis: the role of pancreatitis-associated ascitic fluid (PAAF), p38-MAPK, and caspase-3 in inducing hepatocyte apoptosis. 1260 Apr 44

In pancreatic acini, the G-protein-activated phosphoinositide 3-kinase-gamma (PI3K gamma) regulates several key pathological responses to cholecystokinin hyperstimulation in vitro. Thus, using mice lacking PI3K gamma, we studied the function of this enzyme in vivo in two different models of acute pancreatitis. The disease was induced by supramaximal concentrations of cerulein and by feeding mice a choline-deficient/ethionine-supplemented diet. Although the secretive function of isolated pancreatic acini was identical in mutant and control samples, in both models, genetic ablation of PI3K gamma significantly reduced the extent of acinar cell injury/necrosis. In agreement with a protective role of apoptosis in pancreatitis, PI3K gamma-deficient pancreata showed an increased number of apoptotic acinar cells, as determined by terminal dUTP nick-end labeling and caspase-3 activity. In addition, neutrophil infiltration within the pancreatic tissue was also reduced, suggesting a dual action of PI3K gamma, both in the triggering events within acinar cells and in the subsequent neutrophil recruitment and activation. Finally, the lethality of the choline-deficient/ethionine-supplemented diet-induced pancreatitis was significantly reduced in mice lacking PI3K gamma. Our results thus suggest that inhibition of PI3K gamma may be of therapeutic value in acute pancreatitis.
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PMID:Ablation of phosphoinositide 3-kinase-gamma reduces the severity of acute pancreatitis. 1557 43

Mutations in the human cationic trypsinogen are associated with hereditary pancreatitis. The cDNA coding for human cationic trypsinogen was subcloned into the expression vector pcDNA3. The mutations R122H, N29I, A16V, D22G, and K23R were introduced by site directed mutagenesis. We constructed an expression vector coding for active trypsin by subcloning the cDNA of trypsin lacking the coding region for the trypsin activating peptide behind an appropriate signal peptide. Expression of protein was verified by Western blot and measurement of enzymatic activity. AR4-2J cells were transiently transfected with the different expression vectors and cell viability and intracellular caspase-3 activity were quantified. In contrast to wild-type trypsinogen, expression of active trypsin and mutated trypsinogens reduced cell viability of AR4-2J cells. Expression of trypsin and R122H trypsinogen induced caspase-3 activity. Acinar cells might react to intracellular trypsin activity by triggering apoptosis.
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PMID:Expression of mutated cationic trypsinogen reduces cellular viability in AR4-2J cells. 1603 33

Endoplasmic reticulum (ER) stress mechanisms have been found to play critical roles in a number of diseases states, such as diabetes mellitus and Alzheimer disease, but whether they are involved in acute pancreatitis is unknown. Here we show for the first time that all major ER stress sensing and signaling mechanisms are present in exocrine acini and are activated early in the arginine model of experimental acute pancreatitis. Pancreatitis was induced in rats by intraperitoneal injection of 4.0 g/kg body wt arginine. Pancreatitis severity was assessed by analysis of serum amylase, pancreatic trypsin activity, water content, and histology. ER stress-related molecules PERK, eIF2alpha, ATF6, XBP-1, BiP, CHOP, and caspase-12 were analyzed. Arginine treatment induced rapid and severe pancreatitis, as indicated by increased serum amylase, pancreatic tissue edema, and acinar cell damage within 4 h. Arginine treatment also caused an early activation of ER stress, as indicated by phosphorylation of PERK and its downstream target eIF2alpha, ATF6 translocation into the nucleus (within 1 h), and upregulation of BiP (within 4 h). XBP-1 splicing and CHOP expression were observed within 8 h. After 24 h, increased activation of the ER stress-related proapoptotic molecule caspase-12 was observed along with an increase in caspase-3 activity and TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labeling (TUNEL) staining in exocrine acini. These results indicate that ER stress is an important early acinar cell event that likely contributes to the development of acute pancreatitis in the arginine model.
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PMID:Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis. 1657 87

Acute pancreatitis induces liver injury by upregulating Kupffer cell-derived Fas/FasL; on the other hand, acute pancreatitis induces apoptosis of Kupffer cells via NF-kappaB-dependent pathways. The balance between upregulation of Fas/FasL and Fas/FasL-induced apoptosis of its originator cell may determine the severity of pancreatitis-related liver injury. The aim of our study was to determine the role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis. Acute pancreatitis was induced in NIH Swiss mice by a choline-deficient ethionine-supplement (CDE) diet. In vitro mouse Kupffer cell line was transfected with p65 siRNA and treated with pancreatic elastase to mimic pancreatitis. CDE pancreatitis upregulated nuclear translocation of p65 NF-kappaB/RelA, Fas/FasL, caspase-3, and DNA fragmentation in mice livers (all P < 0.001). In vitro, pancreatic elastase mimicked CDE-pancreatitis by upregulating nuclear translocation of p65 NF-kappaB/RelA, Fas/FasL, caspase-3, DNA fragmentation, and apoptosis in Kupffer cells (all P < 0.001). Transfection with p65 siRNA attenuated the elastase-induced nuclear translocation of p65 NF-kappaB/RelA, upregulation of Fas/FasL, caspase-3, DNA fragmentation, and apoptosis in Kupffer cells (all P < 0.001). Acute pancreatitis activates p65 NF-kappaB/RelA and induces apoptosis of Kupffer cells. Inhibition of p65NF-kappaB/RelA attenuates elastase-induced upregulation of proapoptotic pathways and apoptosis in Kupffer cells. The ability of Kupffer cells to autoregulate their stress response by inducing self-apoptosis warrants further investigation.
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PMID:The role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis. 1676 40

Clusterin is overexpressed in pancreas during the acute phase of pancreatitis. We intended to clarify the role of clusterin expression in stressed exocrine pancreas. We performed in vitro experiments in transfected AR4-2J cells with modified expression levels of clusterin and in vivo studies in clusterin-deficient mice. AR4-2J cells were exposed to agents mimicking cell-stress during pancreatitis (cerulein, hydrogen peroxide, staurosporine or lysophosphatidylcholine). Clusterin-overexpressing AR4-2J cells showed higher viability after cell stress and accordingly reduced rates of apoptosis and lessened caspase-3 activation. Blockage of endogenous clusterin expression reduced viability and enhanced apoptosis. Presence of clusterin reduced NF-kappaB activation and expression of the NF-kappaB target genes TNF-alpha and MOB-1 under cell stress. Clusterin-deficient mice showed a more severe course of acute experimental pancreatitis with enhanced rates of apoptosis and inflammatory cell infiltration. We concluded that clusterin was protective during inflammation of exocrine pancreas because of its anti-apoptotic and anti-inflammatory functions.
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PMID:Clusterin is protective in pancreatitis through anti-apoptotic and anti-inflammatory properties. 1735 35

NADPH oxidase has been considered a major source of reactive oxygen species in phagocytic and non-phagocytic cells. Apoptosis linked to oxidative stress has been implicated in pancreatitis. Recently, we demonstrated that NADPH oxidase subunits Nox1, p27phox, p47phox, and p67phox are constitutively expressed in pancreatic acinar cells, which are activated by cerulein, a cholecystokinin analogue. Cerulein induces an acute and edematous form of pancreatitis. We investigated whether inhibition of NADPH oxidase by diphenyleneiodonium suppresses the production of reactive oxygen species and apoptosis by determining viable cell numbers, DNA fragmentation, TUNEL staining, caspase-3 activity, and the expression of apoptosis-inducing factor in pancreatic acinar AR42J cells stimulated with cerulein. Inhibition on NADPH oxidase by diphenyleneiodonium was assessed by the alterations in NADPH oxidase activity and translocation of the cytosolic subunits p67phox and p47phox to the membrane. Intracellular Ca2+ level was monitored to investigate the relationship between NADPH oxidase and Ca2+ in cells stimulated with cerulein. As a result, cerulein induced the activation of NADPH, increased production of reactive oxygen species, and apoptotic indices determined by the expression of apoptosis-inducing factor, caspase-3 activation, TUNEL staining, DNA fragmentation, and cell viability. Treatment with DPI inhibited cerulein-induced activation of NADPH oxidase, the production of reactive oxygen species, and apoptosis, but not the increase of intracellular Ca2+ levels in pancreatic acinar cells. These results demonstrate that the cerulein-induced increase in intracellular Ca2+ level may be an upstream event of NADPH oxidase activation. Diphenyleneiodonium, an NADPH oxidase inhibitor, inhibits the expression of apoptosis-inducing factor and caspase-3 activation, and thus apoptosis in pancreatic acinar cells.
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PMID:Diphenyleneiodonium suppresses apoptosis in cerulein-stimulated pancreatic acinar cells. 1762 47


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