摘要:

Platelet-activating factor (PAF) may play a critical and primary role in the pathogenesis of acute pancreatitis and pancreatitis-associated distant organ injury. The present study evaluated the effect of a PAF antagonist, lexipafant (an (S)-4-methyl-2 (methyl-imidazo {4,5-c} pyridin-l-ylmethyl)-benzenesulphonyl]-amino} pentanoic acid ethyl ester, BB-882; British Biotech Ltd.), on the potential prevention of gut barrier dysfunction, by measuring gut origin sepsis, bidirectional permeability of the intestinal barrier, and pancreatic capillary endothelial barrier integrity, in acute pancreatitis induced by intraductal infusion of 5% sodium taurodeoxycholate. Pancreatic endothelial permeability significantly increased in animals with acute pancreatitis, whereas pretreatment with lexipafant had a preventive effect (p<0.05 vs. pancreatitis with saline). Similarly, alterations noted in hematocrit and plasma levels of lipase and calcium were counteracted by the PAF antagonist. It also prevented the increase in albumin leakage from blood to the mucosal interstitium and from blood to the intestinal lumen in acute pancreatitis. Albumin passage from the gut lumen to blood in animals with pancreatitis pretreated with saline increased from 3 h and on, and lexipafant prevented alterations in mucosal epithelial permeability. Bacterial translocation was commonly seen in pancreatitis, whereas only a few positive cultures were observed in pancreatitis animals given lexipafant. Microthrombosis in intestinal villi seemed less frequent after lexipafant pretreatment. We conclude that (a) PAF may play a role in the pathogenesis of pancreatitis-associated intestional dysfunction, (b) PAF may be involved in the development of distant organ dysfunction by triggering endothelial barrier dysfunction, and (c) PAF antagonists may provide potential agents for preventing pancreatitis-associated gut barrier dysfunction.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We have reported previously that administration of a sublethal low dose of lipopolysaccharide (LPS; 50 $mUg/kg) prior to the induction of cerulein (Cn) pancreatitis mitigates the pathological course. To clarify the mechanism, we examined apoptosis in the pancreas using the same model. Apoptosis was evaluated by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) and transitional electron microscopy. LPS pretreatment at a dose of 50 $mUg/kg increased remarkably the incidence of acinar cell apoptosis in Cn pancreatitis rats compared with LPS-untreated Cn pancreatitis rats. Apoptosis was observed selectively in acinar cells but was not shown in endocrine cells or ductal epithelial cells. Infiltration of inflammatory cells was scarcely observed. These acinar cells showed the characteristic morphological features of apoptosis by electron microscopy. Administration of LPS at a dose of 50 $mUg/kg alone caused acinar cell apoptosis but the incidence was much lower than that in the LPS-pretreated Cn pancreatitis rats. The TUNEL labeling was significantly increased depending on the dose of LPS and on the interval between the administration of LPS and that of Cn. These results suggest that the pathological features of acute pancreatitis might be modified by the presence of nonfatal endotoxemia through the induction of acinar cell apoptosis.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Release of GP2, a glycosyl phosphatidylinositollinked protein on the apical plasma membrane of the pancreatic acinar cell, is associated with activation of endocytosis. Released GP2 is also an integral component of intraductal plugs in patients with alcohol-induced chronic pancreatitis. Our purpose was to determine the effect of ethanol on exocytosis and endocytosis and its association with release of membrane-bound GP2. Rats were fed Lieber-DeCarli diets with and without ethanol for 2 weeks. Endocytosis was then assessed in acini by measuring horseradish peroxidase (HRP) uptake, GP2 release by Western blotting, and exocytosis by measuring amylase release. In ethanol-fed rats, HRP uptake was inhibited by 90% compared to that in control rats. In contrast, no significant difference in cholecystokinin-stimulated amylase secretion was found. In vitro, ethanol inhibited HRP uptake in a dosedependent manner, with 50% inhibition at 50 mM ethanol. Despite the inhibition of endocytosis, GP2 release increased linearly over 60 min and was significantly higher from acini incubated with ethanol compared to controls. These data indicate that ethanol selectively inhibits endocytosis in pancreatic acinar cells. The release of GP2 into the pancreatic duct was no longer coupled to endocytosis in animals fed ethanol.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Early assessment of severity in acute pancreatitis (AP) has a major impact on further treatment. Previous studies have shown that human pancreas-specific protein (hPASP)/procarboxypeptidase B (PCPB) is a new diagnostic and prognostic marker in AP. In the present study we focused on the prognostic properties of this parameter and analyzed the clinical value of hPASP in discriminating edematous from necrotizing AP. The results were compared to those for C-reactive protein (CRP) and lactate dehydrogenase (LDH). A total of 70 patients was enrolled in this prospective study. Based on contrast-enhanced computed tomography or intraoperative results, 39 patients (27 male, 12 female; median age, 42 years; median Ranson score, 6) suffered from necrotizing pancreatitis (NP) and 31 patients (12 male, 19 female; median age, 57; median Ranson score, 1.5) from acute interstitial-edematous pancreatitis (AIP). Serum concentrations of hPASPPCPB, CRP, and LDH were measured at 24-h intervals over 14 days after admission by a radioimmunoassay (upper normal value, 60 ng/ml), a lasernephelometric assay (upper normal value, 4 mg/L), and an enzymekinetic method (upper normal value, 240 UL), respectively. During the overall observation period concentrations of hPASP/PCPB, CRP, and LDH were significantly higher in patients with NP compared to those with AIP. Based on receiver operating characteristics, the best cutoff levels for predicting NP were >200 ng/ml for hPASP/PCPB, >140 mg/L for CRP, and >290 U/L for LDH. Discrimination between AIP and NP was best on day 3 for both hPASP/PCPB (sensitivity, 91%; specificity, 64%; accuracy, 79%) and CRP (sensitivity, 83%; specificity, 84%; accuracy, 83%) and on day 5 of AP for LDH (sensitivity, 88%; specificity, 100%; accuracy, 91%). The overall accuracy in differentiating AIP from NP within the first 4 days after onset of symptoms was 74% for hPASP/PCPB, 75% for CRP, and 76% for LDH. None of the parameters correlated with the extent of necrosis or the etiology of AP. hPASP/PCPB provides good discrimination between AIP and NP at an early stage of the disease, with results comparable to those for CRP and LDH. Although hPASP/PCPB is both disease specific and predictive for necrosis, the clinical use of this test in its present form is limited due to drawbacks in terms of test performance and cost factors.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

To elucidate the role of thromboxane A2(TxA2) and prostaglandin I2(PGI2) in acute necrotizing pancreatitis (ANP) in rats and to determine the effect of the TxA2synthesis inhibitor OKY-046 and the PGI, analogue OP-2507, the levels of two prostanoids (TxB2, 6-keto PGF1$aL) and two types of phospholipase A2(PLA2) activity (cytosolic and secretory) were measured in plasma and three tissues (pancreas, lung, and kidney) after injection of a mixed solution of 5% sodium taurocholate and 0.1% trypsin into the pancreatic duct to induce ANP. The survival rate 24 h after inducing ANP was 33.3% in the nontreated group, versus 83.3 and 58.3% in the groups treated with OKY-046 and OP-2507, respectively. Only the group treated with OKY-046 showed significant improvement compared with the nontreated group. The plasma, pancreatic, and pulmonary TxB2levels decreased significantly in the group treated with OKY-046, and the histopathological changes were not as severe. The levels of pancreatic and pulmonary cytosolic PLA, activities decreased, and plasma and pancreatic secretory PLA, activities also decreased. In conclusion, the levels of both types of PLA, activity and TxA2production decreased, and the survival rate improved as a result in the group treated with OKY-046, but OP-2507 had no effect on ANP. TxA2and two types of PLA2activity play an important role in the process of aggravation of acute pancreatitis.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Parenchymal perfusion of the normal human pancreas using dynamic computed tomography (CT) was evaluated and correlated with patient demographic characteristics. The results of 23 patients (10 men and 13 women; age range, 25-71 years) who underwent enhanced CT of the upper abdomen and perfusion measurement were retrospectively reviewed. They had no evidence of pancreatic disease or diffuse liver disease, clinically or radiographically. Regions of interest were drawn in the pancreatic body and within the aorta. Pancreatic parenchymal perfusion per volume was then calculated by dividing the peak gradient of the pancreatic time-attenuation curve by the peak aortic CT number in increase. Perfusion in these patients ranged from 0.554 to 1.698 ml min−1ml−1(mean ± SD, 0.963 ± 0.064) and showed a negative correlation with the patient's age (r= 0.699,p<0.0005). Pancreatic parenchymal density before contrast material injection (mean ± SD, 48.86 ± 0.978) was not correlated with perfusion measured by dynamic CT or age. No differences were observed in perfusion or density between men and women. In conclusion, parenchymal perfusion of the normal human pancreas measured by dynamic CT appears to decline with age.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The aim of this study was to test the hypothesis that apoptosis can protect against experimental pancreatitis and induction of apoptosis by an extract of Artemisia asiatica (DA-9601) is beneficial in cerulein-induced pancreatis in rats. Pancreatitis was induced in 6-week-old male SPF Sprague-Dawley rats by two intravenous (iv) administrations of 40 $mUg/kg cerulein. To investigate the effects of DA-9601 on the seventy of pancreatitis and extent of apoptosis, rats were treated with intragastric DA-9601, 30 mg/kg (D30), 100 mg/kg (D100), or 300 mg/kg (D300), intraperitoneal superoxide dismutase, 10,000 $mU/kg (SOD), and iv gabexate mesilate, 40 mg/kg (Foy), three times (30 min before cerulein injection, 30 and 90 min after cerulein injection). The control group was administered vehicle alone. Ten rats were included in each treatment group and control group. Rats were sacrificed 5 h after cerulein treatment. Serum amylase, histological activity index (HAI), pancreatic lipid peroxide levels, and apoptotic index [in situ hybridization by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL)] were determined. Gel electrophoresis was performed for the presence of DNA fragmentations. The results were as follows. Serum amylase was significantly increased in all cerulein-treated groups compared to normal controlsp<0.001). The HA1 was significantly decreased in only the D300 group compared to the controlsp<0.05). The apoptotic index of the cerulein-alone group was 3.8 ± 2.7, but the mean apoptotic indexes of the SOD and Foy groups were 16.4 ± 4.6 and 13.3 ± 1.8, respectively, a significant increase (p<0.01). The apoptotic index was more significantly increased in the DA-9601-treated groups, dose dependently (8.4 ± 3.4 in D30, 14.8 ± 4.3 in D100, 24.2 ± 4.7 in D300). A smearing pattern of DNA electrophoresis was noted in the DA-9601-treated groups. In conclusion, DA-9601, an extract of Artemisia, induced apoptosis of pancreatic acinar cells dose dependently and concomitantly attenuated the severity of pancreatitis.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Cyclin D1 is an important regulator of the G, phase of the cell cycle. In this study we examined the expression and localization of cyclin D1 in chronic pancreatitis (CP), a condition associated with fibrosis, acinar cell degeneration, and foci of duct cell proliferation. Northern blotting of total RNA from the normal pancreas and from the pancreas of patients with CP revealed the presence of a 4.4-kb cyclin D1 mRNA transcript in all samples. Densitometric analysis indicated that pancreatic cyclin D1 mRNA levels were 2.0-fold increased in CP compared to normal controls (p= 0.0046). In the normal pancreas, faint cyclin D1 immunoreactivity was present in the nuclei and cytoplasm of some ductal cells and islet cells. In contrast, in CP, moderate to strong cyclin D1 immunoreactivity was present in many ductal and islet cells, as well as in some acinar cells and fibroblasts. These findings raise the possibility that enhanced cyclin D1 expression may contribute to a hyperproliferative state in CP.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The role of oxidative stress as an important pathogenetic factor in experimental AP is commonly accepted, but its role in human AP has still not been evaluated satisfactorily. In the present study we compared the parameters of oxidative stress to the level of PLA2and PMN-E in patients with AP. The study was performed in 77 patients with mild (n = 31), moderate (n = 20), and severe (n = 26) AP (alcoholic and biliary) as assessed according to Ranson's and Balthazar's criteria. Serum and urine malondialdehyde (MDA) concentrations, as an index of oxidant-mediated lipid peroxidation, and sulfhydryl (SH) groups, a major nonenzymatic antioxidant, were measured along with serum PLA2and plasma PMN-E at admission (day 0) and on days 2, 5, and 10 of the disease. The Serum MDA level in severe AP was elevated by 267% on day 0 and 230% after 10 days, in comparison to the control, by 104 and 105% in comparison to mild AP, and by 50 and 76% in comparison to moderate AP, respectively. This was accompanied by a decrease in serum SH groups by 23% on day 0 and 36% after 10 days, in comparison to the control, by 31 and 32% in comparison to mild AP, and by 20 and 11% (ns) in comparison to moderate AP, respectively. In all severity forms of AP, oxidative stress was proportionally accompanied by increased levels of PLA2and plasma PMN-E. In conclusion, oxidative stress is an early phenomenon in patients with AP, and at the time of admission it is detectable in the serum and urine. The intensity of oxidative stress correlates with the severity of AP. Because of the significant correlation between MDA and PLA2or PMNE, we suppose that the parameters of oxidative stress may be useful as another early prognostic factor in human AP.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The fibroblast growth factor (FGF) family is a group of homologous heparin-binding polypeptides that has been implicated in a variety of human neoplasms and presently includes 14 members. FGF signaling is mediated by a dual-receptor system, consisting of four high-affinity tyrosine kinase receptors, termed fibroblast growth factor receptors (FGFRs), and of low-affinity heparan sulfate proteoglycan receptors that enhance ligand presentation to the FGFRs. Several FGFs, including FGF‐1, ‐2, ‐3, ‐4, ‐5, ‐6, and ‐7, and several FGFR variants, among them the 2 immunoglobulin-like form and the IIIc splice variant of FGFR‐1 and the keratinocyte growth factor receptor, a splice variant of FGFR‐2, are expressed in human pancreatic cancer cell lines and are overexpressed in human pancreatic cancers or in the pancreas of chronic pancreatitis and, therefore, may play important roles in the pathobiology of these pancreatic diseases. This review summarizes the current information on the involvement of the FGF family and their receptors in human pancreatic cancer and chronic pancreatitis.

ISSN:0885-3177    

出版商:OVID    

年代:1998

数据来源: OVID