Coordinate regulation of secretory stress proteins (PSP/reg,PAP I,PAP II,and PAP III) in the rat exocrine pancreas during experimental acute pancreatitis

BACKGROUND: Pancreatic stone protein (PSP/reg) is a constitutively secreted protein in pancreatic juice. Pancreatitis-associated protein (PAP) belongs to the same family of proteins. PAP is highly increased during acute pancreatitis, while no exact data exist regarding PSP/reg protein synthesis and secretion. Recently, an attempt to determine PSP/reg and PAP levels in sera of rats with acute pancreatitis showed a significant increase in PAP but failed to demonstrate changes in PSP/reg. Others reported that surgical manipulation of the pancreas, including sham controls, affected mRNA levels of PSP/reg. Neither report determined protein levels of PSP/reg. METHODS: Rats were treated intraperitoneally with a supramaximal dose of caerulein to induce pancreatitis, a physiological dose of caerulein, or a saline injection. Pancreata were analyzed for PAP and PSP/reg using ELISAs. RNA was extracted for Northern blot analysis of PAP I, II, and III and PSP/reg mRNA. RESULTS: Experimental induction of acute pancreatitis caused a coordinate increase in both PSP/reg and PAP. PAP showed an acute response and returned to low levels within 48 h while PSP/reg exhibited a more sustained response. Intraperitoneal application of a physiological dose of caerulein and even a saline injection caused an increase in PSP/reg. CONCLUSION: PSP/reg and PAP levels are increased through similar mechanisms by physiological and supramaximal doses of caerulein. However, PSP/reg regulation appears to sustain high levels while PAP levels are more transient. Since the regulation of this protein family is affected even under mild stress, we define them as secretory stress proteins.     

Coordinate regulation of PSP/reg and PAP isoforms as a family of secretory stress proteins in an animal model of chronic pancreatitis

BACKGROUND: PSP/reg and PAP are secretory stress proteins (SSP) and may be part of a protective mechanism. They share structural homologies and form insoluble fibrils after tryptic activation. To further explore the regulation of these proteins, we investigated the male WBN/Kob rat, a model of pancreatic inflammatory and fibrotic disease similar to chronic pancreatitis. MATERIALS AND METHODS: Expression of PSP/reg and PAP I, II and III in the WBN/Kob rat pancreas was evaluated on the mRNA and protein level, by immunohistochemistry and by highly sensitive isoform specific ELISAs. RESULTS: The SSPs are constitutively secreted, PAP in nanomolar, PSP/reg in micromolar concentrations. Before conventional morphological changes are detectable in the WBN/Kob rat, focally increased expression of secretory stress protein is visible. SSP levels in pancreatic juice of WBN/Kob rats reach peak values 10- to 50-fold higher than in Wistar control rats. The highest expression was localized to acini with inflammatory infiltration. CONCLUSIONS: There is a tight spatial and temporal association between pre-inflammatory changes or inflammation and SSP-expression. These results support our concept that PSP/reg and PAP are coordinately regulated SSP.     

Exocrine meets endocrine: pancreatic stone protein and regenerating protein--two sides of the same coin

BACKGROUND: Regenerating protein (reg) and pancreatic stone protein (PSP) have been discovered independently in the fields of diabetes and pancreatitis. MATERIALS AND METHODS: These proteins are identical; however, because of the gap between the endocrine and exocrine field, there was never a consensus and the nomenclature has not been rectified. Since the time of the initial discovery, more isoforms have been unified. Historically, PSP was discovered long before reg, yet, in many areas outside of the pancreatitis research field, reg is being used. RESULTS: For PSP/reg, a role in proliferation and regeneration of islet cells has been postulated. A hitherto insufficiently understood phenomenon is the massive up-regulation of PSP/reg in pancreatic tissue and juice under conditions of stress. Similarly, PAP (pancreatitis-associated protein)/reg III has been attributed various functional roles. Structurally, the ability to form fibrils after tryptic cleavage is a striking common features of both proteins. However, this biochemical transformation is in itself not enough to gain functional insight. Thus, physiological and genetic approaches are required to further characterize the role of these proteins in the pancreas. Recently, more evidence has been presented in support of the theory that PSP/reg plays a key role in islet neogenesis/regeneration. CONCLUSIONS: In this review we discuss the debate on the localization and functional roles of PSP/reg and PAP/regIII. Therefore, we have summarized hypotheses and experimental results supporting such hypotheses.     

Pancreatic reg gene expression is inhibited during cellular differentiation.

BACKGROUND AND OBJECTIVE: Factors that control pancreatic regenerating (reg I) gene expression are unknown, but it is believed that its expression may correspond with cellular differentiation. The authors recently demonstrated that reg I is expressed in AR42J, a rat acinar cell line whose state of differentiation can be modulated by dexamethasone. They used this line to study reg I expression during cellular proliferation and differentiation. METHODS: After treatment of cells with 10 nmol/L dexamethasone, proliferation was assayed by thymidine incorporation; differentiation by expression of elastase I mRNA. Reg I mRNA levels were measured using a rat reg I cDNA probe, and reg I protein levels assayed by enzyme-linked immunosorbent assay of cellular lysates with a polyclonal antibody. The effect of gastrin, cholecystokinin and glucagon on reg I expression was also studied. RESULTS: When compared with controls, treatment with dexamethasone caused thymidine incorporation to decrease and elastase mRNA levels to increase. Reg I mRNA decreased from controls of 100 +/- 16% to 40 +/- 18% (p < 0.05), and reg I protein levels decreased as well. Gastrointestinal hormones had no significant effect on either elastase or reg I gene expression. CONCLUSIONS: Expression of reg I inversely correlates with the level of cellular differentiation, can be modulated via the glucocorticoid receptor, and is a potential marker of gastrointestinal epithelial differentiation. Despite its presence within a pancreatic acinar cell line, reg I gene expression is not modulated by gastrointestinal hormones.     

Effect of SMS201-995 (a long-acting somatostatin analog) on bile-induced acute hemorrhagic pancreatitis in the dog

Recent reports claim a beneficial role for SMS201-995 (SMS) in pancreatitis. To study the effects of SMS in a canine pancreatitis model, four groups of eight dogs each were subjected to laparotomy; and after cannulation of the dorsal pancreatic duct, a mixture of bile and trypsin was infused to induce pancreatitis. Group I constituted the control group and received no SMS. Group II received SMS intravenously at 5 micrograms/hr beginning 1 hour before the induction of pancreatitis. Group III and Group IV received SMS at the same dose starting at 2 hours and 6 hours, respectively, after the induction of pancreatitis. Infusions were maintained until 24 hours after the induction of pancreatitis. Leukocyte counts, serum lipase and amylase levels were obtained preoperatively and at 24 hours. All dogs were killed at 24 hours and autopsies performed. At autopsy, severity of pancreatitis was graded, based on survival, the presence or absence of pancreatic edema, hemorrhage, and necrosis, as well as the presence and severity of bloody ascites. Only on a dog (Group III) died before the 24-hour period. When SMS was used before the induction of pancreatitis, the pancreatitis seen was less severe (Group I vs Group II, P = .022). No effects were found when using SMS after the induction of pancreatitis (Group III or Group IV vs Group I). The serum lipase, amylase, and leukocyte counts changed significantly in all the dogs (P less than .001) with the onset of pancreatitis, but this difference was not significant between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enterokinase induces severe necrosis and rapid mortality in cerulein pancreatitis: characterization of a novel noninvasive rat model of necro-hemorrhagic pancreatitis

BACKGROUND: Unlike edematous pancreatitis, induction of severe necrotizing pancreatitis in rats generally requires an invasive laparotomy with infusion and/or ligation of the pancreatic duct or duodenal or arterial occlusion. The aim of this study was to establish and characterize a noninvasive model of severe acute pancreatitis in rats. METHODS: Wistar rats were infused intravenously with cerulein or a combination of cerulein and enterokinase. Saline (154-mmol/L NaCl) or enterokinase only was infused in controls. In a first set of experiments, intrapancreatic protease activation and the release of cytokines were correlated with the severity of organ injury. Pancreatic and pulmonary injuries were determined at 6 h. In a second set of experiments, we assessed 24-h survival, serum parameters possibly reflecting the course of the disease, and morphologic changes later in the course of the disease. RESULTS: The severity of pancreatic injury and survival were correlated strongly with the amount of enterokinase infused simultaneously with cerulein. Trypsin as well as elastase and cathepsin B activity in pancreatic tissue samples were increased markedly in these animals. Marked pancreatic hemorrhage, necrosis, and leukocyte infiltration were present in animals with the greatest amounts of enterokinase infused. IL-6 and LDH, but not IL-1beta, CRP, and amylase, in serum correlated with the severity of pancreatitis. CONCLUSIONS: This noninvasive rat model of acute pancreatitis is characterized by major pancreatic necrosis, hemorrhage, and fatality. The simple and noninvasive induction technique may have advantages for future studies on inflammatory changes and sepsis in necrotizing pancreatitis compared with other currently available invasive models.     

Effects of heparin in experimental models of acute pancreatitis and post-ERCP pancreatitis

BACKGROUND: Acute pancreatitis (AP) is a complication of diagnostic or therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In a recent clinical trial, a decreased rate of post-ERCP pancreatitis was shown after prophylactic heparin treatment. The aim of this study was to evaluate the effects of prophylactic heparin application in various experimental models of AP and pancreatic duct obstruction and to assess the underlying mechanisms. METHODS: In various experimental models, pancreatic injury of graded severity was induced in Wistar rats: (1) mild pancreatitis by IV cerulein infusion over 6 hours; (2) severe pancreatitis by infusion of glycodeoxycholic acid into the pancreatic duct plus IV cerulein application over 6 hours. The clinical ERCP situation was imitated in groups (3) obstruction of the pancreatic duct and (4) infusion of contrast medium into the pancreatic duct plus obstruction. In every group the animals received either no heparin (n=six per group) or continuous IV heparin (n=six per group) starting before pancreatic injury. Histologic changes, amylase, and lipase in plasma were evaluated 12 hours after induction of pancreatic injury. Additional animals were treated to investigate pancreatic microcirculation by intravital microscopy (n=six per group). RESULTS: In groups 1, 3, and 4 (mild AP/duct obstruction/duct obstruction plus contrast medium), IV heparin-treated animals showed reduced edema, inflammation, and peak amylase values compared with the corresponding non-heparin-treated animals (P<.05). Moreover, mean erythrocyte velocity was significantly higher and leukocyte-endothelium interaction was reduced in these groups after prophylactic administration of heparin. In contrast, group 2 (severe AP) did not show any difference between control animals and animals that received heparin as assessed by histology and intravital microscopy. CONCLUSIONS: Prophylactic systemic application of heparin provides a protective effect in mild AP and in experimental post-ERCP pancreatitis. The mechanism of the protective effects of heparin seems to be the reduction of leukocyte-endothelium interaction and the normalization of pancreatic microcirculation.     

The clinical and histopathological effects of pancreatic duct occlusion in experimental acute pancreatitis in dogs

A continuous production of significant pancreatic enzymes, which are thought to be responsible for the maintenance of the digesting process, is frequently found in fulminant necrotizing pancreatitis. Since the medical therapies known to be effective are based upon the rationale of slowing pancreatic secretion, a simple measure which permits the "burning out" of residual pancreatic tissue might therefore have a therapeutic value. In this study, 2 hr after the induction of acute hemorrhagic pancreatitis, 5 dogs (Group I) were treated with 1.5 ml Ethibloc injected into the pancreatic duct; 5 other animals (Group II) were given 1.5 ml saline; Group III (5 dogs) had no treatment. All animals in Group II and 4 of the 5 animals in Group III expired within 8 days postoperatively. In contrast, 4 of 5 animals from Group I survived. Although some of the biochemical parameters showed significant changes after the induction of acute pancreatitis, no differences were seen between the three groups. In the expired animals, the picture of histological examination was that of a fulminant acute hemorrhagic pancreatitis of the left lobe. In the survival dogs although normal pancreatic tissue was present in the right lobe at necropsy at intervals, there was always a pancreatic atrophy of the left lobe and striking adhesions with the surrounding tissues suggesting the severity of the disease in the acute phase. These findings suggest that pancreatic duct occlusion causing the exocrine secretion to stop may have beneficial effects in the treatment of acute fulminant pancreatitis in the acute phase and may improve the survival rate.     

Decreased mortality of severe acute pancreatitis after proximal cytokine blockade.

OBJECTIVE: This study determined the ability of interleukin-1 receptor antagonist (IL-1ra) to decrease the mortality of experimental acute pancreatitis. The response of the inflammatory cytokine cascade and its subsequent effects on pancreatic morphology were measured to determine the role of these peptides in mediating pancreatic injury. SUMMARY BACKGROUND DATA: Previous studies have shown that proinflammatory cytokines are produced in large amounts during acute pancreatitis and that blockade at the level of the IL-1 receptor significantly decreases intrinsic pancreatic damage. The subsequent effect on survival is not known. METHODS: A lethal form of acute hemorrhagic necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented (CDE) diet for 72 hours. For determination of mortality, the animals were divided into 3 groups of 45 animals each: control subjects received 100/microL normal saline intraperitoneally every 6 hours for 5 days; IL-1ra early mice received recombinant interleukin-1 receptor antagonist 15 mg/kg intraperitoneally every 6 hours for 5 days beginning at time 0; IL-1ra late mice received IL-1ra 15 mg/kg intraperitoneally every 6 hours for 3.5 days beginning 1.5 days after introduction of the CDE diet. A parallel experiment was conducted simultaneously with a minimum of 29 animals per group, which were sacrificed daily for comparisons of serum amylase, lipase, IL-1, IL-6, tumor necrosis factor-alpha, IL-1ra, pancreatic wet weight, and blind histopathologic grading. RESULTS: The 10-day mortality in the untreated control group was 73%. Early and late IL-1ra administration resulted in decreases of mortality to 44% and 51%, respectively (both p < 0.001). Interleukin-1 antagonism also was associated with a significant attenuation in the rise in pancreatic wet weight and serum amylase and lipase in both early and late IL-1ra groups (all p < 0.05). All control animals developed a rapid elevation of the inflammatory cytokines, with maximal levels reached on day 3. The IL-1ra-treated animals, however, demonstrated a blunted rise of these mediators (all p < 0.05). Blind histologic grading revealed an overall decrease in the severity of pancreatitis in those animals receiving the antagonist. CONCLUSIONS: Early or late blockade of the cytokine cascade at the level of the IL-1 receptor significantly decreases the mortality of severe acute pancreatitis. The mechanism by which this is accomplished appears to include attenuation of systemic inflammatory cytokines and decreased pancreatic destruction.     

Effects of timing of diatrizoate (water-soluble contrast medium) administration on pancreatic microcirculatory derangement in cerulein pancreatitis in rats

OBJECTIVE: We investigated whether the timing of administration of contrast medium after onset of acute pancreatitis is critical in determining the magnitude of microcirculatory derangement. METHODS: An acute pancreatitis model in male Sprague-Dawley rats (225-275 g) was established by continuous infusion of cerulein (15 mg/kg per hour). The mean arterial pressure was monitored continuously by means of a femoral artery catheter. Diatrizoate (Hypaque-76), a water-soluble contrast medium, was delivered through a femoral vein catheter at doses corresponding to those given to humans, either 1, 2, or 3 hours after pancreatitis induction. In vivo microscopy and laser-Doppler flowmetry were used to investigate microcirculatory derangement. The water contents of the pancreas and lung, the malondialdehyde levels of the pancreas, and the trypsinogen activation peptide levels in the serum were measured at the end of the experiment (8 hours after infusion of cerulein). RESULTS: Early administration of contrast medium (1 hour after pancreatitis induction) resulted in significantly greater changes in microcirculation and mean arterial pressure than did late administration (2 or 3 hours after pancreatitis induction). Rats given contrast medium 1 hour after induction also had highest pancreas and lung water contents, the highest pancreas malondialdehyde levels, and the highest serum trypsinogen activation peptide levels. CONCLUSION: These results show that a water soluble contrast medium that is often used for computed tomographic imaging of the pancreas can adversely affect the pancreatic microcirculatory parameters, such as tissue perfusion and leukocyte sticking, and hemodynamics in a cerulein-induced model of acute pancreatitis. Early administration seems to cause more severe derangement of the pancreatic microcirculation.     

Effects of caffeic acid phenethyl ester on pancreatitis in rats

BACKGROUND: This study investigated the effect of caffeic acid phenethyl ester (CAPE) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. CAPE, an active component of honeybee propolis, has previously been determined to have antioxidant, anti-inflammatory, antiviral, and anticancer activities. MATERIALS AND METHODS: Forty-eight rats were divided into four groups of 12. Group 1 animals received intraductal saline and intravenous saline infusion treatment. Group 2 was given intraductal saline and intraperitoneal CAPE infusion treatment. ANP was induced in the animals in group 3 (ANP with saline infusion), and group 4 had induced ANP plus CAPE infusion treatment (ANP with CAPE infusion). Sampling was performed 48 h after treatment. RESULTS: ANP induction significantly increased mortality rate, pancreatic necrosis, and bacterial infection in pancreatic and extrapancreatic organs. ANP also increased levels of amylase and alanine aminotransferase (ALT) in serum, increased levels of urea and lactate dehydrogenase in bronchoalveolar lavage fluid (BAL LDH), increased the activities of myeloperoxidase (MPO) and malondialdehyde (MDA) in pancreas and lung tissue, and decreased the serum calcium levels. The use of CAPE did not significantly reduce the mortality rate but significantly reduced the ALT and BAL LDH levels, the activities of MPO and MDA in the pancreas, the activity of MDA in the lungs, and pancreatic damage. The administration of CAPE did not reduce the bacterial infection. CONCLUSIONS: These results indicate that CAPE had beneficial effects on the course of ANP in rats and suggest that CAPE shows promise as a treatment for ANP.     

Comparison of prostate secretory protein with prostate specific antigen and prostatic acid phosphatase as a serum biomarker for diagnosis and monitoring patients with prostate carcinoma

Serum prostate secretory protein (PSP) levels were measured in 49 patients with benign prostatic hyperplasia (BPH), 144 patients with various stages of prostatic carcinoma (CaP), and 82 CaP patients who were followed serially. PSP values were compared with serum levels of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). In the BPH group, PSP was elevated (> 10 ng/ml) in 41% of patients, whereas PSA (> 4 ng/ml) and PAP (> 3.3 ng/ml) were elevated in 39% and 23% of the cases, respectively. PSP levels were elevated in 48% of the CaP pretreatment specimens, compared to 79% for PSA and 40% for PAP. PSP levels in cancer patients who had intracapsular disease were about two to three times higher than those observed for PAP. PSP was found to be the only marker elevated in eight (6%) pretreatment CaP patient serum specimens, while PAP was never found to be elevated when PSA was normal. PSP serum concentrations correlated with the clinical course of the disease in 79% of patients, compared with 90% for PSA and 66% for PAP. In certain patients, monitored over time, disease correlation was reflected in serum values with only a single biomarker, i.e., 1% with PAP, 8% with PSP, and 10% with PSA. This study has shown that PSP is a less sensitive serum biomarker than PSA, but more sensitive than PAP for detection and monitoring the early stages of prostate cancer. This suggests that PSP as a biomarker may be a useful adjunct for the management of a subpopulation of low-stage and -grade CaP. © 1993 Wilcy-Liss, Inc.     

Effects of protease inhibitors on coagulation abnormalities in acute canine pancreatitis

Coagulation abnormalities associated with severe pancreatitis were studied in 24 dogs. Group I consists of six control subjects who had duodenotomy alone. Group II consists of six dogs with pancreatitis induced by bile injection ( lcm3 /kg) into the pancreatic duct. The six dogs in Group III and the six in Group IV were given aprotinin (trasylol) 1.0 mg/kg and S-2441 (10mg/kg), a new synthetic protease inhibitor, respectively. These were given over 10 minutes by intravenous infusion, 20 minutes after bile induced pancreatitis. Blood was drawn for amylase, prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, and platelets, in addition to markers for hypercoagulation, fibrinopeptide A, antithrombin III, and markers for fibrinolysis, B beta 15-42 immunoreactive peptides and alpha 2 antiplasmin at baseline, 30 minutes, 1 hour, 3 hours, 6 hours, and daily for 3 days after injection of bile or duodenotomy. There was no significant difference in PT, platelets, antithrombin III, and fibrinopeptide A among the four groups. Fibrinogen levels and PTT were minimally elevated in animals with bile induced pancreatitis, but these changes reached significance only at 24 hours and 48 hours, respectively (P less than 0.05). Immunoreactive B beta 15-42 became elevated at 30 minutes indicating fibrinolysis in animals with pancreatitis, and these changes were significant compared with Group I control subjects (P less than 0.05) throughout the study. Levels of alpha 2 antiplasmin were decreased in Group II animals with pancreatitis, which also suggests fibrinolysis. Amylase was elevated in Group II animals with pancreatitis (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes of acinar cells in the pancreato-biliary duct ligation with exocrine pancreatic stimulation model in rats; protective effects of a new potent protease inhibitor, ONO3307]

To evaluate the changes of pancreatic acinar cells in the pancreatic duct obstructed animals as well as the protective effects of a new potent protease inhibitor, ONO3307, we measured the serum amylase levels, pancreatic water content, histological changes, lysosomal fragility in in-vitro incubation, cathepsin B distribution in acinar cells, and cathepsin B and amylase output into pancreatic juice after short-termed (3 hrs) pancreatic duct obstruction with caerulein (0.2 micrograms/kg.hr) infusion in rats. Serum amylase levels, pancreatic water content, and lysosomal fragility in duct obstructed with caerulein infused animals were significantly increased compared with the control groups, and remarkable shift of cathepsin B from lysosomal fraction to zymogen fraction was observed in this group. These changes tended to continue 24 hours after removal of duct obstruction. But with infusion of ONO3307, these changes observed in duct-obstructed with caerulein infusion groups were significantly, almost completely attenuated. These results indicate the intimate relationship between the pathogenesis of acute pancreatitis and lysosomes and some known proteases which are inhibited by ONO 3307 and suggest the usefulness of such a kind of protease inhibitor in the treatment of acute pancreatitis.     

Erythropoietin: a possible cytoprotective cytokine in acute necrotizing pancreatitis

Background/purpose  Despite decades of research and clinical trials, a specific therapeutic treatment for acute pancreatitis (AP) has yet to be developed. The aim of the present study was to investigate the effects of erythropoietin on the severity of taurocolic acid-induced acute necrotizing pancreatitis. Methods  Forty-seven male Wistar albino rats were randomized into seven experimental groups. In group I, animals were sham-operated (n = 5). In groups II, III, IV, IIepo, IIIepo, and IVepo, AP was induced by sodium taurodeoxycholate treatment (n = 7). In groups II, III, and IV, 1 ml normal saline and in groups IIepo, IIIepo, and IVepo, 1000 U/kg body weight erythropoietin (EPO) was administered intramuscularly immediately after the induction of AP. Animals were killed at 24, 48, and 72 h postoperatively. Histopathological and biochemical evaluations were performed. Results  The serum levels of interleukin-6 (IL-6) and tissue levels of malondialdehyde were found to be significantly lower in EPO-administered groups when compared with the levels in groups without EPO treatment. The severity of pancreatic edema, acinar necrosis, inflammation, and perivascular infiltrate were reduced in all the EPO groups compared with the no-treatment groups. Conclusions  Our findings may reflect the possible cytoprotective effect of EPO in acute necrotizing pancreatitis.     

促发水肿型胰腺炎向坏死型胰腺炎转变的机理研究

目的:借助于一种新的大鼠模型,研究急性水肿性胰腺炎(AEP)向出血坏死性胰腺炎(AHNP)转变的机理.方法:Sprague-Dawley大鼠52只,随机分为三组:Ⅰ组,假手术组;Ⅱ组,采用胰管结扎及静脉推注蛙皮素(100μg/kg)、促胰液素(10μg/kg)以诱发AEP;Ⅲ组,在AEP模型的基础上静注10%高分子右旋糖酐(分子量110000)500mg/kg诱发AHNP.各组分别于造模型后3、gh行组织学及电镜等检查.结果:AEP和AHNP组大鼠血清淀粉酶浓度均明显增高;AHNP组胰腺细胞质膜Ca~(2 )-ATPase活性明显降低.AHNP组3h及9h时腹水量明显多于AEP组,胰实质出血或/和坏死明显,并有胰腺组织细胞内钙沉积、小静脉扩张、红细胞沉积、粒细胞聚集等现象.电镜观察显示:AEP组有大小不等的酶原颗粒聚集于细胞内.AHNP组见毛细血管内皮细胞坏死、剥脱,基膜不完整.结论:静注大剂量Dextran-110在AEP模型基础上通过引起胰微血管损害而促发AHNP.     

Active interleukin-1 receptor required for maximal progression of acute pancreatitis.

OBJECTIVE: The authors' aim was to determine the requirement for an active interleukin (IL)-1 receptor during the development and progression of acute pancreatitis. SUMMARY OF BACKGROUND DATA: Interleukin-1 is a pro- inflammatory cytokine that has been shown to be produced during acute pancreatitis. Earlier animal studies of moderate and severe pancreatitis have shown that blockade of this powerful mediator is associated with attenuated pancreatic destruction and dramatic increases in survival. The exact role played by IL-1 and the requirement for activation of its receptor in the initiation and progression of pancreatitis is unknown. METHODS: Conventional and IL-1 receptor ¿knockout¿ animals were used in parallel experiments of acute pancreatitis induced by intraperitoneal injection of cerulean (50 microg/kg every 1 hour X 4). The conventional mouse strain had the IL-1 receptor blocked prophylactically by means of a recombinant IL-1 receptor antagonist (10 mg/kg injected intraperitoneally every 2 hours). The second mouse strain was genetically engineered by means of gene targeting in murine embryonic stem cells to be devoid of type 1 IL-1 receptor (IL-1 receptor knockout). Animals were killed at 0, 0.5, 1, 2, 4, and 8 hours, with the severity of pancreatitis determined by serum amylase, lipase, and IL-6 levels and blind histologic grading. Strain-specific controls were used for comparison. RESULTS: The genetic absence of the IL-1 receptor or its pharmacologic blockade resulted in significantly attenuated pancreatic vacuolization, edema, necrosis, inflammation, and enzyme release. Serum IL-6, a marker of inflammation severity, was dramatically decreased in both groups. CONCLUSIONS: Activation of the IL-1 receptor is not required for the development of pancreatitis but apparently is necessary for the maximal propagation of pancreatic injury and its associated inflammation.     

Blocking pulmonary ICAM-1 expression ameliorates lung injury in established diet-induced pancreatitis

OBJECTIVE: To determine whether blocking the cell surface expression of intracellular adhesion molecules (ICAM-1) in established severe acute pancreatitis (AP) would ameliorate pulmonary injury. SUMMARY BACKGROUND DATA: Lung injury in AP is in part mediated by infiltrating leukocytes, which are directed to lung tissue by ICAM-l. The authors' laboratory has previously demonstrated that AP results in overproduction of inflammatory cytokines, upregulation of pulmonary ICAM-1 expression, and a concomitant infiltration of neutrophils, which results in lung injury. METHODS: Young female mice were fed a choline-deficient/ethionine-supplemented diet to induce AP and were treated with a blocking dose of monoclonal antibody specific to the ICAM-1 receptor. Antibody treatment was administered at 72, 96, and 120 hours after beginning the diet, and all animals were killed at 144 hours. The degree of pancreatitis was evaluated by serum biochemical and tumor necrosis factor alpha levels as well as histology. The dual radiolabeled monoclonal antibody method was used to quantitate ICAM-1 cell surface expression in pulmonary tissue. Lung injury was assessed histologically and by determining lung microvascular permeability by measuring accumulated 125I-radiolabeled albumin. Pulmonary neutrophil sequestration was determined by the myeloperoxidase assay. RESULTS: All mice developed severe AP, and pancreatic injury was equally severe in both treated and untreated groups. Pulmonary ICAM-1 expression was significantly upregulated in animals with AP compared with controls. Treatment with a blocking dose of anti-ICAM-1 antibody after the induction of AP resulted in inhibited ICAM-1 cell surface expression to near control levels. Compared to untreated animals with AP, mice treated with anti-ICAM-1 mice had significantly reduced histologic lung injury and neutrophil sequestration, and a decreased microvascular permeability by more than twofold. CONCLUSIONS: These results demonstrate for the first time that treatment targeting the cell surface expression of ICAM-1 after the induction of AP ameliorates pulmonary injury, even in the face of severe pancreatic disease.