Elimination of Pancreatic Secretory Trypsin Inhibitor from the Circulation

The elimination of human pancreatic secretory trypsin inhibitor (PSTI) from the circulation of man has been examined in two human volunteers. Serial samplings of blood and urine were made for 55 h, after a rapid intravenous infusion of ¹²⁵I-labeled human PSTI. The findings demonstrated a rapid initial elimination from the circulation. Within 30 min only 30% of the infused label remained (T½, 6 min). This was accompanied by the rapid appearance in the urine of radiolabel. Our results indicate that PSTI would prove a poor diagnostic marker for acute pancreatitis late in the course of the disease. This is opposed to the findings of Ogawa et al., who reported prolonged elevated circulating levels of PSTI weeks into the disease. However, they also noted rises of PSTI during acute pancreatitis in excess of 10 times the levels we have noted. Further exploration of population differences and the behavior of PSTI during acute pancreatitis are necessary to help resolve these findings.     

Immunocytochemical Distribution of Trypsinogen and Pancreatic Secretory Trypsin Inhibitor in Normal and Neoplastic Tissues in Man

Immunoreactive trypsinogen and pancreatic secretory trypsin inhibitor (PSTI) were demonstrated in pancreas by means of an immunoperoxidase technique. They had the same distribution in acinar cells of ‘normal’ human exocrine pancreas tissues. Ductal adenocarcinoma tissue and pancreatic undifferentiated carcinoma contained neither antigen. Scattered ‘normal’-looking cells in the border area between normal and neoplastic tissue of both types of tumor stained positively for trypsinogen and for PSTI.     

Phospholipase Activity in Pancreatic Exudate in Experimental Acute Pancreatitis

Acute pancreatitis was induced in dogs by injecting into the pancreatic duct a mixture of taurocholate and trypsin. Exudate from pancreas was collected outside the body by a special technique in separate portions each covering one hour.

All exudates were found to possess ability to break down lecithin by phospholipase and lysophospholipase action. Calcium, bile, and taurocholate stimulated and EDTA inhibited the degradation of lecithin. The phospholipase activity was studied in the hourly collected portions of pancreatic exudate. It was very high and had a maximum in the portion collected during the first hour, being lower and levelling out in the portions collected during the 4 to 7 hour periods. Amylase activity paralleled the phospholipase activity of the exudate.

The demonstration of an early release in acute pancreatitis of lecithin-hydrolyzing enzyme systems in pancreatic exudate may have bearings on the pathogenesis of acute pancreatitis.     

Secretory immunoglobulin A in pancreatic juice and pancreatic tissue of patients with chronic pancreatitis

Background—The predominace of secretory IgA(S-IgA) in intestinal secretions compared with blood is wellestablished, but concentrations of this protein in pancreatic juice andits origin, especially in chronic pancreatitis, are unknown.
Aims—To investigate the role of S-IgA in chronic pancreatitis.
Patients—Twenty one patients with chronicpancreatitis (group I), three patients with proven malignancies (groupII), and 12 patients without pancreatic disease (group III).
Methods—Pure human pancreatic juice was collectedendoscopically in four fractions after consecutive stimulation withsecretin and cholecystokinin (CCK). Samples were analysed for S-IgA,protein, trypsinogen, and proteolytic activity.
Results—The S-IgA level was significant increasedin fraction 1 of pancreatic juice of group I (1210 (1411) ng/ml)compared with controls (33 (70) ng/ml). Protein concentrations andtrypsinogen content were lower in group I than in the other groups.Proteolytic activity could be observed in 53% of all 133 pancreaticjuice samples, but in 87% of fraction 1. In pancreatic tissue of three patients with chronic pancreatitis both IgA and secretory component were detected by immunohistology. Expression of the secretory componentby human pancreatic epithelial cells was increased in patients withchronic pancreatitis compared with normal controls. The concentrationof S-IgA in pancreatic juice did not correlate with the serum S-IgAlevel. In contrast, serum levels of S-IgA were decreased in patientswith chronic pancreatitis.
Conclusion—There are high levels of S-IgA inhuman pancreatic juice following chronic inflammation and a protectiverole is suggested for this immunoglobulin.

Keywords:chronic pancreatitis; pancreatic juice; proteaseactivity; protease inhibitors; secretory IgA; immunohistochemistry

     

Golimumab Ameliorates Pancreatic Inflammatory Response in the Cerulein-Induced Acute Pancreatitis in Rats

Background:The aim of the study was to evaluate whether a new and successful treatment opportunity can be provided in acute pancreatitis and may prevent symptomatic treatments and show its effect through etiopathogenesis. Therefore, we want to investigate the efficacy of golimumab in an experimental rat model of cerulein-induced acute pancreatitis.Methods:A total of 35 rats, including 7 rats in each group, were distributed into 5 groups (sham, acute pancreatitis, placebo, acute pancreatitis + golimumab 5 mg/kg, and acute pancreatitis + golimumab 10 mg/kg). An experimental cerulein-induced acute pancreatitis model was accomplished by intraperitoneal cerulein injections. After sacrification, rat blood samples were collected for amylase, IL-6, and IL-1beta measurements. Histopathological analysis of the pancreas was performed with Tunel and hematoxylin & eosin staining.Results:Amylase, IL-6, and IL-1beta levels were found to be increased in the acute pancreatitis group. IL-1beta, amylase, IL-6 levels, and pancreatic inflammation were all significantly decreased in golimumab groups (P < .01). Moreover, in both golimumab groups, golimumab treatment significantly reduced apoptosis in pancreatic tissues (P < .05). Golimumab treatment was found to significantly reduce edema formation, inflammation, vacuolization, and fat necrosis of pancreatic tissues (P < .05).Conclusion:Firstly in the literature, we investigated the efficacy of golimumab in the experimental acute pancreatitis model. In the light of our findings, it could be suggested that golimumab may be an effective and safe therapeutic option in the treatment of patients with acute pancreatitis.     

Serum Phospholipase A2, Immunoreactive Trypsin,and Trypsin Inhibitors During Human Acute Pancreatitis

Serum immunoreactive trypsin and phospholipase A₂ were analyzed at regular intervals in seven patients hospitalized as a result of acute hemorrhagic pancreatitis. α₁-Antitrypsin and α₂-macroglobulin levels and trypsin-inhibitor capacity of serum were determined simultaneously. Serum trypsin concentrations were markedly raised in all patients. The levels of immunoreactive trypsin remained elevated for longer periods than those of urinary amylase. α₁-Antitrypsin and trypsin-inhibitor capacity were also significantly increased as compared with the post-illness values, but α₂-macroglobulin decreased considerably, reaching the lowest levels on the 5th day after admission. Consequently, phospholipase and trypsin are released to the circulation during hemorrhagic pancreatitis, but the increase in trypsin is compensated for by an increase in trypsin-inhibitor capacity of serum due to elevated α₁-antitrypsin levels. The decrease of α₂-macroglobulin in hemorrhagic pancreatitis was one of the most interesting findings, and it is proposed that this inhibitor may be consumed in the elimination of proteases through the reticuloendothelial system. The two patients who died had higher phospholipase values than those who recovered, but the prognosis could not be predicted from the values of the other measured variables.     

Pancreatic Sphincterotomy and Pure Pancreatic Juice Collection for Treatment of Chronic Pancreatitis

Abstract: After our introduction of endoscopic pancreatic sphincterotomy for treatment of chronic pancreatitis in 1985, our interest has been focused to the value of pure pancreatic juice collection with or without pancreatic sphincterotomy for management of chronic pancreatitis. Through pancreatic sphincterotomy, pain relief was obtained in 13 out of 16 cases with moderate and marked chronic pancreatitis. After pancreatic sphincterotomy extraction of pancreatic calculi using basket forceps was done successfully in 2 of these cases, Spontaneous stone passage occured in the other 2. In pure pancreatic juice collection without pancreatic sphincterotomy, pain relief was seen in 6 out of 13 cases with mild and moderate chronic pancreatitis. The protein plug was simultaneously aspirated during the procedure in 3 cases. Recently, we have indicated in these patients both pancreatic sphincterotomy and pure pancreatic juice collection and noted pain relief was obtained in all of the 8 cases with this approach. With an improvement in the technology of pancreatic drainage, these endoscopic treatment modalities may be possibly useful to stop the progression of chronic pancreatitis.     

Role of Proteases and Antiprotease in the Etiology of Chronic Pancreatitis

Background/Aim:

Chronic pancreatitis (CP) is the progressive and irreversible destruction of the pancreas characterized by the permanent loss of endocrine and exocrine function. Trypsin, the most important digestive enzyme plays a central role in the regulation of all other digestive enzymes. Chymotrypsin, an endopeptidase hydrolyzes peptides at amino acids with aromatic side chains. Alpha-1-antitrypsin is a principal antiprotease which protects the mucosal tissue from the proteolytic effects of trypsin and chymotrypsin by the formation of molar complexes. The present study is aimed at examining the role of proteases (trypsin and chymotrypsin) and anti-protease (α1-anti-trypsin) in the etiopathogenesis of chronic pancreatitis.

Patients and Methods:

A total of 90 CP patients and 110 age and sex matched controls were considered for the study. Serum trypsin, chymotrypsin and α1-anti-trypsin levels were determined prospectively in CP patients and compared to healthy controls as described previously.

Results:

The mean activity of trypsin were found to be increased in CP patients (X ± SD = 0.82 ± 0.838) in comparison to normal control group (X ± SD = 0.55 ± 0.328), (P = 0.001). Chymotrypsin activity were also found to be elevated in CP patients (X ± SD = 0.63 ± 0.278) in comparison to control group (X ± SD = 0.39 ± 0.295), (P = 0.0001). The mean α-1-anti-trypsin activity were found to be lowered in CP patients (X ± SD = 0.42 ± 0.494) in comparison to control group (X ± SD = 0.67 ± 0.465), with the variation being significant (P = 0.0003).

Conclusion:

The findings suggest an imbalance in the synthesis and degradation of proteolytic enzymes and antiprotease indicating an altered aggressive and defensive role in the pathogenesis of chronic pancreatitis.     

Peptide Leukotriene Receptor Antagonist Diminishes Pancreatic Edema Formation in Rats with Cerulein-Induced Acute Pancreatitis

Background: This study was designed to evaluate the protective effect of a peptide leukotriene receptor antagonist, pranlukast hydrate, against pancreatic injuries during acute pancreatitis. Methods: Acute pancreatitis was induced in rats by intravenous infusion of a supramaximal dose of cerulein (5 μg/kg·h for 4 h). In this model marked hyperamylasemia, a significant increase in pancreatic water content, and a significant increase in pancreatic microvascular leakage of Evans blue dye were observed. Pancreatic subcellular redistribution of the lysosomal enzyme cathepsin B from the lysosomal fraction to the zymogen fraction was also observed. Results: Pretreatment with pranlukast hydrate at a dose of 10 mg/kg (twice, 8 and 4 h before cerulein infusion) significantly inhibited these pancreatic injuries, including hyperamylasemia, increased pancreatic microvascular permeability, and redistribution of cathepsin B in pancreatic acinar cells. Conclusions: These results suggest that peptide leukotrienes may be involved in the pathogenesis of acute pancreatitis in the early stage of the disease and that peptide leukotriene receptor antagonist might be of therapeutic value for treatment of acute pancreatitis.     

Pancreatic Polypeptide Secretion in Patients with Chronic Pancreatitis and After Pancreatic Surgery

Aim. We investigated polypeptide (PP) secretion under basal conditions, in response to bombesin infusion and to meal ingestion in patients with chronic pancreatitis (CP) and patients after different types of pancreatic surgery. Methods. Included were patients with CP without (n=20) and with (n=30) exocrine pancreatic insufficiency, patients after duodenum preserving resection of the head of the pancreas (DPRHP; n=20), after Whipple’s procedure (n=19), following distal pancreatectomy (DP; n=12), and healthy controls (n=36). Results. In CP patients basal and bombesin stimulated PP levels were significantly (p<0.01) reduced compared to controls only when exocrine insufficiency was present. Meal-stimulated PP secretion was significantly (p<0.01−0.05) reduced in CP patients both with and without exocrine insufficiency. Plasma PP peak increments after bombesin and meal ingestion correlated significantly with exocrine function. Basal PP, meal, and bombesin-stimulated PP secretion had low sensitivities of 22%, 42%, and 60% respectively, in detecting chronic pancreatitis. In patients after pancreatic surgery that included pancreatic head resection (DPRHP or Whipple operation) basal and stimulated PP secretion were significantly (p<0.01−0.05) reduced. Conclusion. Basal and meal or bombesin-stimulated PP levels are significantly reduced in patients with CP only when exocrine insufficiency is present. Determination of plasma PP levels has low sensitivity and is not useful in detecting chronic pancreatitis without exocrine insufficiency. In patients after pancreatic surgery, PP secretion is dependent on the type of operation (head vs tail resection).     

白介素10对实验性急性坏死性胰腺炎胰腺缺血的影响

目的通过建立大鼠急性胰腺炎(acute necrotizing pancreatitis,ANP)模型,探讨白介素10(IL-10)对急性坏死性胰腺炎胰腺缺血的影响,进一步探讨ANP的发病机制,观察IL-10对ANP的治疗作用。方法将92只SD大鼠随机分为正常对照组(C组)、ANP模型组(A组)、IL-10干预组(I组)。C组接受生理盐水对照;A组用大剂量腹腔注射左旋精氨酸(L-Arginine)的方法诱导ANP模型;Ⅰ组在诱导ANP模型后应用IL-10后干预。分别观察各组光镜下病理评分、血清淀粉酶、白介素1β(IL-1β)、血栓素A2(TXA2)、前列环素(PGI2)的稳定代谢产物浓度TXB2和6-keto-PGF1α浓度变化。结果A组的病理评分、血清淀粉酶、IL-1β、TXB2、6-keto-PGF1α浓度在4、12、24、48时点都明显升高,与C组对比皆有显著差异(P<0.05);应用IL-10干预后的Ⅰ级组大鼠胰腺损伤较轻。结论胰腺缺血是急性坏死胰腺炎的损害因素之一,IL-10可以通过细胞因子网络改善胰腺缺血,对ANP有一定的治疗作用。     

Exocrine and Endocrine Pancreatic Function in 21 Patients Suffering from Autoimmune Pancreatitis before and after Steroid Treatment

Background/Aim: Autoimmune pancreatitis (AIP) responds rapidly and dramatically to steroid therapy. The aim of this study was to evaluate pancreatic exocrine and endocrine function in patients suffering from AIP both before and after steroid therapy. Patients and Methods: Fecal elastase 1 and diabetes were evaluated before steroid therapy and within 1 month of its suspension in 21 patients (13 males and 8 females, mean age 43 ± 16.5 years) diagnosed as having AIP between 2006 and 2008. Results: At clinical onset, fecal elastase 1 was 107 ± 126μg/g stool.Thirteen patients (62%) showed severe pancreatic insufficiency (<100 μg/g stool), 4 (19%) had mild insufficiency (100–200 μg/g stool), while 4 (19%) had normal pancreatic function (1200 μg/g stool). Before steroids, diabetes was diagnosed in 5 patients (24%), all of whom had very low levels of fecal elastase 1 (<19 μg/g stool). Following steroids, fecal elastase 1 increased in all patients (237 8 193 μg/g stool) and observed levels were significantly higher than those seen before steroids (p = 0.001). Conclusions: Patients suffering from AIP display exocrine and/or endocrine pancreatic insufficiency at clinical onset. These insufficiencies improve after steroid therapy.     

卡托普利与基质金属蛋白酶9在重症急性胰腺炎微循环障碍相关机理的实验研究

目的 :探讨卡托普利与基质金属蛋白酶 9(MMP 9)在重症急性胰腺炎 (SAP)微循环障碍的相关机制并证实卡托普利在SAP微循环障碍的价值。方法 :SD大鼠随机分为 :假手术组 (n =1 0 )和SAP组 (n =1 0 ) ,及MMP抑制剂干预组 (n =1 0 )。检测各组大鼠胰损伤评分、胰湿重、血清淀粉酶量、腹腔灌洗液细胞数、腹腔灌洗液中和血液中Evens染料量比、胰组织MMP 9表达等有关指标。结果 :SAP组大鼠胰损伤评分、胰湿重、血清淀粉酶量、腹腔灌洗液细胞数、腹腔灌洗液中和血液中Evens染料量比均明显高于假手术组和MMP组 (P <0 .0 1 )。胰腺组织内MMP 9的阳性表达率 ,SAP组、假手术组、MMP组三组分别为 1 0 0 %、1 1 %和 2 5 % ,组内比较差异有显著性意义 (P <0 .0 1 )。结论 :MMP 9在SAP中因炎性细胞受炎症因子的激活而大量释放 ,与SAP时微循环障碍有密切关系。应用卡托普利可减轻该病理过程 ,从而成为SAP治疗的新靶点     

Therapeutic Small-Volume Resuscitation Preserves Pancreatic Microcirculation in Acute Experimental Pancreatitis of Graded Severity in Rats

Background: Microcirculatory disorders play a major part in the pathogenesis of acute pancreatitis. Improvement of microcirculation is hypothesized to open a therapeutic window. The aim of this study was to evaluate the effects of small-volume resuscitation in acute pancreatitis. Methods: In rats, acute pancreatitis of graded severity was induced and pancreatic microcirculation was observed in vivo with an epiluminescent microscope. Primary outcome measures were microcirculation, leukocyte adherence, concentration oftrypsinogen-activating peptide, amylase activity and histopathologic tissue damage. Results: In necrotizing pancreatitis patients receiving prophylactic intervention with 7.5% hypertonic saline the functional capillary density was 76%. Postcapillary venular leukocyte adherence was 45% of vein cross-section. The median histopathologic damage scored 8 points. In controls, a complete microcirculatory breakdown was observed, and in the group with therapeutic intervention no significant difference was detected. In intermediate pancreatitis, the number of perfused capillaries remained 55.0 versus 23.3% in controls. Leukocyte adherence was 40.0 versus 51.7%. The histopathologic damage scored 6.0 versus 9.0 points. Trypsinogen-activating peptide concentration was reduced to 164 versus 402 nM in controls. In cerulein pancreatitis, the number of perfused capillaries was equally preserved in both groups. Conclusion: Small-volume resuscitation preserves capillary microcirculation and prevents pancreatic injury in intermediate necrotizing pancreatitis.     

The Penetration of Ciprofloxacin into Human Pancreatic and Peripancreatic Necroses in Acute Necrotizing Pancreatitis

Background: Antibiotic prophylaxis in necrotizing pancreatitis has recently gained acceptance. Published studies, however, used different antibiotic regimes and some antibiotics penetrated pancreatic tissue or pancreatic necroses only poorly. The aim of this study was to assess the penetration of ciprofloxacin (CIP) into necrotic pancreatic and peripancreatic tissue. Patients and Methods: Serum, pancreatic necroses, peripancreatic fat tissue necroses and infected omental fluid levels of CIP were measured after 51 operations in 14 patients. Results: The median penetration ratio of CIP was 137.5% (range 11–196%) in infected omental bursa fluid, 59.6% (3–214%) in pancreatic necroses and 67.1% (1–250%) in peripancreatic necroses. Chemotherapeutical ratios of CIP as a marker for antimicrobial potency were high against most relevant pathogens in necrotizing pancreatitis. Conclusion: Due to its antimicrobial spectrum and the good penetration into the relevant compartments, CIP may be useful in preventing local infection in necrotizing pancreatitis. Received: August 28, 2000 · Revision accepted: August 28, 2001     

Analysis of Pancreatic Elastase-1 Concentrations in Duodenal Aspirates from Healthy Subjects and Patients with Chronic Pancreatitis

Fecal pancreatic elastase 1 (PE-1) has been advocated as a noninvasive marker of pancreatic function and allows detection of moderate and severe exocrine insufficiency. Few studies have evaluated the utility of measuring PE-1 in duodenal fluid for the diagnosis of pancreatic insufficiency. Our purpose was (1) to determine the feasibility of measuring PE-1 concentrations in duodenal aspirates obtained through our endoscopic pancreatic function test (ePFT) in healthy subjects and patients with chronic pancreatitis (CP) and (2) to determine correlations between duodenal PE-1 concentrations and bicarbonate and lipase concentrations in duodenal fluid. Healthy subjects (HS) and CP patients underwent an ePFT with CCK or secretin. CP was defined as endoscopic retrograde pancreatography (ERP) Cambridge class III-IV, endoscopic ultrasound (EUS) score >5, or presence of pancreatic calcifications on CT scan. Duodenal fluid PE-1, lipase, and bicarbonate concentrations were measured in each study group. Duodenal lipase and bicarbonate concentrations were measured using an autoanalyzer (Roche Diagnostics, Indianapolis, IN). PE-1 was measured using an ELISA (Genova Diagnostics, Asheville, NC). Ten HS and 10 CP patients were studied. In the CCK test the median peak lipase for HS and CP was 1605 and 113 IU/L, respectively (P < 0.008). In the secretin test the median peak bicarbonate for HS and CP was 102 and 40 mEq/L, respectively (p < 0.008). Median PE-1 concentrations for HS and CP were 317 and 63 microg/ml, respectively, after CCK stimulation (p = 0.046) and 87 and 17 microg/ml, respectively, after secretin stimulation (p = 0.033). Statistically significant correlations were found between [PE-1] and peak [lipase] (r = 0.83, P < 0.001), as well as [PE-1] and peak [HCO3(3)-] (r = 0.65, P = 0.037). Conclusions are as follows: (1) PE-1 concentrations can be measured from duodenal fluid obtained by endoscopic aspiration. (2) Duodenal fluid PE-1 concentrations are decreased in CP compared to HS. (3) Duodenal fluid [PE-1] has an excellent correlation with [lipase] and therefore is a marker of acinar cell function. (4) Secretin-stimulated endoscopic function testing with measurement of bicarbonate and PE-1 may provide a simultaneous assessment of both ductal cell and acinar cell function.     

急性胰腺炎血浆白介素-18水平与急性时相蛋白的关系

目的探索急性胰腺炎病人血浆白介素-18(IL-18)水平变化情况,及其与急性时相蛋白变化的关系,了解急性胰腺炎病人血浆IL-18水平的变化及其意义。方法将病人分为3组:急性水肿型胰腺炎组、急性坏死型胰腺炎组和对照组。分别检测血浆C反应蛋白(CRP)、前白蛋白(PA)、转铁蛋白(TRA)和IL-18水平。结果急性胰腺炎病人血浆IL-18和CRP明显升高,TRA和PA明显降低。IL-18水平与CRP呈正相关,与TRA和PA呈负相关。结论IL-18可能作为一种新的应激指标,反映机体的炎症情况,对急性胰腺炎的严重程度和预后评估有一定的临床应用价值。     

Morphological and Functional Evaluation of the Pancreatic Duct with Secretin-Stimulated Magnetic Resonance Cholangiopancreatography in Alcoholic Pancreatitis Patients

Objectives The aim of this investigation was to evaluate the pancreatographic findings and dynamics of pancreatic duct diameter, as determined by secretin-enhanced magnetic resonance cholangiopancreatography (S-MRCP), in patients with acute alcoholic pancreatitis or chronic alcoholic pancreatitis and in a control group. Methods S-MRCP was performed in patients with acute alcoholic pancreatitis who did not manifest the functional and radiological (ultrasonography and computed tomography) criteria of chronic pancreatitis (n = 21), in patients with chronic alcoholic pancreatitis (n = 28) and in a control group (n = 16). The diameter of the main pancreatic duct (MPD) was monitored before secretin administration and at 3 and 10 min after secretin administration. Morphological features were also assessed before and after the administration of secretin. Results All ductal diameters were significantly larger in chronic alcoholic pancreatitis (P < 0.0001). There were no differences in MPD caliber between patients with acute alcoholic pancreatitis and the control group. The percentage of variation between basal MPD diameter and at 3 min post-secretin administration was lower in patients with chronic (35.5%) pancreatitis than in those with acute alcoholic pancreatitis (52.3%) and the control group (52.5%). There were no significant differences between patients with acute alcoholic pancreatitis and the control group in terms of the frequency of visualization of side branches, ductal narrowing, intraluminal filling defects, and ductal irregularity. One patient with acute alcoholic pancreatitis presented ductal criteria of chronic pancreatitis following the administration of secretin. Conclusions The dynamics of MPD visualized on S-MRCP in patients with acute alcoholic pancreatitis is similar to that observed in the control group and different from that observed in patients with chronic alcoholic pancreatitis. There were no significant differences between patients with acute alcoholic pancreatitis and the control group in terms of morphological pancreatographic features.