Co-localization hypothesis： A mechanism for the intrapancreatic activation of digestive enzymes during the early phases of acute pancreatitis

Acute pancreatitis is generally believed to be a disease in which the pancreas is injured by digestive enzymes that it normally produces. Most of the potentially harmful digestive enzymes produced by pancreatic acinar cells are synthesized and secreted as inactive zymogens which are normally activated only upon entry into the duodenum but, during the early stages of acute pancreatitis, those zymogens become prematurely activated within the pancreas and, presumably, that activation occurs within pancreatic acinar cells. The mechanisms responsible for intracellular activation of digestive enzyme zymogens have not been elucidated with certainty but, according to one widely recognized theory (the "co-localization hypothesis"), digestive enzyme zymogens are activated by lysosomal hydrolases when the two types of enzymes become co-localized within the same intracellular compartment. This review focuses on the evidence supporting the validity of the co-localization hypothesis as an explanation for digestive enzyme activation during the early stages of pancreatitis. The findings, summarized in this review, support the conclusion that co-localization of lysosomal hydrolases with digestive enzyme zymogens plays a critical role in permitting the intracellular activation of digestive enzymes that leads to acinar cell injury and pancreatitis.     

Acute pancreatitis at the beginning of the 21st century： The state of the art

Acute pancreatitis is an acute inflammatory disease of the pancreas which can lead to a systemic inflammatory response syndrome with significant morbidity and mortality in 20% of patients. Gallstones and alcohol consumption are the most frequent causes of pancreatitis in adults. The treatment of mild acute pancreatitis is conservative and supportive; however severe episodes characterized by necrosis of the pancreatic tissue may require surgical intervention. Advanced understanding of the pathology, and increased interest in assessment of disease severity are the cornerstones of future management strategies of this complex and heterogeneous disease in the 21st century.     

Endoscopic pancreatic duct stent placement for inflammatory pancreatic diseases

The role of endoscopic therapy in the management of pancreatic diseases is continuously evolving; at present most pathological conditions of the pancreas are successfully treated by endoscopic retrograde cholangio- pancreatography （ERCP） or endoscopic ultrasound （EUS）, or both. Endoscopic placement of stents has played and still plays a major role in the treatment of chronic pancreatitis, pseudocysts, pancreas divisum, main pancreatic duct injuries, pancreatic fistulae, complications of acute pancreatitis, recurrent idiopathic pancreatitis, and in the prevention of post-ERCP pancreatitis. These stents are currently routinely placed to reduce intraductal hypertension, bypass obstructing stones, restore lumen patency in cases with dominant, symptomatic strictures, seal main pancreatic duct disruption, drain pseudocysts or fluid collections, treat symptomatic major or minor papilla sphincter stenosis, and prevent procedure-induced acute pancreatitis. The present review aims at updating and discussing techniques, indications, and results of endoscopic pancreatic duct stent placement in acute and chronic inflammatory diseases of the pancreas.     

Role of endoscopic retrograde cholangiopancreatography in acute pancreatitis

Endoscopic retrograde cholangiopancreatography （ERCP） is a useful tool in the evaluation and management of acute pancreatitis. This review will focus on the role of ERCP in specific causes of acute pancreatitis, including microlithiasis and gallstone disease, pancreas divisum, Sphincter of Oddi dysfunction, tumors of the pancreaticobiliary tract, pancreatic pseudocysts, and pancreatic duct injury. Indications for endoscopic techniques such as biliary and pancreatic sphincterotomy, stenting, stricture dilation, treatment of duct leaks, drainage of fluid collections and stone extraction will also be discussed in this review. With the advent of less invasive and safer diagnostic modalities including endoscopic ultrasound （EUS） and magnetic retrograde cholangiopancreatography （MRCP）, ERCP is appropriately becoming a therapeutic rather than diagnostic tool in the management of acute pancreatitis and its complications.     

Evidence for a role of mitogen-activated protein kinases in the treatment of experimental acute pancreatitis

Acute pancreatitis(AP) is an inflammatory disease characterized by acute inflammation and necrosis of the pancreatic parenchyma. AP is often associated with organ failure, sepsis, and high mortality. The pathogenesis of AP is still not well understood. In recent years several papers have highlighted the cellular and molecular events of acute pancreatitis. Pancreatitis is initiated by activation of digestive enzymes within the acinar cells that are involved in autodigestion of the gland, followed by a massive infiltration of neutrophils and macrophages and release of inflammatory mediators, responsible for the local and systemic inflammatory response. The hallmark of AP is parenchymal cell necrosis that represents the cause of the high morbidity and mortality, so that new potential therapeutic approaches are indispensable for the treatment of patients at high risk of complications. However, not all factors that determine the onset and course of the disease have been explained. Aim of this article is to review the role of mitogen-activated protein kinases in pathogenesis of acute pancreatitis.     

High-mobility group box 1 protein and its role in severe acute pancreatitis

The high mobility group box 1(HMGB1),which belongs to the subfamily of HMG-1/-2,is a highly conserved single peptide chain consisting of 215 amino acid residues with a molecular weight of approximately 24894 Da.HMGB1 is a ubiquitous nuclear protein in mammals and plays a vital role in inflammatory diseases.Acute pancreatitis is one of the most common causes of acute abdominal pain with a poor prognosis.Acute pancreatitis is an acute inflammatory process of the pancreas(duration of less than six months),for which the severe form is called severe acute pancreatitis(SAP).More and more studies have shown that HMGB1 has a bidirectional effect in the pathogenesis of SAP.Extracellular HMGB1 can aggravate the pancreatic inflammatory process,whereas intracellular HMGB1 has a protective effect against pancreatitis.The mechanism of HMGB1 is multiple,mainly through the nuclear factor-κB pathway.Receptors for advanced glycation endproducts and toll-like receptors(TLR),especially TLR-2 and TLR-4,are two major types of receptors mediating the inflammatory process triggered by HMGB1 and may be also the main mediators in the pathogenesis of SAP.HMGB1 inhibitors,such as ethyl pyruvate,pyrrolidine dithiocarbamate and Scolopendra subspinipes mutilans,can decrease the level of extracellular HMGB1 and are the promising targets in the treatment of SAP.     

Acute pancreatitis:The stress factor

Acute pancreatitis is an inflammatory disorder of the pancreas that may cause life-threatening complications.Etiologies of pancreatitis vary,with gallstones accounting for the majority of all cases,followed by alcohol.Other causes of pancreatitis include trauma,ischemia,mechanical obstruction,infections,autoimmune,hereditary,and drugs.The main events occurring in the pancreatic acinar cell that initiate and propagate acute pancreatitis include inhibition of secretion,intracellular activation of proteases,and generation of inflammatory mediators.Small cytokines known as chemokines are released from damaged pancreatic cells and attract inflammatory cells,whose systemic action ultimately determined the severity of the disease.Indeed,severe forms of pancreatitis may result in systemic inflammatory response syndrome and multiorgan dysfunction syndrome,characterized by a progressive physiologic failure of several interdependent organ systems.Stress occurs when homeostasis is threatened,and stressors can include physical or mental forces,or combinations of both.Depending on the timing and duration,stress can result in beneficial or harmful consequences.While it is well established that a previous acute-short-term stress decreases the severity of experimentally-induced pancreatitis,the worsening effects of chronic stress on the exocrine pancreas have received relatively little attention.This review will focus on the influence of both prior acute-short-term and chronic stress in acute pancreatitis.     

Acute recurrent pancreatitis: Etiopathogenesis,diagnosis and treatment

Acute recurrent pancreatitis(ARP)refers to a clinical entity characterized by episodes of acute pancreatitis which occurs on more than one occasion.Recurrence of pancreatitis generally occurs in a setting of normal morpho-functional gland,however,an established chronic disease may be found either on the occasion of the first episode of pancreatitis or during the follow-up.The aetiology of ARP can be identified in the majority of patients.Most common causes include common bile duct stones or sludge and bile crystals;sphincter of oddi dysfunction;anatomical ductal variants interfering with pancreatic juice outflow;obstruction of the main pancreatic duct or pancreatico-biliary junction;genetic mutations;alcohol consumption.However,despite diagnostic technologies,the aetiology of ARP still remains unknown in up to 30%of cases:in these cases the term“idiopathic”is used.Because occult bile stone disease and sphincter of oddi dysfunction account for the majority of cases,cholecystectomy,and eventually the endoscopic biliary and/or pancreatic sphincterotomy are curative in most of cases.Endoscopic biliary sphincterotomy appeared to be a curative procedure per se in about 80%of patients.Ursodeoxycholic acid oral treatment alone has also been reported effective for treatment of biliary sludge.In uncertain cases toxinbotulin injection may help in identifying some sphincter of oddi dysfunction,but this treatment is not widely used.In the last twenty years,pancreatic endotherapy has been proven effective in cases of recurrent pancreatitis depending on pancreatic ductal obstruction,independently from the cause of obstruction,and has been widely used instead of more aggressive approaches.     

Pancreatic trauma: A concise review

Traumatic injury to the pancreas is rare and difficult to diagnose.In contrast,traumatic injuries to the liver,spleen and kidney are common and are usually identified with ease by imaging modalities.Pancreatic injuries are usually subtle to identify by different diagnostic imaging modalities,and these injuries are often overlooked in cases with extensive multiorgan trauma.The most evident findings of pancreatic injury are posttraumatic pancreatitis with blood,edema,and soft tissue infiltration of the anterior pararenal space.The alterations of post-traumatic pancreatitis may not be visualized within several hours following trauma as they are time dependent.Delayed diagnoses of traumatic pancreatic injuries are associated with high morbidity and mortality.Imaging plays an important role in diagnosis of pancreatic injuries because early recognition of the disruption of the main pancreatic duct is important.We reviewed our experience with the use of various imaging modalities for diagnosis of blunt pancreatic trauma.     

Pituitary adenylate cyclase activating-peptide and its receptor antagonists in development of acute pancreatitis in rats

AIM: Pituitary adenylate cyclase activating-peptide (PACAP) is a late member of the secretin/glucagon/vasoactive intestinal peptide (VIP) family of brain-gut peptides. It is unknown whether PACAP takes part in the development of acute pancreatitis and whether PACAP or its antagonists can be used to suppress the progression of acute pancreatitis. We investigated the actions of PACAP and its receptor antagonists in acute pancreatitis on rats. METHODS: Acute pancreatitis was induced in rats with caerulein or 3.5% sodium taurocholate. The rats were continuously infused with 5-30 μg/kg PACAP via jugular vein within the first 90 min, while 10-100 μg/kg PACAP6-27 and (4-CI-D-Phe6, Leu17) VIP (PACAP receptor antagonists) were intravenously infused for 1 h. Biochemical and histopathological assessments were made at 4 h after infusion. Pancreatic and duodenal PACAP concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Chinese ink-perfused pancreas was fixed, sectioned and cleared for counting the functional capillary density. RESULTS: PACAP augmented caerulein-induced pancreatitis and failed to ameliorate sodium taurocholate-induced pancreatitis. ELISA revealed that relative concentrations of PACAP in pancreas and duodenum were significantly increased in both sodium taurocholate- and caerulein-induced pancreatitis compared with those in normal controls. Unexpectedly, PACAP6-27 and (4-CI-D-Phe6, Leu17) VIP could induce mild acute pancreatitis and aggravate caerulein-induced pancreatitis with characteristic manifestations of acute hemorrhagic/necrotizing pancreatitis. Functional capillary density of pancreas was interpreted in the context of pancreatic edema, and calibrated functional capillary density (calibrated FCD), which combined measurement of functional capillary density with dry weight/wet weight ratio, was introduced. Hyperemia or congestion, rather than ischemia, characterized pancreatic microcirculatory changes in acute pancreatitis. CONCLUSION: PACAP may take part in the pathogenesis of acute pancreatitis in rats. The two PACAP receptor antagonsits might act as partial agonists. Calibrated functional capillary density can reflect pancreatic microcirculatory changes in acute pancreatitis.     

Integrity of the pancreatic duct-acinar system in the pathogenesis of acute pancreatitis

BACKGROUND:Acute pancreatitis is an acute inflammatory process of the pancreas that frequently involves peripancreatic tissues and at times remote organ systems.For a long time, the etiology and pathogenesis of acute pancreatitis has been intensively investigated worldwide,but the pathogenetic theories are controversial.The integrity of the pancreatic ductacinar system might play an important role in the pathogenesis of this disease.DATA SOURCES:Web of Science and PubMed databases were searched for published studies(between January 1966 and June 2009)to identify relevant articles using the "acinar hyperstimulation","pathogenesis","acute pancreatitis", "pancreatic duct-acinar system",and"pancreatic duct pressure".Most of the relevant articles were reviewed.RESULTS:From critical reading of the relevant articles,we found that the underlying mechanisms involved in the pathogenesis of acute pancreatitis are still under debate and ill-understood.On the basis of the relevant studies,we propose a hypothesis for the pathogenesis of acute pancreatitis, in which the integrity of the pancreatic duct-acinar system plays an essential role in the onset and progression of various forms of the disease.CONCLUSIONS:In our hypothesis,pancreatic duct obstruction and hyperstimulation of the exocrine pancreas are preconditions for the onset of acute pancreatitis;under the common conditions of pancreatic duct obstruction and acinar hyperstimulation,acute pancreatitis arises and develops.This may be an important common pathophysiological mechanism causing various forms of acute pancreatitis.     

CCK-A receptor induction and P38MAPK and NF-κB activation in acute pancreatitis

Bile-pancreatic duct ligation in rats excludes bile-pancreatic juice from the gut and induces acute pancreatitis. Bile-pancreatic juice exclusion from the gut results in increased plasma cholecystokinin (CCK) levels. CCK-A receptor-mediated exocrine pancreatic hyperstimulation is implicated in disease pathogenesis. In the present study, we show for the first time a progressive rise in CCK-A receptor protein expression in ligation-induced acute pancreatitis in rats. As CCK-A receptor induction could amplify CCK-mediated acinar hyperstimulation and exacerbate acinar cell stress with activation of the p38^MAPK stress kinase pathway, we studied CCK-A receptor protein expression and p38^MAPK activation in duct ligation-induced acute pancreatitis in rats. Compared to sham-operated controls, acute pancreatitis induced by bile-pancreatic duct ligation associates with a temporal increase in pancreatic CCK-A receptor protein expression, p38^MAPK expression and activation, and NF-κB activation. These findings may have significance in the mechanism of disease pathogenesis in this experimental model.     

Biliary pancreatic reflux-induced acute pancreatitis--myth or possibility?

OBJECTIVE: The mechanism whereby gallstone passage through the choledochoduodenal junction initiates acute pancreatitis is not known. We mimicked different patterns of stone impaction at the choledochoduodenal junction in a rabbit model and studied whether these result in biliary pancreatic reflux and the initiation of pancreatic inflammation. METHODS: In rabbits, catheters were introduced into the common bile duct (CBD) and the pancreatic duct. In five experiments, obstruction of these catheters at various time intervals mimicked different patterns of stone obstruction of both ducts prior to a stone impaction at the papilla of Vater: experiment I--no obstruction of the pancreatic duct and the CBD; experiment II--separate obstruction of the CBD and the pancreatic duct; experiment III--selective obstruction of the CBD; experiment IV--separate obstruction of the CBD and the pancreatic duct and subsequent decompression of the pancreatic duct; experiment V--obstruction pattern as in experiment IV associated with a bacterial infection of bile (10(8) E. coli/ml). Ductal pressures were recorded for 24 h. In order to study the effects of a subsequent impaction of the stone at the papilla of Vater, the catheters in the CBD and in the pancreatic duct were connected and mimicked a common channel behind a papillary stone. The flow direction of bile and pancreatic juice was directly observed. Pancreatic histology was analysed 24 h later. RESULTS: In experiments I-III, neither biliary pancreatic reflux nor acute pancreatitis was observed. In experiments IV and V, obstruction of the CBD caused an increase in the biliary pressure to 17 +/- 3 cm H2O, whereas the pancreatic duct pressure dropped to subnormal levels following obstruction and selective decompression (2 +/- 0.5 cm H2O). After the creation of a 'common channel', biliary pancreatic reflux was observed for 118 +/- 21 min. Flow of sterile bile into the pancreas was not harmful to the gland. Infected biliary pancreatic reflux initiated acute pancreatitis. CONCLUSIONS: 1. Bile flow into the pancreas may occur. 2. Biliary pancreatic reflux may initiate acute pancreatitis. 3. Bile reflux-induced acute pancreatitis requires previous biliary hypertension, temporary pancreatic duct obstruction, and the bacterial infection of choledochal secretions.     

Bile exclusion from the gut exacerbates acute pancreatitis caused by pancreatic duct obstruction in rats.

Acute pancreatic duct obstruction causes hyperamylasemia and mild pancreatic inflammation. We hypothesized that bile exclusion from the gut, which stimulates pancreatic secretion, exacerbates acute pancreatitis caused by pancreatic duct obstruction. Rats were surgically prepared with gastric, duodenal, bile, and pancreatic fistula catheters and a jugular vein catheter. After a 4-day recovery, groups of rats (a) served as controls, (b) had complete pancreatic duct obstruction for 6 h, or (c) had bile excluded from the gut for 24 h and then, during the final 6 h, complete pancreatic duct obstruction. Plasma amylase was measured, and all rats were euthanized at the end of experiments. Each pancreas was excised and weighed, and portions were fixed in formalin and glutaraldehyde. In blind fashion, each pancreas was examined under light microscopy and assigned a pancreatitis score based on presence of edema and severity of acinar cell changes and inflammation. Acute pancreatic duct obstruction was associated with increased pancreas weight, hyperamylasemia, and elevated pancreatitis score; moderate acinar cell vacuoles, which were observed in the cytoplasm near the basolateral membrane, and loss of microvilli were noted with electron microscopy. Bile exclusion from the gut exacerbated the acute pancreatitis caused by pancreatic duct obstruction; acinar cell distortion and destruction, as well as marked inflammation, were seen microscopically. These observations suggest that the absence of intestinal bile contributes to the pathogenesis of acute pancreatitis associated with pancreatic duct obstruction.     

Biliopancreatic reflux—pathophysiology and clinical implications

The common bile duct and the main pancreatic duct open into the duodenum, where they frequently form a common channel. The sphincter of Oddi is located at the distal end of the pancreatic and bile ducts; it regulates the outflow of bile and pancreatic juice. In patients with a pancreaticobiliary maljunction, the action of the sphincter does not functionally affect the junction. Therefore, in these patients, two-way regurgitation (pancreatobiliary and biliopancreatic reflux) occurs. This results in various pathological conditions of the biliary tract and the pancreas. Biliopancreatic reflux could be confirmed by: operative or postoperative T-tube cholangiography; CT combined with drip infusion cholangiography; histological detection of gallbladder cancer cells in the main pancreatic duct; and reflux of bile on the cut surface of the pancreas. Biliopancreatic reflux occurs frequently in patients with a long common channel. Although the true prevalence, degree, and pathophysiology of biliopancreatic reflux remain unclear, biliopancreatic reflux is related to the occurrence of acute pancreatitis. Obstruction of a long common channel easily causes bile flow into the pancreas. Even if no obstruction is present, biliopancreatic reflux can still result in acute pancreatitis in some cases.     

Pancreatic and bile duct obstruction exacerbates rat caerulein-induced pancreatitis: a new experimental model of acute hemorrhagic pancreatitis

Background Pancreatic duct obstruction induces edematous but not hemorrhagic pancreatitis even when combined with maximal secretory stimulation. The aim of the present study was to test the hypothesis that pancreatic and bile duct obstruction exacerbates edematous pancreatitis induced by supramaximal secretory stimulation by caerulein. Methods In in vivo studies using rats, biliopancreatic duct ligation was combined with supramaximal stimulation of caerulein, and pancreatic histology, serum amylase level, pancreatic edema, and intrapancreatic trypsin activation were evaluated. In in vitro studies, the pancreatic acini were isolated from the rats with biliopancreatic duct ligation, and amylase secretion, intracellular trypsin activation, and acinar cell fragility were evaluated. Results Biliopancreatic duct ligation exacerbated caerulein-induced pancreatitis from edematous to hemorrhagic only when the obstruction preceded caerulein administration. The amylase secretion from the acini was inhibited, and intracellular trypsin activation and the acinar cell fragility on the supramaximal stimulation with cholecystokinin in vitro were enhanced by the preceding in vivo biliopancreatic duct obstruction. Conclusions Preceding biliopancreatic duct obstruction exacerbates caerulein-induced pancreatitis. Enhancement of intracellular trypsin activation is possibly involved in this mechanism.     

Trypsinogen activation and glutathione content are linked to pancreatic injury in models of biliary acute pancreatitis

Summary Conclusion In models of biliary acute pancreatitis, which might resemble the situation in humans, premature activation of trypsinogen inside the pancreas (“autodigestion”) occurs and is correlated with the extent of ductal and parencymal injury. It is accompanied by a critical spending of protease inhibitors and glutathione, compromising important acinar cell defense and maintenance mechanisms. Background Premature activation of pancreatic digestive enzymes and profound changes of levels of certain biochemical compounds have been implicated in the pathophysiology of acute pancreatitis. Hitherto, little information on their role in biliary acute pancreatitis has been available. Methods Three types of injury to the pancreaticobiliary duct system of various severity were induced in rats—ligation of the common bile-pancreatic duct, retrograde infusion of electrolyte, or retrograde infusion of taurocholate solution—and were compared to sham-operated animals. Trypsin, trypsin inhibitory capacity (TIC), reduced glutathione (GSH), and other compounds were measured in pancreatic tissue. Histopathology, as well as serum amylase, lipase, and γ-glutamyl transferase (γGT) were assessed. Results Histopathology and elevated activity of γGT in the serum revealed increasing severity of pancreatic injury from sham operation through retrograde duct infusion with taurocholate. GSH was diminished even in macroscopically normal-appearing tissue, but significantly lower in altered (hemorrhagic)-looking sections. Conversely, tissue levels of trypsin were significantly increased. TIC was elevated only in the duct obstruction model, whereas it was reduced in the retrograde duct infusion models. This work is dedicated to Prof. Dr. Georg Strohmeyer (former chief of the Division of Gastroenterology at the Heinrich-Heine-University, Düsseldorf, Germany) on occasion of his 70th birthday.     

Acute pancreatitis associated with anomalous union of the pancreaticobiliary ductal system.

Between 1978 and 1989, 13 of 48 patients with anomalous union of the pancreaticobiliary ductal system (AUPBD) were diagnosed as having acute pancreatitis. We have studied the clinical, radiologic, and surgical features of these 13 patients. A transient rise in the intraductal pressure of the pancreatic duct during an episode of abdominal pain is responsible for pancreatitis in patients with AUPBD. This rise in the intraductal pressure must be due to bile reflux into the pancreatic duct when an abnormally long common channel is blocked by cholelithiasis, protein plug, or dysfunction of the sphincter of Oddi. The pancreatitis resolves when the common channel obstruction is removed, and bile and pancreatic juice flow easily into the duodenum. We believe that this phenomenon is responsible for acute relapsing pancreatitis. It is our belief that the pancreas appears almost normal during symptom-free intervals.     

The effects of somatostatin on the microperfusion of the pancreas during acute necrotizing pancreatitis in rats

BACKGROUND/AIMS: Autodigestion and impairment of microcirculation of the pancreas play an important role in the pathogenesis of acute pancreatitis. Somatostatin with the reducing effect on the hepato-splanchnic blood flow decreases exocrine pancreatic secretion. Microcirculatory changes are central to the pathogenesis of acute pancreatitis. However, little is known about the effects of somatostatin on the pancreatic tissue oxygen pressure and acinar cell injury during acute pancreatitis. The aim was to evaluate somatostatin by measuring its effect on the pancreatic tissue oxygen pressure and acinar injury in acute pancreatitis. METHODOLOGY: Acute necrotizing pancreatitis was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptide was measured to verify comparable disease severity. After the induction of acute necrotizing pancreatitis, animals randomly received either ringer lactate or somatostatin. Monitoring included cardiorespiratory parameters, hematocrit, amylase, pancreatic tissue oxygen pressure, and trypsinogen activation peptide levels. At the end of the experiments the pancreas was removed for evaluation of acinar cell injury. RESULTS: The two study groups were comparable with regard to mean arterial pressure, heart rate, arterial blood gases, hematocrit, and serum amylase. The induction of pancreatitis resulted in the significant decrease of pancreatic tissue oxygen pressure in both groups. The use of somatostatin did not increase pancreatic tissue oxygen pressure. There were no significant differences in plasma trypsinogen activation peptide and serum amylase levels in the animals of two treatment groups. Only somatostatin decreased pancreatic damage significantly. CONCLUSIONS: The use of somatostatin did not improve pancreatic microcirculation or trypsinogen activation peptide level in acute necrotizing pancreatitis; however, it reduced pancreatic damage. Therefore, it has a limited value in the treatment of the acute pancreatitis.