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Sendler M.,University of Greifswald | Beyer G.,University of Greifswald | Mahajan U.M.,University of Greifswald | Kauschke V.,University of Greifswald | And 12 more authors.
Gastroenterology | Year: 2015

Background & Aims Little is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients. Methods Chronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling. Results During the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood. Conclusions In mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis. © 2015 AGA Institute.

Hegyi P.,University of Szeged | Hegyi P.,MTA SZTE Lendulet Translational Gastroenterology Research Group | Rakonczay Z.,University of Szeged
Pancreatology | Year: 2015

Pancreatic ducts secrete 2.5l of alkaline, HCO3 --rich fluid daily which greatly contributes to the homeostasis of the pancreas. Ducts are also important in the pathophysiology of the pancreas; alteration of ductal function can lead to severe diseases such as cystic fibrosis and chronic pancreatitis. The role of pancreatic ducts in the development of acute pancreatitis has only been uncovered recently. Pancreatitis inducing agents like bile acids and ethanol dose-dependently affect pancreatic ductal secretion; low concentrations stimulate, whereas high concentrations inhibit secretion. The majority of the review will focus on the central role of cystic fibrosis transmembrane conductance regulator (CFTR), a critical protein in the regulation of ductal secretion, in the pathogenesis of acute pancreatitis which is highlighted by numerous investigations. Downregulation of CFTR expression results in increased severity of acute pancreatitis in mice. Furthermore, human genetic studies have demonstrated statistically significant association of CFTR mutations with acute recurrent pancreatitis. Overall, the data support the involvement of pancreatic ducts in the pathogenesis of acute pancreatitis. © 2015 IAP and EPC.

Dubravcsik Z.,Bacs Kiskun County Hospital | Madacsy L.,Semmelweis University | Gyokeres T.,Health-U | Vincze A.,University of Pecs | And 6 more authors.
Pancreatology | Year: 2015

Background The outcome of the most common biliary form of acute pancreatitis has not changed even with the better described indications for early endoscopic intervention. It may be due to the fact that this intrevention theoretically can cause further pancreatic injury or cannot always relieve the pancreatic duct obstruction. We hypothesize that maintaining the outflow of the pancreatic duct with preventive pancreatic stents at the early ERCP improves the outcome of acute biliary pancreatitis. Methods/Design PREPAST is a prospective, randomized, controlled, multicenter trial. Patients with acute biliary pancreatitis with coexisting cholangitis are randomized to undergo urgent endoscopic intervention with or without pancreatic stenting within 48 h from the onset of pain, and in addition patients without signs of cholangitis but cholestasis are randomly allocated to recieve conservative treatment or early endoscopic intervention with or without pancreatic stenting within 48 h from the onset of pain. Patients without acute cholangitis and signs of cholestasis recieve conservative treatment. 230 patients are planned to be enrolled during a 48 months period from different centers. The primary endpoint is the outcome of acute biliary pancreatitis as described by the latest guidelines. Secondary endpoints include mortality data, and other variables not analyzed as a primary endpoint but related to the pancreatitis or the pancreatic stenting. Discussion The PREPAST trial is designed to show whether early endoscopic intervention with the usage of preventive pancreatic stenting improves the outcome of acute biliary pancreatitis. Copyright © 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

Maleth J.,University of Szeged | Hegyi P.,University of Szeged | Hegyi P.,MTA SZTE Lendulet Translational Gastroenterology Research Group | Rakonczay Z.,University of Szeged | Venglovecz V.,University of Szeged
Pancreatology | Year: 2015

Acute pancreatitis is a severe inflammatory disease with unacceptably high mortality and without specific therapy. Clinical studies revealed that energy supplementation of patients via enteral feeding decreases systemic infections, multi-organ failure and mortality. These clinical observations have been supported by invitro and invivo experimental studies which showed that the most common pancreatitis inducing factors, such as bile acids, ethanol and non-oxidative ethanol metabolites induce intracellular ATP depletion and mitochondrial damage both in pancreatic acinar and ductal cells. Notably, the invitro supplementation of ATP prevented the cellular damage and restored cell functions in both cell types. These observations suggest that either prevention of mitochondrial damage or restoration of intracellular ATP level might provide therapeutical benefits. © 2015 IAP and EPC.

Maleth J.,University of Szeged | Balazs A.,University of Szeged | Pallagi P.,University of Szeged | Balla Z.,University of Szeged | And 23 more authors.
Gastroenterology | Year: 2015

Background & Aims Excessive consumption of ethanol is one of the most common causes of acute and chronic pancreatitis. Alterations to the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) also cause pancreatitis. However, little is known about the role of CFTR in the pathogenesis of alcohol-induced pancreatitis. Methods We measured CFTR activity based on chloride concentrations in sweat from patients with cystic fibrosis, patients admitted to the emergency department because of excessive alcohol consumption, and healthy volunteers. We measured CFTR levels and localization in pancreatic tissues and in patients with acute or chronic pancreatitis induced by alcohol. We studied the effects of ethanol, fatty acids, and fatty acid ethyl esters on secretion of pancreatic fluid and HCO3 -, levels and function of CFTR, and exchange of Cl- for HCO3 - in pancreatic cell lines as well as in tissues from guinea pigs and CFTR knockout mice after administration of alcohol. Results Chloride concentrations increased in sweat samples from patients who acutely abused alcohol but not in samples from healthy volunteers, indicating that alcohol affects CFTR function. Pancreatic tissues from patients with acute or chronic pancreatitis had lower levels of CFTR than tissues from healthy volunteers. Alcohol and fatty acids inhibited secretion of fluid and HCO3 -, as well as CFTR activity, in pancreatic ductal epithelial cells. These effects were mediated by sustained increases in concentrations of intracellular calcium and adenosine 3′,5′-cyclic monophosphate, depletion of adenosine triphosphate, and depolarization of mitochondrial membranes. In pancreatic cell lines and pancreatic tissues of mice and guinea pigs, administration of ethanol reduced expression of CFTR messenger RNA, reduced the stability of CFTR at the cell surface, and disrupted folding of CFTR at the endoplasmic reticulum. CFTR knockout mice given ethanol or fatty acids developed more severe pancreatitis than mice not given ethanol or fatty acids. Conclusions Based on studies of human, mouse, and guinea pig pancreata, alcohol disrupts expression and localization of the CFTR. This appears to contribute to development of pancreatitis. Strategies to increase CFTR levels or function might be used to treat alcohol-associated pancreatitis. © 2015 AGA Institute.

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