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      Pathophysiology of Acute Pancreatitis

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          Abstract

          Acute pancreatitis is a common clinical condition. It is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. The exact mechanisms by which diverse etiological factors induce an attack are still unclear. It is generally believed that the earliest events in acute pancreatitis occur within acinar cells. Acinar cell injury early in acute pancreatitis leads to a local inflammatory reaction. If this inflammatory reaction is marked, it leads to a systemic inflammatory response syndrome (SIRS). An excessive SIRS leads to distant organ damage and multiple organ dysfunction syndrome (MODS).MODS associated with acute pancreatitis is the primary cause of morbidity and mortality in this condition. Recent studies have established the role played by inflammatory mediators in the pathogenesis of acute pancreatitis and the resultant MODS. At the same time, recent research has demonstrated the importance of acinar cell death in the form of apoptosis and necrosis as a determinant of pancreatitis severity. In this review, we will discuss about our current understanding of the pathophysiology of acute pancreatitis.

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          Most cited references76

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          Chemokine receptors: multifaceted therapeutic targets

          Key Points The chemokine family is responsible for the specific, specialized trafficking of leukocytes. Inflammation is characterized by an excessive, inappropriate cellular recruitment. Chemokine receptors are necessary for HIV infection. The large number of chemokines and receptors point to a redundant system. In vitro studies support this, but in vivo studies provide evidence for specificity in the chemokine system. Clinical evidence shows that chemokines and receptors are expressed abundantly in samples and biopsies from patients suffering from inflammatory disorders. Patients that lack CCR5 are resistant to HIV infection. Studies using gene-deleted mice, neutralization of ligands or receptors and small molecule inhibitors have all contributed to our understanding of the chemokine system. Chemokine receptors are valid therapeutic targets for the treatment of inflammation and HIV infection.
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            Clinical and genetic characteristics of hereditary pancreatitis in Europe.

            Hereditary pancreatitis is an autosomal dominant disease that is mostly caused by cationic trypsinogen (PRSS1) gene mutations. The aim was to determine phenotype-genotype correlations of families in Europe. Analysis of data obtained by the European Registry of Hereditary Pancreatitis and Pancreatic Cancer was undertaken using multilevel proportional hazards modelling. There were 112 families in 14 countries (418 affected individuals): 58 (52%) families carried the R122H, 24 (21%) the N29I, and 5 (4%) the A16V mutation, 2 had rare mutations, and 21 (19%) had no PRSS1 mutation. The median (95% confidence interval [CI]) time to first symptoms for R122H was 10 (8, 12) years of age, 14 (11, 18) years for N29I, and 14.5 (10, 21) years for mutation negative patients (P = 0.032). The cumulative risk (95% CI) at 50 years of age for exocrine failure was 37.2% (28.5%, 45.8%), 47.6% (37.1%, 58.1%) for endocrine failure, and 17.5% (12.2%, 22.7%) for pancreatic resection for pain. Time to resection was significantly reduced for females (P < 0.001) and those with the N29I mutation (P = 0.014). The cumulative risk (95% CI) of pancreatic cancer was 44.0% (8.0%, 80.0%) at 70 years from symptom onset with a standardized incidence ratio of 67% (50%, 82%). Symptoms in hereditary pancreatitis start in younger patients and endpoints take longer to be reached compared with other forms of chronic pancreatitis but the cumulative levels of exocrine and endocrine failure are much higher. There is an increasingly high risk of pancreatic cancer after the age of 50 years unrelated to the genotype.
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              Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis.

              Autodigestion of the pancreas by its own prematurely activated digestive proteases is thought to be an important event in the onset of acute pancreatitis. The mechanism responsible for the intrapancreatic activation of digestive zymogens is unknown, but a recent hypothesis predicts that a redistribution of lysosomal cathepsin B (CTSB) into a zymogen-containing subcellular compartment triggers this event. To test this hypothesis, we used CTSB-deficient mice in which the ctsb gene had been deleted by targeted disruption. After induction of experimental secretagogue-induced pancreatitis, the trypsin activity in the pancreas of ctsb(-/-) animals was more than 80% lower than in ctsb(+/+) animals. Pancreatic damage as indicated by serum activities of amylase and lipase, or by the extent of acinar tissue necrosis, was 50% lower in ctsb(-/-) animals. These experiments provide the first conclusive evidence to our knowledge that cathepsin B plays a role in intrapancreatic trypsinogen activation and the onset of acute pancreatitis.
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                Author and article information

                Journal
                PAN
                Pancreatology
                10.1159/issn.1424-3903
                Pancreatology
                S. Karger AG
                1424-3903
                1424-3911
                2005
                May 2005
                09 May 2005
                : 5
                : 2-3
                : 132-144
                Affiliations
                Department of Pharmacology, National University of Singapore, Singapore, Singapore
                Article
                85265 Pancreatology 2005;5:132–144
                10.1159/000085265
                15849484
                3b7357a1-1c9f-4861-9f54-3ad9426b044d
                © 2005 S. Karger AG, Basel and IAP

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                Page count
                Figures: 2, References: 125, Pages: 13
                Categories
                Review

                Oncology & Radiotherapy,Gastroenterology & Hepatology,Surgery,Nutrition & Dietetics,Internal medicine
                Chemokines,Cytokines,Acute pancreatitis,Substance P,Leukocytes,Multiple organ dysfunction syndrome,Adult respiratory distress syndrome,Neurogenic inflammation

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