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1
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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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2
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Masarweh OM, Al-Moussally F, Meruvia Garron JP, Kunadia A, Karasik O, Asmar A. A Fatal Case of Lisinopril-Induced Acute Necrotizing Pancreatitis. Cureus 2023; 15:e40071. [PMID: 37304386 PMCID: PMC10250023 DOI: 10.7759/cureus.40071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 06/06/2023] [Indexed: 06/13/2023] Open
Abstract
Angiotensin-converting enzyme inhibitors (ACE-I), such as lisinopril, are used as first-line therapy in the treatment of hypertension, heart failure with reduced ejection fraction, and proteinuric chronic kidney disease due to their beneficial effects on reducing morbidity and mortality. Commonly cited adverse effects of lisinopril include hyperkalemia, acute kidney injury, and angioedema, and while uncommon, there have been reports of lisinopril-induced necrotizing pancreatitis in the literature. The true incidence of drug-induced pancreatitis is unknown since establishing a causal relationship between medication's adverse effects and disease occurrence is difficult; however, there are validated tools such as the Adverse Drug Reaction Probability Scale that can aid in determining causality. Here, we present a case of a 63-year-old man with a history of hypertension who was being treated with lisinopril for eight months and developed a fatal case of lisinopril-induced severe necrotizing pancreatitis.
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Affiliation(s)
- Omar M Masarweh
- Internal Medicine, University of Central Florida College of Medicine, Orlando, USA
| | - Feras Al-Moussally
- Internal Medicine, University of Central Florida College of Medicine, Orlando, USA
| | | | - Anuj Kunadia
- Internal Medicine, University of Central Florida College of Medicine, Orlando, USA
| | - Olga Karasik
- Internal Medicine, University of Central Florida College of Medicine, Orlando, USA
| | - Abdo Asmar
- Internal Medicine, University of Central Florida College of Medicine, Orlando, USA
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3
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Buxbaum JL, Freeman M, Amateau SK, Chalhoub JM, Chowdhury A, Coelho-Prabhu N, Das R, Desai M, Elhanafi SE, Forbes N, Fujii-Lau LL, Kohli DR, Kwon RS, Machicado JD, Marya NB, Pawa S, Ruan WH, Sadik J, Sheth SG, Thiruvengadam NR, Thosani NC, Zhou S, Qumseya BJ. American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: methodology and review of evidence. Gastrointest Endosc 2023; 97:163-183.e40. [PMID: 36517309 DOI: 10.1016/j.gie.2022.09.011] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 09/26/2022] [Indexed: 01/22/2023]
Affiliation(s)
- James L Buxbaum
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Martin Freeman
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Stuart K Amateau
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jean M Chalhoub
- Department of Gastroenterology and Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, New York, USA
| | - Aneesa Chowdhury
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | | | - Rishi Das
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Madhav Desai
- Department of Gastroenterology, Kansas City VA Medical Center, Kansas City, Missouri, USA
| | - Sherif E Elhanafi
- Department of Gastroenterology, Texas Tech University, El Paso, Texas, USA
| | - Nauzer Forbes
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Divyanshoo R Kohli
- Pancreas and Liver Clinic, Providence Sacred Heart Hospital, Spokane, Washington, USA
| | - Richard S Kwon
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jorge D Machicado
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Neil B Marya
- Division of Gastroenterology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, USA
| | - Swati Pawa
- Department of Gastroenterology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA
| | - Wenly H Ruan
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
| | - Jonathan Sadik
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Sunil G Sheth
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Nikhil R Thiruvengadam
- Department of Gastroenterology and Hepatology, Loma Linda University, Loma Linda, California, USA
| | - Nirav C Thosani
- Center for Interventional Gastroenterology at UTHealth, McGovern Medical School, Houston, Texas, USA
| | - Selena Zhou
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Bashar J Qumseya
- Department of Gastroenterology, University of Florida, Gainesville, Florida, USA
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4
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Buxbaum JL, Freeman M, Amateau SK, Chalhoub JM, Coelho-Prabhu N, Desai M, Elhanafi SE, Forbes N, Fujii-Lau LL, Kohli DR, Kwon RS, Machicado JD, Marya NB, Pawa S, Ruan WH, Sheth SG, Thiruvengadam NR, Thosani NC, Qumseya BJ. American Society for Gastrointestinal Endoscopy guideline on post-ERCP pancreatitis prevention strategies: summary and recommendations. Gastrointest Endosc 2023; 97:153-162. [PMID: 36517310 DOI: 10.1016/j.gie.2022.10.005] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 10/04/2022] [Indexed: 01/22/2023]
Affiliation(s)
- James L Buxbaum
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA
| | - Martin Freeman
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Stuart K Amateau
- Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jean M Chalhoub
- Department of Gastroenterology and Internal Medicine, Staten Island University Hospital, Northwell Health, Staten Island, New York, USA
| | | | - Madhav Desai
- Department of Gastroenterology, Kansas City VA Medical Center, Kansas City, Missouri, USA
| | - Sherif E Elhanafi
- Department of Gastroenterology, Texas Tech University, El Paso, Texas, USA
| | - Nauzer Forbes
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | | | - Divyanshoo R Kohli
- Pancreas and Liver Clinic, Providence Sacred Heart Hospital, Spokane, Washington, USA
| | - Richard S Kwon
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jorge D Machicado
- Division of Gastroenterology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Neil B Marya
- Division of Gastroenterology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, USA
| | - Swati Pawa
- Department of Gastroenterology, Wake Forest School of Medicine, Winston Salem, North Carolina, USA
| | - Wenly H Ruan
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
| | - Sunil G Sheth
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Nikhil R Thiruvengadam
- Department of Gastroenterology and Hepatology, Loma Linda University, Loma Linda, California, USA
| | - Nirav C Thosani
- Center for Interventional Gastroenterology at UTHealth, McGovern Medical School, Houston, Texas, USA
| | - Bashar J Qumseya
- Department of Gastroenterology, University of Florida, Gainesville, Florida, USA
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5
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Zhang T, Gan Y, Zhu S. Association between autophagy and acute pancreatitis. Front Genet 2023; 14:998035. [PMID: 36793898 PMCID: PMC9923090 DOI: 10.3389/fgene.2023.998035] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 01/19/2023] [Indexed: 01/31/2023] Open
Abstract
Autophagy pathway involves maintaining intracellular homeostasis by regulating the degradation of cytoplasmic components. Disfunction of autophagic process has been confirmed to be critical mechanism in many diseases, including cancer, inflammation, infection, degeneration and metabolic disorders. Recent studies have shown that autophagy is one of the early events in acute pancreatitis. Impaired autophagy promotes the abnormal activation of zymogen granules and results in apoptosis and necrosis of exocrine pancreas. Furthermore, multiple signal paths involve progression of acute pancreatitis by regulating autophagy pathway. This article provides a comprehensive review of the recent advances in epigenetic regulation of autophagy and the role of autophagy in acute pancreatitis.
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Affiliation(s)
- Tao Zhang
- Department of Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, China,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China
| | - Yu Gan
- Department of Urology, Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Yu Gan, ; Shuai Zhu,
| | - Shuai Zhu
- Department of Pancreatic Surgery, Xiangya Hospital, Central South University, Changsha, China,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, China,*Correspondence: Yu Gan, ; Shuai Zhu,
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6
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The Pancreas and Known Factors of Acute Pancreatitis. J Clin Med 2022; 11:jcm11195565. [PMID: 36233433 PMCID: PMC9571992 DOI: 10.3390/jcm11195565] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 08/11/2022] [Accepted: 08/30/2022] [Indexed: 11/16/2022] Open
Abstract
Pancreatitis is regarded by clinicians as one of the most complicated and clinically challenging of all disorders affecting the abdomen. It is classified on the basis of clinical, morphological, and histological criteria. Causes of acute pancreatitis can easily be identified in 75–85% of patients. The main causes of acute, recurrent acute, and chronic pancreatitis are gallstone migration and alcohol abuse. Other causes are uncommon, controversial, or unexplained. For instance, cofactors of all forms of pancreatitis are pancreas divisum and hypertriglyceridemia. Another factor that should be considered is a complication of endoscopic retrograde cholangiopancreatography: post-endoscopic retrograde cholangiopancreatography acute pancreatitis. The aim of this study is to present the known risk factors for acute pancreatitis, beginning with an account of the morphology, physiology, and development of the pancreas.
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Cridge H, Lim SY, Algül H, Steiner JM. New insights into the etiology, risk factors, and pathogenesis of pancreatitis in dogs: Potential impacts on clinical practice. J Vet Intern Med 2022; 36:847-864. [PMID: 35546513 PMCID: PMC9151489 DOI: 10.1111/jvim.16437] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 12/11/2022] Open
Abstract
While most cases of pancreatitis in dogs are thought to be idiopathic, potential risk factors are identified. In this article we provide a state‐of‐the‐art overview of suspected risk factors for pancreatitis in dogs, allowing for improved awareness and detection of potential dog‐specific risk factors, which might guide the development of disease prevention strategies. Additionally, we review important advances in our understanding of the pathophysiology of pancreatitis and potential areas for therapeutic manipulation based thereof. The outcome of pathophysiologic mechanisms and the development of clinical disease is dependent on the balance between stressors and protective mechanisms, which can be evaluated using the critical threshold theory.
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Affiliation(s)
- Harry Cridge
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Sue Yee Lim
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, Texas, USA
| | - Hana Algül
- Gastrointestinal Cancer and Inflammatory Research Laboratory, Technical University of Munich, Munich, Germany
| | - Jörg M Steiner
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, Texas, USA
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8
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Yao W, Wang Z, Yang Y, Lan Z, Song J, Jin D, Shi M, Wang G, Bo W, Li M. Treatment of acute pancreatitis with early pancreatic stenting: a case series of 336 patients. Gland Surg 2021; 10:2780-2789. [PMID: 34733727 DOI: 10.21037/gs-21-574] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022]
Abstract
Background Pancreatic duct (PD) obstruction and hypertension may play a central role in the onset and progression of acute pancreatitis (AP). However, only a few studies have reported using pancreatic stenting to relieve PD obstruction in the early phase of AP, with conflicting results. Whether pancreatic stenting is effective in the early phase of AP remains unknown. We conducted this experiment in order to study the therapeutic efficacy and safety of pancreatic stenting in the early stage of AP. Methods We conducted a retrospective analysis of 336 AP patients from 2011 to 2018 who underwent pancreatic stenting within 48 hours of admission. Results A total of 330 (98.2%) patients underwent successful pancreatic stenting, of whom 23 (7.0%) had severe AP, 178 (53.9%) had moderately severe AP, and 129 (39.1%) had mild AP. Visible PD obstructive material was observed in 94 (28.5%) patients. The mean oral refeeding time since admission and length of hospital stay were 3.5±2.7 and 7.4±6.7 days, respectively. Procedure-related adverse events, in-hospital mortality, and local complication rates were 0.3%, 0.3%, and 7.6%, respectively. Conclusions Early endoscopic pancreatic stenting in AP patients effectively shortened the fasting time and length of hospital stay and did not increase the risk of adverse events, death, or local complications. A further prospective randomized controlled clinical trial is currently underway to validate the safety and efficacy of this procedure.
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Affiliation(s)
- Weijie Yao
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Zuozheng Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Yafei Yang
- Department of Clinical Medicine/Surgery, Ningxia Medical University, Yinchuan, China
| | - Zhu Lan
- Department of Clinical Medicine/Surgery, Ningxia Medical University, Yinchuan, China
| | - Jianjun Song
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Dong Jin
- Department of General Surgery & Vascular Surgery, Cardiovascular and Cerebrovascular Disease Hospital of Ningxia Medical University General Hospital, Yinchuan, China
| | - Minghai Shi
- Radiology Department, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Genwang Wang
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Wenping Bo
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
| | - Ming Li
- Department of Hepatobiliary Surgery, General Hospital of Ningxia Medical University, Yinchuan, China
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9
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Petersen OH, Gerasimenko JV, Gerasimenko OV, Gryshchenko O, Peng S. The roles of calcium and ATP in the physiology and pathology of the exocrine pancreas. Physiol Rev 2021; 101:1691-1744. [PMID: 33949875 DOI: 10.1152/physrev.00003.2021] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
This review deals with the roles of calcium ions and ATP in the control of the normal functions of the different cell types in the exocrine pancreas as well as the roles of these molecules in the pathophysiology of acute pancreatitis. Repetitive rises in the local cytosolic calcium ion concentration in the apical part of the acinar cells not only activate exocytosis but also, via an increase in the intramitochondrial calcium ion concentration, stimulate the ATP formation that is needed to fuel the energy-requiring secretion process. However, intracellular calcium overload, resulting in a global sustained elevation of the cytosolic calcium ion concentration, has the opposite effect of decreasing mitochondrial ATP production, and this initiates processes that lead to necrosis. In the last few years it has become possible to image calcium signaling events simultaneously in acinar, stellate, and immune cells in intact lobules of the exocrine pancreas. This has disclosed processes by which these cells interact with each other, particularly in relation to the initiation and development of acute pancreatitis. By unraveling the molecular mechanisms underlying this disease, several promising therapeutic intervention sites have been identified. This provides hope that we may soon be able to effectively treat this often fatal disease.
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Affiliation(s)
- Ole H Petersen
- School of Biosciences, Cardiff University, Cardiff, United Kingdom
| | | | | | | | - Shuang Peng
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, Guangdong, People's Republic of China
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10
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Tran QT, Tran VH, Sendler M, Doller J, Wiese M, Bolsmann R, Wilden A, Glaubitz J, Modenbach JM, Thiel FG, de Freitas Chama LL, Weiss FU, Lerch MM, Aghdassi AA. Role of Bile Acids and Bile Salts in Acute Pancreatitis: From the Experimental to Clinical Studies. Pancreas 2021; 50:3-11. [PMID: 33370017 PMCID: PMC7748038 DOI: 10.1097/mpa.0000000000001706] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022]
Abstract
ABSTRACT Acute pancreatitis (AP) is one of the most common gastroenterological disorders leading to hospitalization. It has long been debated whether biliary AP, about 30% to 50% of all cases, is induced by bile acids (BAs) when they reach the pancreas via reflux or via the systemic blood circulation.Besides their classical function in digestion, BAs have become an attractive research target because of their recently discovered property as signaling molecules. The underlying mechanisms of BAs have been investigated in various studies. Bile acids are internalized into acinar cells through specific G-protein-coupled BA receptor 1 and various transporters. They can further act via different receptors: the farnesoid X, ryanodine, and inositol triphosphate receptor. Bile acids induce a sustained Ca2+ influx from the endoplasmic reticulum and release of Ca2+ from acidic stores into the cytosol of acinar cells. The overload of intracellular Ca2+ results in mitochondrial depolarization and subsequent acinar cell necrosis. In addition, BAs have a biphasic effect on pancreatic ductal cells. A more detailed characterization of the mechanisms through which BAs contribute to the disease pathogenesis and severity will greatly improve our understanding of the underlying pathophysiology and may allow for the development of therapeutic and preventive strategies for gallstone-inducedAP.
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Affiliation(s)
- Quang Trung Tran
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
- Department of Internal Medicine, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Van Huy Tran
- Department of Internal Medicine, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Matthias Sendler
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Julia Doller
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Mats Wiese
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Robert Bolsmann
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Anika Wilden
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Juliane Glaubitz
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | | | | | | | - Frank Ulrich Weiss
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Markus M. Lerch
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ali A. Aghdassi
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
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11
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Choi S, Kim H. The Remedial Potential of Lycopene in Pancreatitis through Regulation of Autophagy. Int J Mol Sci 2020; 21:ijms21165775. [PMID: 32806545 PMCID: PMC7460830 DOI: 10.3390/ijms21165775] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/05/2020] [Accepted: 08/11/2020] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an evolutionarily conserved process that degrades damaged organelles and recycles macromolecules to support cell survival. However, in certain disease states, dysregulated autophagy can play an important role in cell death. In pancreatitis, the accumulation of autophagic vacuoles and damaged mitochondria and premature activation of trypsinogen are shown in pancreatic acinar cells (PACs), which are the hallmarks of impaired autophagy. Oxidative stress mediates inflammatory signaling and cytokine expression in PACs, and it also causes mitochondrial dysfunction and dysregulated autophagy. Thus, oxidative stress may be a mediator for autophagic impairment in pancreatitis. Lycopene is a natural pigment that contributes to the red color of fruits and vegetables. Due to its antioxidant activity, it inhibited oxidative stress-induced expression of cytokines in experimental models of acute pancreatitis. Lycopene reduces cell death through the activation of 5′-AMP-activated protein kinase-dependent autophagy in certain cells. Therefore, lycopene may ameliorate pancreatitis by preventing oxidative stress-induced impairment of autophagy and/or by directly activating autophagy in PACs.
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12
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AL-Saffar FJ, Nasif RH. Morphological Study of The Pancreas and Duodenum in Adult Guinea Pigs (Cavia porcellus). THE IRAQI JOURNAL OF VETERINARY MEDICINE 2020. [DOI: 10.30539/ijvm.v44i1.928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The present study aimed to investigate the morphological features of the pancreas and duodenum of the adult males and females guinea pigs. Eight animals of each sex were collected to conduct this project. The selected organs were photographed in situ and macro morphometric measurements were conducted on them. Gross findings revealed that the pancreas of guinea pig was of compact type, of two lobes (right and left) connected by large central part (body). The organ drains the pancreatic secretion toward the last part of the ascending duodenum via minor pancreatic duct with absence of major pancreatic duct. The duodenum of the guinea pig was very short and V-shaped. The beginning of the duodenum contains duodenal papilla in which found central orifice for the exit of bile secretions of the common bile duct. In conclusions, the present findings showed the presence of only one minor pancreatic duct and such result was significantly different than most rodents by having major pancreatic duct. The duodenum in the studied guinea pigs was characteristically very short and V-shaped differently to other animals that have U-shaped and long duodenum.
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13
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Maatman TK, Heimberger MA, Lewellen KA, Roch AM, Colgate CL, House MG, Nakeeb A, Ceppa EP, Schmidt CM, Zyromski NJ. Visceral artery pseudoaneurysm in necrotizing pancreatitis: incidence and outcomes. Can J Surg 2020; 63:E272-E277. [PMID: 32436687 DOI: 10.1503/cjs.009519] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background Visceral artery pseudoaneurysms (VA-PSA) occur in necrotizing pancreatitis; however, little is known about their natural history. This study sought to evaluate the incidence and outcomes of VA-PSA in a large cohort of patients with necrotizing pancreatitis. Methods Data for patients with necrotizing pancreatitis who were treated between 2005 and 2017 at Indiana University Health University Hospital and who developed a VA-PSA were reviewed to assess incidence, presentation, treatment and outcomes. Results Twenty-eight of 647 patients with necrotizing pancreatitis (4.3%) developed a VA-PSA between 2005 and 2017. The artery most commonly involved was the splenic artery (36%), followed by the gastroduodenal artery (24%). The most common presenting symptom was bloody drain output (32%), followed by incidental computed tomographic findings (21%). The median time from onset of necrotizing pancreatitis to diagnosis of a VA-PSA was 63.5 days (range 1-957 d). Twenty-five of the 28 patients who developed VA-PSA (89%) were successfully treated with percutaneous angioembolization. Three patients (11%) required surgery: 1 patient rebled following embolization and required operative management, and 2 underwent upfront operative management. The mortality rate attributable to hemorrhage from a VA-PSA in the setting of necrotizing pancreatitis was 14% (4 of 28 patients). Conclusion In this study, VA-PSA occurred in 4.3% of patients with necrotizing pancreatitis. Percutaneous angioembolization effectively treated most cases; however, mortality from VA-PSA was high (14%). A high degree of clinical suspicion remains critical for early diagnosis of this potentially fatal problem.
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Affiliation(s)
- Thomas K Maatman
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Mark A Heimberger
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Kyle A Lewellen
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Alexandra M Roch
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Cameron L Colgate
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Michael G House
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Attila Nakeeb
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Eugene P Ceppa
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - C Max Schmidt
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
| | - Nicholas J Zyromski
- From the Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana (Maatman, Roch, House, Nakeed, Ceppa, Schmidt, Zyromski); the Indiana University School of Medicine, Indianapolis, Indiana (Heimberger, Lewellen); and the Center for Outcomes Research in Surgery (CORES), Indiana University School of Medicine, Indianapolis, Indiana (Colgate)
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14
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Sundar V, Senthil Kumar KA, Manickam V, Ramasamy T. Current trends in pharmacological approaches for treatment and management of acute pancreatitis – a review. J Pharm Pharmacol 2020; 72:761-775. [DOI: 10.1111/jphp.13229] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
Abstract
Objectives
Acute pancreatitis (AP) is an inimical disorder associated with overall mortality rates between 10-15%. It is a disorder of the exocrine pancreas which is characterized by local and systemic inflammatory responses primarily driven by oxidative stress and death of pancreatic acinar cells. The severity of AP ranges from mild pancreatic edema with complete recuperative possibilities to serious systemic inflammatory response resulting in peripancreatic/pancreatic necrosis, multiple organ failure, and death.
Key findings
We have retrieved the potential alternative approaches that are developed lately for efficacious treatment of AP from the currently available literature and recently reported experimental studies. This review summarizes the need for alternative approaches and combinatorial treatment strategies to deal with AP based on literature search using specific key words in PubMed and ScienceDirect databases.
Summary
Since AP results from perturbations of multiple signaling pathways, the so called “monotargeted smart drugs” of the past decade is highly unlikely to be effective. Also, the conventional treatment approaches were mainly involved in providing palliative care instead of curing the disease. Hence, many researchers are beginning to focus on developing alternate therapies to treat AP effectively. This review also summarizes the recent trends in the combinatorial approaches available for AP treatment.
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Affiliation(s)
- Vaishnavi Sundar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | | | - Venkatraman Manickam
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Tamizhselvi Ramasamy
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
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15
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Ozbeyli D, Sen A, Cilingir Kaya OT, Ertas B, Aydemir S, Ozkan N, Yuksel M, Sener G. Myrtus communis leaf extract protects against cerulein-induced acute pancreatitis in rats. J Food Biochem 2019; 44:e13130. [PMID: 31851766 DOI: 10.1111/jfbc.13130] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/27/2019] [Accepted: 11/28/2019] [Indexed: 12/13/2022]
Abstract
In this study, the aim was to examine the potential protective effects of Myrtus communis subsp. communis leaf ethanol extract (MC) treatment against acute pancreatitis (AP) in rats. Thirty-two rats were grouped as the saline-pretreated control (C), MC-pretreated control (MC), saline-pretreated AP (AP), and MC-pretreated AP (MC + AP) groups. To induce AP, cerulein was administered (50 µg/kg) two times. The rats were given MC for 14 days before cerulein injection. Six hours after the final cerulein injection, the rats were sacrificed. Pancreatic damage was associated with an increase in the serum activity of lipase and amylase, the pancreatic activity of myeloperoxidase, and the pancreatic level of malondialdehyde, interleukin-1β, and interleukin-6. AP also led to a decrease in the pancreatic level of anti-inflammatory interleukin-10 and glutathione. Pretreatment with MC before the induction of AP significantly reduced the pancreatic damage observed during the histological examination as well as reversed the biochemical changes evoked by AP. PRACTICAL APPLICATIONS: Acute pancreatitis is characterized by high mortality (average about 5%; severe cases may reach about 30%). The current treatment for acute pancreatitis is mainly symptomatic. The introduction of herbal drugs may lead to the development of a new strategy in the treatment of this disease. This study revealed that MC reduced pancreatic injury by decreasing pro-inflammatory cytokines, increasing antioxidant capacity and anti-inflammatory cytokine, IL-10. To the authors' knowledge, this research is the first report showing that MC inhibits the development of AP. This observation suggests that MC may be useful in the prevention and the treatment of AP in clinical settings.
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Affiliation(s)
- Dilek Ozbeyli
- Department of Pathology Laboratory Techniques, Vocational School of Health Services, Marmara University, Istanbul, Turkey
| | - Ali Sen
- Department of Pharmacognosy, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
| | | | - Busra Ertas
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
| | - Sezgin Aydemir
- Department of Pathology Laboratory Techniques, Vocational School of Health Services, Marmara University, Istanbul, Turkey
| | - Naziye Ozkan
- Department of Pathology Laboratory Techniques, Vocational School of Health Services, Marmara University, Istanbul, Turkey
| | - Meral Yuksel
- Department of Medical Laboratory Techniques, Vocational School of Health Services, Marmara University, Istanbul, Turkey
| | - Goksel Sener
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, Istanbul, Turkey
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16
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Zhan X, Wan J, Zhang G, Song L, Gui F, Zhang Y, Li Y, Guo J, Dawra RK, Saluja AK, Haddock AN, Zhang L, Bi Y, Ji B. Elevated intracellular trypsin exacerbates acute pancreatitis and chronic pancreatitis in mice. Am J Physiol Gastrointest Liver Physiol 2019; 316:G816-G825. [PMID: 30943050 PMCID: PMC6620583 DOI: 10.1152/ajpgi.00004.2019] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/28/2019] [Accepted: 03/29/2019] [Indexed: 01/31/2023]
Abstract
Intra-acinar trypsinogen activation occurs in the earliest stages of pancreatitis and is believed to play important roles in pancreatitis pathogenesis. However, the exact role of intra-acinar trypsin activity in pancreatitis remains elusive. Here, we aimed to examine the specific effects of intra-acinar trypsin activity on the development of pancreatitis using a transgenic mouse model. This transgenic mouse model allowed for the conditional expression of a mutant trypsinogen that can be activated specifically inside pancreatic acinar cells. We found that expression of this active mutated trypsin had no significant effect on triggering spontaneous pancreatitis. Instead, several protective compensatory mechanisms, including SPINK1 and heat shock proteins, were upregulated. Notably, these transgenic mice developed much more severe acute pancreatitis, compared with control mice, when challenged with caerulein. Elevated tissue edema, serum amylase, inflammatory cell infiltration and acinar cell apoptosis were dramatically associated with increased trypsin activity. Furthermore, chronic pathological changes were observed in the pancreas of all transgenic mice, including inflammatory cell infiltration, parenchymal atrophy and cell loss, fibrosis, and fatty replacement. These changes were not observed in control mice treated with caerulein. The alterations in pancreata from transgenic mice mimicked the histological changes common to human chronic pancreatitis. Taken together, we provided in vivo evidence that increased intra-acinar activation of trypsinogen plays an important role in the initiation and progression of both acute and chronic pancreatitis. NEW & NOTEWORTHY Trypsinogen is activated early in pancreatitis. However, the roles of trypsin in the development of pancreatitis have not been fully addressed. Using a genetic approach, we showed trypsin activity is critical for the severity of both acute and chronic pancreatitis.
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Affiliation(s)
- Xianbao Zhan
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
- Department of Oncology, Changhai Hospital, Second Military Medical University , Shanghai , China
| | - Jianhua Wan
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Guowei Zhang
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University , Guangzhou , China
| | - Lele Song
- Department of Oncology, Changhai Hospital, Second Military Medical University , Shanghai , China
| | - Fu Gui
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Yuebo Zhang
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Yinghua Li
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Jia Guo
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Rajinder K Dawra
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami , Miami, Florida
| | - Ashok K Saluja
- Department of Surgery, Sylvester Comprehensive Cancer Center, University of Miami , Miami, Florida
| | - Ashley N Haddock
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
| | - Lizhi Zhang
- Department of Pathology, Mayo Clinic , Rochester, Minnesota
| | - Yan Bi
- Department of Gastroenterology and Hepatology, Mayo Clinic , Jacksonville, Florida
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic , Jacksonville, Florida
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Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis. Gastroenterology 2019; 156:1951-1968.e1. [PMID: 30660731 PMCID: PMC6903413 DOI: 10.1053/j.gastro.2018.11.081] [Citation(s) in RCA: 224] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 02/07/2023]
Abstract
Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
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Affiliation(s)
- Julia Mayerle
- Medical Department II, University Hospital, LMU, Munich, Germany,Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Eszter Hegyi
- Institute for Translational Medicine, University of Pécs, Hungary
| | - Georg Beyer
- Medical Department II, University Hospital, LMU, Munich, Germany
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Miklós Sahin-Tóth
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118
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18
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Saluja A, Dudeja V, Dawra R, Sah RP. Early Intra-Acinar Events in Pathogenesis of Pancreatitis. Gastroenterology 2019; 156:1979-1993. [PMID: 30776339 DOI: 10.1053/j.gastro.2019.01.268] [Citation(s) in RCA: 173] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/09/2019] [Accepted: 01/21/2019] [Indexed: 12/11/2022]
Abstract
Premature activation of digestive enzymes in the pancreas has been linked to development of pancreatitis for more than a century. Recent development of novel models to study the role of pathologic enzyme activation has led to advances in our understanding of the mechanisms of pancreatic injury. Colocalization of zymogen and lysosomal fraction occurs early after pancreatitis-causing stimulus. Cathepsin B activates trypsinogen in these colocalized organelles. Active trypsin increases permeability of these organelles resulting in leakage of cathepsin B into the cytosol leading to acinar cell death. Although trypsin-mediated cell death leads to pancreatic injury in early stages of pancreatitis, multiple parallel mechanisms, including activation of inflammatory cascades, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction in the acinar cells are now recognized to be important in driving the profound systemic inflammatory response and extensive pancreatic injury seen in acute pancreatitis. Chymotrypsin, another acinar protease, has recently been shown be play critical role in clearance of pathologically activated trypsin protecting against pancreatic injury. Mutations in trypsin and other genes thought to be associated with pathologic enzyme activation (such as serine protease inhibitor 1) have been found in familial forms of pancreatitis. Sustained intra-acinar activation of nuclear factor κB pathway seems to be key pathogenic mechanism in chronic pancreatitis. Better understanding of these mechanisms will hopefully allow us to improve treatment strategies in acute and chronic pancreatitis.
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19
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Tao L, Lin X, Tan S, Lei Y, Liu H, Guo Y, Zheng F, Wu B. β-Arrestin1 alleviates acute pancreatitis via repression of NF-κBp65 activation. J Gastroenterol Hepatol 2019; 34:284-292. [PMID: 30144357 DOI: 10.1111/jgh.14450] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 08/10/2018] [Accepted: 08/10/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM β-Arrestins (β-arrs) are regulators and mediators of G protein-coupled receptor signaling that are functionally involved in inflammation. Nuclear factor-κB p65 (NF-κBp65) activation has been observed early in the onset of pancreatitis. However, the effect of β-arrs in acute pancreatitis (AP) is unclear. The aim of this study is to investigate whether β-arrs are involved in AP through activation of NF-κBp65. METHODS Acute pancreatitis was induced by either caerulein injection or choline-deficient supplemented with ethionine diet (CDE). β-arr1 wild-type and β-arr1 knockout mice were used in the experiment. The survival rate was calculated in the CDE model mice. Histological and western blot analyses were performed in the caerulein model. Inflammatory mediators were detected by real-time polymerase chain reaction in the caerulein-induced AP mice. Furthermore, AR42J and PANC-1 cell lines were used to further study the effects of β-arr1 in caerulein-induced pancreatic cells. RESULTS β-Arr1 but not β-arr2 is significantly downregulated in caerulein-induced AP in mice. Targeted deletion of β-arr1 notably upregulated expression of the pancreatic inflammatory mediators including tumor necrosis factor α and interleukin 1β as well as interleukin 6 and aggravated AP in caerulein-induced mice. β-Arr1 deficiency increased mortality in mice with CDE-induced AP. Further, β-arr1 deficiency enhanced caerulein-induced phosphorylation of NF-κBp65 both in vivo and in vitro. CONCLUSION β-Arr1 alleviates AP via repression of NF-κBp65 activation, and it is a potentially therapeutic target for AP.
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Affiliation(s)
- Li Tao
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xianyi Lin
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Siwei Tan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yiming Lei
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuwei Guo
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fengping Zheng
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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20
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Plavsic I, Žitinić I, Mikolasevic I, Poropat G, Hauser G. Endoscopic retrograde cholangiopancreatography-induced and non-endoscopic retrograde cholangiopancreatography-induced acute pancreatitis: Two distinct clinical and immunological entities? World J Gastrointest Endosc 2018; 10:259-266. [PMID: 30364685 PMCID: PMC6198307 DOI: 10.4253/wjge.v10.i10.259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 06/10/2018] [Accepted: 08/01/2018] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is common gastrointestinal disease of varied aetiology. The most common cause of AP is gallstones, followed by alcohol abuse as an independent risk factor. With the increased need for invasive techniques to treat pancreatic and bile duct pathologies such as endoscopic retrograde cholangiopancreatography (ERCP), AP has emerged as the most frequent complication. While severe AP following ERCP is rare (0.5%), if it does develop it has a greater severity index compared to non-ERCP AP. Development of a mild form of AP after ERCP is not considered a clinically relevant condition. Differences in the clinical presentation and prognosis of the mild and severe forms have been found between non-ERCP AP and post-endoscopic pancreatitis (PEP). It has been proposed that AP and PEP may also have different immunological responses to the initial injury. In this review, we summarise the literature on clinical and inflammatory processes in PEP vs non-ERCP AP.
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Affiliation(s)
- Ivana Plavsic
- Department of Anesthesiology and Critical care medicine, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Ivana Žitinić
- Department of Emergency Medicine, Clinical Hospital Centre, Rijeka 51000, Croatia
| | - Ivana Mikolasevic
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Poropat
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, University of Rijeka, Rijeka 51000, Croatia
| | - Goran Hauser
- Department of Internal Medicine, Division of Gastroenterology, Clinical Hospital Centre, Medical Faculty, Faculty of health Studies, University of Rijeka, Rijeka 51000, Croatia
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21
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Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis-Knowledge Gaps and Research Opportunities: Overview Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2018; 47:1180-1184. [PMID: 30325855 PMCID: PMC6201320 DOI: 10.1097/mpa.0000000000001176] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A workshop was sponsored by the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, on July 25, 2018, in Pittsburgh, Penn. The workshop was designed to bring together a multidisciplinary group of experts to accelerate the development of therapeutics for clinical application in inflammatory diseases of the exocrine pancreas. Three separate working groups (acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis) were formed to address the needs, gaps, and opportunities. The working groups included patients with pancreatic diseases, pharmaceutical company leaders, basic scientists, clinical researchers, and representatives from the US Food and Drug Administration to assist with regulatory considerations and to identify the unmet needs, research targets, and opportunities to provide direction for successful development of therapeutic agents in these diseases. This article represents the summary of the overview presentations at the National Institute of Diabetes and Digestive and Kidney Diseases workshop including an ongoing drug trial in acute pancreatitis; a successful drug development network developed by the Cystic Fibrosis Foundation; and considerations for subject selection in drug trials, incorporating Food and Drug Administration guidelines on clinical trial design and clinical outcome measures. The summaries of each working group follow separately in accompanying articles.
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22
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Abu-El-Haija M, Gukovskaya AS, Andersen DK, Gardner TB, Hegyi P, Pandol SJ, Papachristou GI, Saluja AK, Singh VK, Uc A, Wu BU. Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis: Summary of the Working Group on Drug Development and Trials in Acute Pancreatitis at the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Pancreas 2018; 47:1185-1192. [PMID: 30325856 PMCID: PMC6692135 DOI: 10.1097/mpa.0000000000001175] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
A workshop was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases to focus on research gaps and opportunities on drug development for pancreatitis. This conference was held on July 25, 2018, and structured into 3 working groups (WG): acute pancreatitis (AP) WG, recurrent AP WG, and chronic pancreatitis WG. This article reports the outcome of the work accomplished by the AP WG to provide the natural history, epidemiology, and current management of AP; inform about the role of preclinical models in therapy selection; and discuss clinical trial designs with clinical and patient-reported outcomes to test new therapies.
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Affiliation(s)
- Maisam Abu-El-Haija
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Anna S. Gukovskaya
- Department of Medicine, University of California, Los Angeles
- Pancreatic Research Group, UCLA/VA Greater Los Angeles Healthcare System, Los Angeles, CA
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Timothy B. Gardner
- Department of Medicine, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine, Darmouth University, Hanover, NH
| | - Peter Hegyi
- MTA-SZTE Translational Gastroenterology Research Group, University of Szeged, Szeged
- Institute for Translational Medicine and First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Stephen J. Pandol
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | - Georgios I. Papachristou
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh Medical Center
- Division of Gastroenterology and Hepatology, Veterans Affairs Pittsburgh Health System, Pittsburgh, PA
| | - Ashok K. Saluja
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL
| | - Vikesh K. Singh
- Division of Gastroenterology, Department of Medicine, University of John’s Hopkins, Baltimore, MD
| | - Aliye Uc
- Stead Family Department of Pediatrics, University of Iowa, Stead Family Children’s Hospital, Iowa City, IA
| | - Bechien U. Wu
- Center for Pancreatic Care, Department of Gastroenterology, Kaiser Permanente Los Angeles Medical Center, Los Angeles, CA
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Majidi S, Golembioski A, Wilson SL, Thompson EC. Acute Pancreatitis: Etiology, Pathology, Diagnosis, and Treatment. South Med J 2017; 110:727-732. [PMID: 29100225 DOI: 10.14423/smj.0000000000000727] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Acute pancreatitis is a fascinating disease. In the United States, the two most common etiologies of acute pancreatitis are gallstones and excessive alcohol consumption. The diagnosis of acute pancreatitis is made with a combination of history, physical examination, computed tomography scan, and laboratory evaluation. Differentiating patients who will have a benign course of their pancreatitis from patients who will have severe pancreatitis is challenging to the clinician. C-reactive protein, pro-calcitonin, and the Bedside Index for Severity of Acute Pancreatitis appeared to be the best tools for the early and accurate diagnosis of severe pancreatitis. Early laparoscopic cholecystectomy is indicated for patients with mild gallstone pancreatitis. For patients who are going to have a prolonged hospitalization, enteral nutrition is preferred. Total parenteral nutrition should be reserved for patients who cannot tolerate enteral nutrition. Prophylactic antibiotics are not indicated for patients with pancreatic necrosis. Surgical intervention for infected pancreatic necrosis should be delayed as long as possible to improve patient outcomes.
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Affiliation(s)
- Shirin Majidi
- From the Joan Edwards School of Medicine, Marshall University, Huntington, West Virginia
| | - Adam Golembioski
- From the Joan Edwards School of Medicine, Marshall University, Huntington, West Virginia
| | - Stephen L Wilson
- From the Joan Edwards School of Medicine, Marshall University, Huntington, West Virginia
| | - Errington C Thompson
- From the Joan Edwards School of Medicine, Marshall University, Huntington, West Virginia
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Luo S, Li P, Li S, Du Z, Hu X, Fu Y, Zhang Z. N,N-Dimethyl Tertiary Amino Group Mediated Dual Pancreas- and Lung-Targeting Therapy against Acute Pancreatitis. Mol Pharm 2017; 14:1771-1781. [PMID: 28247763 DOI: 10.1021/acs.molpharmaceut.7b00028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Acute pancreatitis (AP) is a sudden inflammation of the pancreas with high mortality rate worldwide. As a severe complication to AP, acute lung injury has been the major cause of death among patients with AP. Poor penetration across the blood pancreas barrier (BPB) and insufficient drug accumulation at the target site often result in poor therapeutic outcome. Our previous work successfully demonstrated a dual-specific targeting strategy to pancreas and lung using a phenolic propanediamine moiety. Inspired by this, a simplified ligand structure, N,N-dimethyl tertiary amino group, was covalently conjugated to celastrol (CLT) to afford tertiary amino conjugates via either an ester (CP) or an amide linkage (CTA). With sufficient plasma stability, CTA was subjected to the following studies. Compared to CLT, CTA exhibited excellent cellular uptake efficiency in both rat pancreatic acinar cell line (AR42J) and human pulmonary alveolar epithelial cell line (A549). Organic cation transporters were proven to be responsible for this active transport process. Given systemically, CTA specifically distributed to pancreases and lungs in rats thus resulting in a 2.59-fold and 3.31-fold increase in tissue-specific accumulation as compared to CLT. After CTA treatment, tissue lesions were greatly alleviated and the levels of proinflammatory cytokines were downregulated in rats with sodium taurocholate induced AP. Furthermore, CTA demonstrated marginal adverse effect against major organs with reduced cardiac toxicity compared to CLT. Together, tertiary amine mediated dual pancreas- and lung-targeting therapy represents an efficient and safe strategy for AP management.
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Affiliation(s)
- Shi Luo
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Peiwen Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Sha Li
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Zhengwu Du
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Xun Hu
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Yao Fu
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
| | - Zhirong Zhang
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Chengdu 610041, China
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Abstract
OBJECTIVES To evaluate the effects of certolizumab, a pegylated monoclonal antibody to tumor necrosis factor α (TNF-α), on experimentally induced acute pancreatitis. METHODS Healthy Wistar Albino male rats (n = 36) were randomly divided into 4 groups (9 rats in each group): group 1, control group; group 2, certolizumab group; group 3, cerulein group; and group 4, cerulein + certolizumab group. Acute edematous pancreatitis was induced via intraperitoneal injection of 80-μg/kg cerulein (20 μg/kg, 4 times at 1-hour intervals) in groups 3 and 4. Certolizumab (10 μg) was intraperitoneally administered in groups 2 and 4. Serum levels of amylase, lipase, TNF-α, and lactate dehydrogenase were evaluated. Histopathology and immunohistochemistry of the pancreatic tissue for assessing the activities of malondialdehyde, myeloperoxidase, TNF-α, and caspase-3 were also performed after 72 hours. RESULTS Certolizumab treatment significantly decreased the serum levels of amylase, lipase, and lactate dehydrogenase. Histopathological edema, hemorrhage, parenchymal necrosis, and infiltration scores were also decreased, along with a decrease in malondialdehyde, myeloperoxidase, TNF-α, and caspase-3 activities. CONCLUSION This study suggests that certolizumab is a beneficial treatment mode for reducing the severity of acute pancreatitis.
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Mukherjee R, Mareninova OA, Odinokova IV, Huang W, Murphy J, Chvanov M, Javed MA, Wen L, Booth DM, Cane MC, Awais M, Gavillet B, Pruss RM, Schaller S, Molkentin JD, Tepikin AV, Petersen OH, Pandol SJ, Gukovsky I, Criddle DN, Gukovskaya AS, Sutton R. Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut 2016; 65:1333-46. [PMID: 26071131 PMCID: PMC4920725 DOI: 10.1136/gutjnl-2014-308553] [Citation(s) in RCA: 151] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 03/16/2015] [Accepted: 04/07/2015] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Acute pancreatitis is caused by toxins that induce acinar cell calcium overload, zymogen activation, cytokine release and cell death, yet is without specific drug therapy. Mitochondrial dysfunction has been implicated but the mechanism not established. DESIGN We investigated the mechanism of induction and consequences of the mitochondrial permeability transition pore (MPTP) in the pancreas using cell biological methods including confocal microscopy, patch clamp technology and multiple clinically representative disease models. Effects of genetic and pharmacological inhibition of the MPTP were examined in isolated murine and human pancreatic acinar cells, and in hyperstimulation, bile acid, alcoholic and choline-deficient, ethionine-supplemented acute pancreatitis. RESULTS MPTP opening was mediated by toxin-induced inositol trisphosphate and ryanodine receptor calcium channel release, and resulted in diminished ATP production, leading to impaired calcium clearance, defective autophagy, zymogen activation, cytokine production, phosphoglycerate mutase 5 activation and necrosis, which was prevented by intracellular ATP supplementation. When MPTP opening was inhibited genetically or pharmacologically, all biochemical, immunological and histopathological responses of acute pancreatitis in all four models were reduced or abolished. CONCLUSIONS This work demonstrates the mechanism and consequences of MPTP opening to be fundamental to multiple forms of acute pancreatitis and validates the MPTP as a drug target for this disease.
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Affiliation(s)
- Rajarshi Mukherjee
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Olga A Mareninova
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA
| | - Irina V Odinokova
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
| | - Wei Huang
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
- Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - John Murphy
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Michael Chvanov
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Muhammad A Javed
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Li Wen
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - David M Booth
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Matthew C Cane
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Muhammad Awais
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Bruno Gavillet
- Debiopharm Research and Manufacturing S.A., Lausanne, Switzerland
| | | | | | - Jeffery D Molkentin
- Howard Hughes Medical Institute, Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Alexei V Tepikin
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Ole H Petersen
- Cardiff School of Biosciences, University of Cardiff, Cardiff, Wales, UK
| | - Stephen J Pandol
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA
| | - Ilya Gukovsky
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA
| | - David N Criddle
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Anna S Gukovskaya
- Veterans Affairs Greater Los Angeles Healthcare System, University of California Los Angeles and Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Los Angeles, California, USA
| | - Robert Sutton
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Liverpool, UK
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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Korhonen JT, Dudeja V, Dawra R, Kubes P, Saluja A. Neutrophil Extracellular Traps Provide a Grip on the Enigmatic Pathogenesis of Acute Pancreatitis. Gastroenterology 2015; 149:1682-5. [PMID: 26505817 DOI: 10.1053/j.gastro.2015.10.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
- Juha T Korhonen
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland
| | - Vikas Dudeja
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Rajinder Dawra
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Paul Kubes
- Department of Anaesthesiology, Intensive Care and Pain Medicine, University of Helsinki, Helsinki, Finland; Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
| | - Ashok Saluja
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
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Abstract
Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF-VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis.
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Sah RP, Dudeja V, Dawra RK, Saluja AK. Cerulein-induced chronic pancreatitis does not require intra-acinar activation of trypsinogen in mice. Gastroenterology 2013; 144:1076-1085.e2. [PMID: 23354015 PMCID: PMC3928043 DOI: 10.1053/j.gastro.2013.01.041] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2012] [Revised: 01/02/2013] [Accepted: 01/07/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Premature activation of trypsinogen activation can cause pancreatic injury and has been associated with chronic pancreatitis (CP). Mice that lack intra-acinar activation of trypsinogen, such as trypsinogen-7-null (T(-/-)) and cathepsin B-null (CB(-/-)) mice, have been used to study trypsin-independent processes of CP development. We compared histologic features and inflammatory responses of pancreatic tissues from these mice with those from wild-type mice after the development of CP. METHODS CP was induced in wild-type, T(-/-), and CB(-/-) mice by twice-weekly induction of acute pancreatitis for 10 weeks; acute pancreatitis was induced by hourly intraperitoneal injections of cerulein (50 μg/kg × 6). Pancreatic samples were collected and evaluated by histologic and immunohistochemical analyses. Normal human pancreas samples, obtained from the islet transplant program at the University of Minnesota, were used as controls and CP samples were obtained from surgical resections. RESULTS Compared with pancreatic tissues from wild-type mice, those from T(-/-) and CB(-/-) mice had similar levels of atrophy, histomorphologic features of CP, and chronic inflammation. All samples had comparable intra-acinar activation of nuclear factor (NF)-κB, a transcription factor that regulates the inflammatory response, immediately after injection of cerulein. Pancreatic tissue samples from patients with CP had increased activation of NF-κB (based on nuclear translocation of p65 in acinar cells) compared with controls. CONCLUSIONS Induction of CP in mice by cerulein injection does not require intra-acinar activation of trypsinogen. Pancreatic acinar cells of patients with CP have increased levels of NF-κB activation compared with controls; regulation of the inflammatory response by this transcription factor might be involved in the pathogenesis of CP.
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Abstract
Acute pancreatitis is an inflammatory disease of the exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. Recent findings from experimental models and genetically altered mice summarized in this review reveal that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis and that one cause of autophagy impairment is defective function of lysosomes. We propose that the lysosomal/autophagic dysfunction is a key initiating event in pancreatitis and a converging point of multiple deranged pathways. There is strong evidence supporting this hypothesis. Investigation of autophagy in pancreatitis has just started, and many questions about the "upstream" mechanisms mediating the lysosomal/autophagic dysfunction and the "downstream" links to pancreatitis pathologies need to be explored. Answers to these questions should provide insight into novel molecular targets and therapeutic strategies for treatment of pancreatitis.
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Affiliation(s)
- Anna S. Gukovskaya
- Veterans Affairs Greater Los Angeles Healthcare System and University of California at Los Angeles, Los Angeles, California
| | - Ilya Gukovsky
- Veterans Affairs Greater Los Angeles Healthcare System and University of California at Los Angeles, Los Angeles, California
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Yamamoto M, Wei L, Otani M, Harada M, Otsuki M. Valsartan, a specific angiotensin II receptor blocker, inhibits pancreatic fluid secretion via vagal afferent pathway in conscious rats. ACTA ACUST UNITED AC 2012; 178:80-5. [DOI: 10.1016/j.regpep.2012.06.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2011] [Revised: 03/24/2012] [Accepted: 06/22/2012] [Indexed: 02/01/2023]
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Abstract
PURPOSE OF REVIEW In this article, recent advances in the pathogenesis of acute pancreatitis have been reviewed. RECENT FINDINGS Pathologic intra-acinar trypsinogen activation had been hypothesized to be the central mechanism of pancreatitis for over a century. This hypothesis could be explored for the first time with the development of a novel mouse model lacking pathologic intra-acinar trypsinogen activation. It became clear that intra-acinar trypsinogen activation contributes to early acinar injury, but local and systemic inflammation progress independently during pancreatitis. Early intra-acinar nuclear factor kappa B (NFκB) activation, which occurs parallel to but independent of trypsinogen activation, may be crucial in pancreatitis. Although the mechanism of NFκB and trypsinogen activation is not entirely clear, further insights have been made into key pathogenic cellular events such as calcium signaling, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, autophagy and impaired trafficking, and lysosomal and secretory responses. Cellular intrinsic damage-sensing mechanisms that lead to activation of the inflammatory response aimed at repair, but lead to disease when overwhelmed, are beginning to be understood. SUMMARY New findings necessitate a paradigm shift in our understanding of acute pancreatitis. Intra-acinar trypsinogen activation leads to early pancreatic injury, but the inflammatory response of acute pancreatitis develops independently, driven by early activation of inflammatory pathways.
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Orlichenko L, Stolz DB, Noel P, Behari J, Liu S, Singh VP. ADP-ribosylation factor 1 protein regulates trypsinogen activation via organellar trafficking of procathepsin B protein and autophagic maturation in acute pancreatitis. J Biol Chem 2012; 287:24284-93. [PMID: 22570480 DOI: 10.1074/jbc.m111.328815] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Several studies have suggested that autophagy might play a deleterious role in acute pancreatitis via intra-acinar activation of digestive enzymes. The prototype for this phenomenon is cathepsin B-mediated trypsin generation. To determine the organellar basis of this process, we investigated the subcellular distribution of the cathepsin B precursor, procathepsin B. We found that procathepsin B is enriched in Golgi-containing microsomes, suggesting a role for the ADP-ribosylation (ARF)-dependent trafficking of cathepsin B. Indeed, caerulein treatment increased processing of procathepsin B, whereas a known ARF inhibitor brefeldin A (BFA) prevented this. Similar treatment did not affect processing of procathepsin L. BFA-mediated ARF1 inhibition resulted in reduced cathepsin B activity and consequently reduced trypsinogen activation. However, formation of light chain 3 (LC3-II) was not affected, suggesting that BFA did not prevent autophagy induction. Instead, sucrose density gradient centrifugation and electron microscopy showed that BFA arrested caerulein-induced autophagosomal maturation. Therefore, ARF1-dependent trafficking of procathepsin B and the maturation of autophagosomes results in cathepsin B-mediated trypsinogen activation induced by caerulein.
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Affiliation(s)
- Lidiya Orlichenko
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
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Dawra R, Sah RP, Dudeja V, Rishi L, Saluja AK, Garg P, Saluja AK. Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis. Gastroenterology 2011; 141:2210-2217.e2. [PMID: 21875495 PMCID: PMC3587766 DOI: 10.1053/j.gastro.2011.08.033] [Citation(s) in RCA: 178] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Revised: 08/11/2011] [Accepted: 08/18/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS The role of trypsinogen activation in the pathogenesis of acute pancreatitis (AP) has not been clearly established. METHODS We generated and characterized mice lacking trypsinogen isoform 7 (T7) gene (T(-/-)). The effects of pathologic activation of trypsinogen were studied in these mice during induction of AP with cerulein. Acinar cell death, tissue damage, early intra-acinar activation of the transcription factor nuclear factor κB (NF-κB), and local and systemic inflammation were compared between T(-/-) and wild-type mice with AP. RESULTS Deletion of T7 reduced the total trypsinogen content by 60% but did not affect physiologic function. T(-/-) mice lacked pathologic activation of trypsinogen, which occurs within acinar cells during early stages of AP progression. Absence of trypsinogen activation in T(-/-) mice led to near complete inhibition of acinar cell death in vitro and a 50% reduction in acinar necrosis during AP progression. However, T(-/-) mice had similar degrees of local and systemic inflammation during AP progression and comparable levels of intra-acinar NF-κB activation, which was previously shown to occur concurrently with trypsinogen activation during early stages of pancreatitis. CONCLUSIONS T7 is activated during pathogenesis of AP in mice. Intra-acinar trypsinogen activation leads to acinar death during early stages of pancreatitis, which accounts for 50% of the pancreatic damage in AP. However, progression of local and systemic inflammation in AP does not require trypsinogen activation. NF-κB is activated early in acinar cells, independently of trypsinogen activation, and might be responsible for progression of AP.
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Abstract
Trypsinogen activation is sufficient to induce acute pancreatitis in an experimental model. However, whether it is a requirement for the pathogenesis of acute and chronic pancreatitis remains to be explored.
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Affiliation(s)
- Raghuwansh P Sah
- Department of Surgery, Division of Basic and Translational Research, University of Minnesota, Minneapolis, MN 55455, USA
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Abstract
PURPOSE OF REVIEW Despite being a subject of much scientific scrutiny, the pathogenesis of acute pancreatitis is still not well understood. This article reviews recent advances in our understanding of acute pancreatitis. RECENT FINDINGS Zymogen activation, observed within acini early during acute pancreatitis for a long time, was shown to be sufficient to induce acute pancreatitis. Another key early event, NFκB activation, has previously been shown to induce acute pancreatitis. The relationship between these two key early steps is beginning to be clarified. Mechanisms of zymogen activation - pathologic calcium signaling, pH changes, colocalization and autophagy, and of NFκB activation have been investigated intensively along with potential therapeutic targets both upstream and downstream of these key events. Additional key findings have been elucidation of the role of bioenergetics and the dual role of oxidative stress in acute pancreatitis, recognition of endoplasmic reticulum stress as an early step and the status of duct cells as important entities in pancreatic injury. SUMMARY Current findings have provided further insight into the roles and mechanisms of zymogen activation and inflammatory pathways in pancreatic injury. Future studies, which will be of great importance in identifying therapeutic targets, are being undertaken to establish the relative contributions of these pathways during acute pancreatitis.
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Yang SJ, Chen HM, Hsieh CH, Hsu JT, Yeh CN, Yeh TS, Hwang TL, Jan YY, Chen MF. Akt pathway is required for oestrogen-mediated attenuation of lung injury in a rodent model of cerulein-induced acute pancreatitis. Injury 2011; 42:638-642. [PMID: 20709317 DOI: 10.1016/j.injury.2010.07.242] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Revised: 07/01/2010] [Accepted: 07/12/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND The phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) is known to be an endogenous negative feedback or compensatory mechanism that serves to limit pro-inflammatory and chemotactic events in response to injury. The aim of this study is to elucidate whether Akt plays any role in 17β-estradiol (E2)-mediated attenuation of lung injury after acute pancreatitis (AP). MATERIALS AND METHODS Male Sprague-Dawley rats underwent cerulein-induced AP. Rats were treated with vehicle (cyclodextrin), E2 (1 mg/kg body weight [BW]), or E2 plus PI3K/Akt inhibitor Wortmannin (100 μg/kg BW) 1h after the onset of AP. At 8 h after sham operation or AP, various parameters were measured. RESULTS AP led to a significant decrease in lung Akt phosphorylation, which was associated with increased lung tissue myeloperoxidase (MPO) activity, wet-to-dry weight ratios, interleukin (IL)-6, tumor necrosis factor (TNF)-α, cytokine-induced neutrophil chemoattractant (CINC)-1, and CINC-3 levels. Administration of E2 after AP restored the AP-induced decrease in Akt phosphorylation and attenuated the increase in lung injury markers (MPO activity and wet-to dry weight ratios) and pro-inflammatory mediator production. The effects of E2 on the lung were abolished by co-administration of Wortmannin. CONCLUSIONS These results collectively suggest evidences that the Akt pathway seems to be required for E2-mediated protection of lung injury after AP.
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Affiliation(s)
- Shang-Ju Yang
- Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, 5, Fushing Street, Kweishan Shiang, Taoyuan 333, Taiwan
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Abstract
OBJECTIVES The discovery of novel and effective treatment methods would be of great help to patients with acute pancreatitis. The aims of this study were to determine the inhibitory effects of vitamin K3 (VK3) against cerulein-induced acute pancreatitis in mice and to examine the mechanisms behind these effects. METHODS Acute pancreatitis in mice was induced by intraperitoneal injection of cerulein 6 times at hourly intervals. Vitamin K3 was administered once before the first injection of cerulein or twice before and after the first injection of cerulein. The degrees of inflammation and autophagy in the pancreatic tissue were estimated by histological examination, measurement of enzyme activity, confocal microscopy, and Western blotting. The inhibitory effects of VK3 against rapamycin-induced autophagy were also examined using HeLa cells stably expressing green fluorescent protein LC3. RESULTS Cerulein-induced acute pancreatitis was markedly attenuated by the administration of VK3. In addition, VK3 led to the inhibition of cerulein-evoked autophagic changes and colocalization of autophagosomes and lysosomes in the pancreatic tissue. Vitamin K3 also reduced rapamycin-induced autophagy in HeLa/green fluorescent protein LC3 cells. CONCLUSIONS Our data suggest that the administration of VK3 reduces pancreatic inflammation in acute pancreatitis through inhibition of the autophagic pathway. Vitamin K3 may be an effective therapeutic strategy against acute pancreatitis.
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Abstract
Heat shock proteins (HSPs) are a highly conserved family of proteins which inhabit almost all subcellular locations and cellular membranes. Depending on their location, these proteins perform a variety of chaperoning functions including folding of newly synthesised polypeptides. HSPs also play a major role in the protection of cells against stressful and injury-inciting stimuli. By virtue of this protective function, HSPs have been shown to prevent acinar cell injury in acute pancreatitis. Also, the levels of HSPs have been shown to be markedly elevated in various forms of cancers when compared with non-transformed cells. Further, inhibition of HSPs has been shown to induce apoptotic cell death in cancer cells suggesting that inhibition of HSPs has a potential to emerge as novel anti-cancer therapy, either as monotherapy or in combination with other chemotherapeutic agents. Several studies have suggested that HSPs can interact with and inhibit both intrinsic and extrinsic pathways of apoptosis at multiple sites. Besides the anti-apoptotic role of HSPs, recent studies suggest that they play a role in the generation of anti-cancer immunity, and attempts have been made to utilise this property of HSPs in the generation of anti-cancer vaccines. The anti-apoptotic function and mechanism of various subtypes of HSPs as well as the current status of anti-HSP therapy are discussed in this review.
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Affiliation(s)
- V Dudeja
- Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA
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Abstract
Acute pancreatitis is an inflammatory disease of the pancreas. The etiology and pathogenesis of acute pancreatitis have been intensively investigated for centuries worldwide. Many causes of acute pancreatitis have been discovered, but the pathogenetic theories are controversial. The most common cause of acute pancreatitis is gallstone impacting the distal common bile-pancreatic duct. The majority of investigators accept that the main factors for acute billiary pancreatitis are pancreatic hyperstimulation and bile-pancreatic duct obstruction which increase pancreatic duct pressure and active trypsin reflux. Acute pancreatitis occurs when intracellular protective mechanisms to prevent trypsinogen activation or reduce trypsin activity are overwhelmed. However, little is known about the other acute pancreatitis. We hypothesize that acute biliary pancreatitis and other causes of acute pancreatitis possess a common pathogenesis. Pancreatic hyperstimulation and pancreatic duct obstruction increase pancreatic duct pressure, active trypsin reflux, and subsequent unregulated activation of trypsin within pancreatic acinar cells. Enzyme activation within the pancreas leads to auto-digestion of the gland and local inflammation. Once the hypothesis is confirmed, traditional therapeutic strategies against acute pancreatitis may be improved. Decompression of pancreatic duct pressure should be advocated in the treatment of acute pancreatitits which may greatly improve its outcome.
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Abstract
Pancreatitis (necroinflammation of the pancreas) has both acute and chronic manifestations. Gallstones are the major cause of acute pancreatitis, whereas alcohol is associated with acute as well as chronic forms of the disease. Cases of true idiopathic pancreatitis are steadily diminishing as more genetic causes of the disease are discovered. The pathogenesis of acute pancreatitis has been extensively investigated over the past four decades; the general current consensus is that the injury is initiated within pancreatic acinar cells subsequent to premature intracellular activation of digestive enzymes. Repeated attacks of acute pancreatitis have the potential to evolve into chronic disease characterized by fibrosis and loss of pancreatic function. Our knowledge of the process of scarring has advanced considerably with the isolation and study of pancreatic stellate cells, now established as the key cells in pancreatic fibrogenesis. The present review summarizes recent developments in the field particularly with respect to the progress made in unraveling the molecular mechanisms of acute and chronic pancreatic injury secondary to gallstones, alcohol and genetic factors. It is anticipated that continued research in the area will lead to the identification and characterization of molecular pathways that may be therapeutically targeted to prevent/inhibit the initiation and progression of the disease.
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Affiliation(s)
- Alain Vonlaufen
- Pancreatic Research Group, South Western Sydney Clinical School, Liverpool Hospital and The University of New South Wales, Sydney, Australia
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Hartwig W, Schimmel E, Hackert T, Fortunato F, Bergmann F, Baczako A, Strobel O, Büchler MW, Werner J. A novel animal model of severe pancreatitis in mice and its differences to the rat. Surgery 2008; 144:394-403. [PMID: 18707038 DOI: 10.1016/j.surg.2008.04.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2007] [Accepted: 04/08/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND A noninvasive model of necrohemorrhagic pancreatitis induced by simultaneous intravenous cerulein/enterokinase (EK) infusion has recently been established in rats. The aim of the present study was to establish this new model in mice and to compare it with the rat model. METHODS Male Balb/C mice (20 to 25 g) were used for the experiments. Pancreatitis was induced by simultaneous intravenous infusion of cerulein and EK. Controls were infused with either 0.9% NaCl, cerulein, or EK. Animals were humanely killed 6 hours after start of infusions. Pancreatic and pulmonary injury was assessed by histology, wet-to-dry weight ratio, and myeloperoxidase activity. Systemic cytokine, amylase, and lactate dehydrogenase (LDH) levels in blood were measured to assess pancreatic and systemic inflammatory response. To evaluate the role of protease activity in this model, trypsin, cathepsin B, and elastase activity were measured in pancreatic tissue. Survival experiments were performed to determine survival time and tissue injury in the later course of the disease. RESULTS Mice with simultaneous cerulein/EK infusion developed marked local and systemic organ injury compared with those animals who received cerulein or EK alone. Pancreatic and pulmonary injury increased with high concentrations of cerulein/EK infusions. Survival decreased in these animals. Whereas acinar cell apoptosis was an early finding, pancreatic necrosis was observed later in the course of the disease. Serum levels of LDH, interleukin (IL)-1 alpha, and IL-1 beta reflected cell damage and the systemic inflammatory response. Protease activity in pancreatic tissue was greatest in animals with simultaneous cerulein/EK infusion. CONCLUSIONS Using intravenous cerulein/EK infusions, a model of lethal acute pancreatitis has been established in mice. Major pancreatic edema, acinar cell apoptosis and necrosis, and pulmonary leukocyte sequestration are characteristic findings in this model. Although pancreatic injury was not as strong as in the rat model, this model may prove useful for future studies in transgenic mice.
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Affiliation(s)
- Werner Hartwig
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
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Pereda J, Escobar J, Sandoval J, Rodríguez JL, Sabater L, Pallardó FV, Torres L, Franco L, Viña J, López-Rodas G, Sastre J. Glutamate cysteine ligase up-regulation fails in necrotizing pancreatitis. Free Radic Biol Med 2008; 44:1599-609. [PMID: 18279677 DOI: 10.1016/j.freeradbiomed.2008.01.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2007] [Revised: 01/07/2008] [Accepted: 01/11/2008] [Indexed: 12/22/2022]
Abstract
Glutathione depletion is a key factor in the development of acute pancreatitis. Our aim was to study the regulation of glutamate cysteine ligase, the rate-limiting enzyme in glutathione synthesis, in edematous or necrotizing pancreatitis in rats. Glutathione levels were kept low in necrotizing pancreatitis for several hours, with no increase in protein or mRNA levels of glutamate cysteine ligase subunits, despite binding of RNA polymerase II to their promoters and coding regions. The survival signal pathway mediated by ERK and c-MYC was activated, and c-MYC was recruited to the promoters. The failure in gene up-regulation seems to be due to a marked increase in cytosolic ribonuclease activity. In contrast, in edematous pancreatitis glutathione levels were depleted and rapidly restored, and protein and mRNA expression of glutamate cysteine ligase increased markedly due to enhanced transcription mediated by recruitment of c-MYC, NF-kappaB, and SP-1 to the promoters. No increase in cytosolic ribonuclease activity was found in this case. We propose a novel pathophysiological mechanism to differentiate necrotizing from edematous pancreatitis, which is the inefficient up-regulation of glutamate cysteine ligase caused by increased cytosolic ribonuclease activity in the severe form of the disease. This mechanism would abrogate a rapid recovery of glutathione levels.
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Affiliation(s)
- Javier Pereda
- Department of Physiology, University of Valencia, 46100 Burjasot (Valencia), Spain
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Abstract
OBJECTIVE To test the hypothesis that disruption of acinar cell membranes is the earliest event that takes place after the onset of acute pancreatitis. METHODS Cerulein and taurocholate pancreatitis were induced in rats. Furthermore, stimulation with different doses of bombesin, pilocarpine, and cerulein was performed. Five to 180 minutes after initiation of treatment, animals were killed. Disruption of cell membranes was detected by the penetration of the experimental animal's own albumin or immunoglobulin G (IgG) into acinar cells by immunocytological localization. Tissue was further analyzed by electron microscopy and electron microscopic immunostaining. RESULTS Animals with pancreatitis displayed significantly greater antialbumin and anti-IgG immunostaining in the cytoplasm of acinar cells and in vacuoles in comparison with controls, confirming membrane disruption. This was not detectable after stimulation with bombesin, pilocarpine, and nonsupramaximal doses of cerulein. The first changes were seen after 5 minutes of induction of pancreatitis. Results were verified by electron microscopy and electron microscopic immunohistochemistry. CONCLUSIONS The penetration of albumin and IgG into acinar cells indicates that wounding of their plasma membrane occurs at the onset of acute pancreatitis. Disruption of the membranes could be expected to allow the influx of calcium ions, causing massive intracellular alterations, and exit of molecules, such as enzymes from acinar cells.
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Meyerholz DK, Samuel I. Morphologic characterization of early ligation-induced acute pancreatitis in rats. Am J Surg 2007; 194:652-8. [PMID: 17936429 PMCID: PMC2128702 DOI: 10.1016/j.amjsurg.2007.07.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2007] [Revised: 07/30/2007] [Accepted: 07/30/2007] [Indexed: 01/03/2023]
Abstract
BACKGROUND Bile-pancreatic duct ligation in rats causes acute pancreatic inflammation. We performed serial morphologic evaluation of the exocrine pancreas after duct ligation to facilitate further investigations using the model. METHODS The pancreas was excised from 74 rats after 0, 1, 3, 5, 24 or 48 hours of duct ligation or sham surgery. A pathologist evaluated 1 hematoxylin- and eosin-stained slide from each rat. Confirmatory immunostaining was performed with markers for apoptosis (activated caspase-3), proliferation (cyclin D3), neutrophils (myeloperoxidase), and macrophages (CD68). RESULTS Interstitial edema and white blood cell infiltration were apparent at 24 hours and increased at 48 hours. Progressive periods of duct ligation were characterized by ductular ectasia (1 to 3 hours), acinar vacuolization (5 to 48 hours), leukocytic margination and neutrophil exocytosis (5 to 48 hours), ductule epithelium hypertrophy and proliferation (24 to 48 hours), and discernible loss of zymogen granules (48 hours). CONCLUSIONS Ligation-induced acute pancreatitis in rats is a useful model to investigate early events in disease pathogenesis.
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Affiliation(s)
- David K Meyerholz
- Department of Pathology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA
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Hartwig W, Kolvenbach M, Hackert T, Fortunato F, Schneider L, Büchler MW, Werner J. Enterokinase induces severe necrosis and rapid mortality in cerulein pancreatitis: Characterization of a novel noninvasive rat model of necro-hemorrhagic pancreatitis. Surgery 2007; 142:327-36. [PMID: 17723883 DOI: 10.1016/j.surg.2007.04.023] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2006] [Revised: 04/12/2007] [Accepted: 04/15/2007] [Indexed: 01/30/2023]
Abstract
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.
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Affiliation(s)
- Werner Hartwig
- Department of General, Visceral, and Transplant Surgery, University of Heidelberg, Heidelberg, Germany
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Van Acker GJD, Weiss E, Steer ML, Perides G. Cause-effect relationships between zymogen activation and other early events in secretagogue-induced acute pancreatitis. Am J Physiol Gastrointest Liver Physiol 2007; 292:G1738-46. [PMID: 17332471 DOI: 10.1152/ajpgi.00543.2006] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We have hypothesized that the colocalization of digestive zymogens with lysosomal hydrolases, which occurs during the early stages of every experimental pancreatitis model, facilitates activation of those zymogens by lysosomal hydrolases such as cathepsin B and that this activation triggers acute pancreatitis by leading to acinar cell injury. Some, however, have argued that the colocalization phenomenon may be the result, rather than the cause, of zymogen activation during pancreatitis. To resolve this controversy and explore the causal relationships between zymogen activation and other early pancreatitis events, we induced pancreatitis in mice by repeated supramaximal secretagogue stimulation with caerulein. Some animals were pretreated with the cathepsin B inhibitor CA-074 me to inhibit cathepsin B, prevent intrapancreatic activation of digestive zymogens, and reduce the severity of pancreatitis. We show that inhibition of cathepsin B by pretreatment with CA-074 me prevents intrapancreatic zymogen activation and reduces organellar fragility, but it does not alter the caerulein-induced colocalization phenomenon or subcellular F-actin redistribution or prevent caerulein-induced activation of NF-kappaB, ERK1/2, and JNK or upregulated expression of cytochemokines. We conclude 1) that the colocalization phenomenon, F-actin redistribution, activation of proinflammatory transcription factors, and upregulated expression of cytochemokines are not the results of zymogen activation, and 2) that these early events in pancreatitis are not dependent on cathepsin B activity. In contrast, zymogen activation and increased subcellular organellar fragility during caerulein-induced pancreatitis are dependent on cathepsin B activity.
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Affiliation(s)
- Gijs J D Van Acker
- Dept. of Surgery, Tufts-New England Medical Center, 860 Washington St., Boston, MA 02111, USA
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Abstract
Many animal models are available to investigate the pathogenesis of pancreatitis, an inflammatory disorder of the pancreas. However, the secretagogue hyperstimulation model of pancreatitis is the most commonly used. Animals infused with high doses of cholecystokinin (CCK) exhibit hyperamylasemia, pancreatic edema, and acinar cell injury, which closely mimic pancreatitis in humans. Intra-acinar zymogen activation is an essential early event in the pathogenesis of secretagogue-induced pancreatitis. Early in the course of pancreatitis, lysosomal hydrolases colocalize with digestive zymogens and activate them. These activated zymogens then cause acinar cell injury and necrosis, a characteristic of pancreatitis. Besides being the site of initiation of injury in pancreatitis, acinar cells also synthesize and release cytokines and chemokines very early in the course of pancreatitis, which then attract and activate inflammatory cells and initiate the disease's systemic phase.
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Affiliation(s)
- Ashok K Saluja
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA.
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Affiliation(s)
- Stephen J Pandol
- Department of Medicine, Department of Veterans Affairs and University of California, Los Angeles, California, USA.
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