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1
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Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
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Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
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2
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Fleming Martinez AK, Storz P. Protein kinase D1 - A targetable mediator of pancreatic cancer development. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119646. [PMID: 38061566 PMCID: PMC10872883 DOI: 10.1016/j.bbamcr.2023.119646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 10/17/2023] [Accepted: 11/30/2023] [Indexed: 01/14/2024]
Abstract
Members of the Protein kinase D (PKD) kinase family each play important cell-specific roles in the regulation of normal pancreas functions. In pancreatic diseases PKD1 is the most widely characterized isoform with roles in pancreatitis and in induction of pancreatic cancer and its progression. PKD1 expression and activation increases in pancreatic acinar cells through macrophage secreted factors, Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling, and reactive oxygen species (ROS), driving the formation of precancerous lesions. In precancerous lesions PKD1 regulates cell survival, growth, senescence, and generation of doublecortin like kinase 1 (DCLK1)-positive cancer stem cells (CSCs). Within tumors, regulation by PKD1 includes chemoresistance, apoptosis, proliferation, CSC features, and the Warburg effect. Thus, PKD1 plays a critical role throughout pancreatic disease initiation and progression.
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Affiliation(s)
| | - Peter Storz
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
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3
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Yang J, Li R. Single-Cell Sequencing Data Analysis Unveiled HDAC1 as the Therapeutic Target for Chronic Pancreatitis. Mol Biotechnol 2024; 66:68-78. [PMID: 37022596 DOI: 10.1007/s12033-023-00718-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 03/08/2023] [Indexed: 04/07/2023]
Abstract
Chronic pancreatitis (CP) as a progressive inflammatory disorder, remains untreatable. The novel treatment strategy for CP is imperative. We attempted to explore the therapeutic biomarkers for CP. The single-cell sequencing data were retrieved from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) in idiopathic CP were identified, followed by function and pathway annotation, and PPI network established. DEGs of interest were verified in human tissue samples. The function of candidate biomarker was determined in the murine model with CP. A total of 208 genes were specially differentially expressed in idiopathic patients. Functional enrichment analysis showed DEGs were mainly enriched in glycogen catabolic process, RNA splicing, and glucagon signaling pathway. A PPI network centered on HDAC1 was constructed. HDAC1 was overexpressed in CP patients. The murine model with CP was induced by repetitive cerulein treatment. Silencing sh-HDAC1 treatment reversed cerulein-induced inflammatory cells accumulation, high expression of TGF-β1, and collagen 1 in pancreas in vivo. HDAC1 might be served as potential biomarker for CP. The present study provided insights into the molecular mechanism of CP that may be useful in further investigations.
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Affiliation(s)
- Jie Yang
- Gastroenterology Department, The First Affiliated Hospital of Suzhou University, 899 Pinghai Road, Gusu District, Suzhou, 215000, Jiangsu, China
- Emergency Department, Jiangnan University Medical Center, Wuxi, 214002, Jiangsu, China
| | - Rui Li
- Gastroenterology Department, The First Affiliated Hospital of Suzhou University, 899 Pinghai Road, Gusu District, Suzhou, 215000, Jiangsu, China.
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4
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Whitcomb DC. High Clinical and Genetic Similarity Between Chronic Pancreatitis Associated With Light-to-Moderate Alcohol Consumption and Classical Alcoholic Chronic Pancreatitis. GASTRO HEP ADVANCES 2022; 2:281-282. [PMID: 39132620 PMCID: PMC11307606 DOI: 10.1016/j.gastha.2022.11.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 08/13/2024]
Affiliation(s)
- David C. Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine and Departments of Cell Biology & Molecular Physiology, and Human Genetics, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania, USA
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Mehra S, Srinivasan S, Singh S, Zhou Z, Garrido V, Silva IDC, Totiger TM, Dosch AR, Dai X, Dawra RK, Jala VR, Shi C, Datta J, VanSaun M, Merchant N, Nagathihalli N. Urolithin A attenuates severity of chronic pancreatitis associated with continued alcohol intake by inhibiting PI3K/AKT/mTOR signaling. Am J Physiol Gastrointest Liver Physiol 2022; 323:G375-G386. [PMID: 36098401 PMCID: PMC9602784 DOI: 10.1152/ajpgi.00159.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 08/23/2022] [Accepted: 09/02/2022] [Indexed: 01/31/2023]
Abstract
Heavy alcohol consumption is the dominant risk factor for chronic pancreatitis (CP); however, treatment and prevention strategies for alcoholic chronic pancreatitis (ACP) remains limited. The present study demonstrates that ACP induction in C57BL/6 mice causes significant acinar cell injury, pancreatic stellate cell (PSC) activation, exocrine function insufficiency, and an increased fibroinflammatory response when compared with alcohol or CP alone. Although the withdrawal of alcohol during ACP recovery led to reversion of pancreatic damage, continued alcohol consumption with established ACP perpetuated pancreatic injury. In addition, phosphokinase array and Western blot analysis of ACP-induced mice pancreata revealed activation of the phosphatidylinositol 3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and cyclic AMP response element binding protein (CREB) signaling pathways possibly orchestrating the fibroinflammatory program of ACP pathogenesis. Mice treated with urolithin A (Uro A, a gut-derived microbial metabolite) in the setting of ACP with continued alcohol intake (during the recovery period) showed suppression of AKT and P70S6K activation, and acinar damage was significantly reduced with a parallel reduction in pancreas-infiltrating macrophages and proinflammatory cytokine accumulation. These results collectively provide mechanistic insight into the impact of Uro A on attenuation of ACP severity through suppression of PI3K/AKT/mTOR signaling pathways and can be a useful therapeutic approach in patients with ACP with continuous alcohol intake.NEW & NOTEWORTHY Our novel findings presented here demonstrate the utility of Uro A as an effective therapeutic agent in attenuating alcoholic chronic pancreatitis (ACP) severity with alcohol continuation after established disease, through suppression of the PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Siddharth Mehra
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Supriya Srinivasan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Samara Singh
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Zhiqun Zhou
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Vanessa Garrido
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Iago De Castro Silva
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Tulasigeri M Totiger
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Austin R Dosch
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Xizi Dai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
| | - Rajinder K Dawra
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | | | - Chanjuan Shi
- Department of Pathology, Duke University School of Medicine, Durham, North Carolina
| | - Jashodeep Datta
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Michael VanSaun
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Nipun Merchant
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Nagaraj Nagathihalli
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
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6
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Takeo M, Nishio A, Masuda M, Aoi K, Okazaki T, Fukui T, Uchida K, Naganuma M, Okazaki K. Repeated Stimulation of Toll-Like Receptor 2 and Dectin-1 Induces Chronic Pancreatitis in Mice Through the Participation of Acquired Immunity. Dig Dis Sci 2022; 67:3783-3796. [PMID: 34424458 DOI: 10.1007/s10620-021-07186-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 07/20/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Stimulation of Toll-like receptor 3 (TLR3) induces autoimmune-mediated pancreatitis in susceptible mice, whereas stimulation of TLR4 causes nonautoimmune-mediated pancreatitis. However, the effects of TLR2 stimulation on the pancreas are unknown. AIMS We investigated the role of TLR2 stimulation on pancreatic damage by repeatedly stimulating mice with TLR2 ligands. METHODS Wild-type (WT) and interleukin 10-deficient (IL-10-knockout (KO)) mice were administered zymosan and lipoteichoic acid (LTA) intraperitoneally at various doses twice weekly for 4 weeks. Syngeneic T-cell-deficient mice, B-cell-deficient mice, recombination activating gene 2-deficient (RAG2-KO) mice and RAG2-KO mice that had been reconstituted with CD4+ or CD8+ T cells isolated from WT mice were treated with zymosan similarly. Mice were killed, the severity of pancreatitis was graded histologically, and serum cytokine levels were measured. RESULTS Repeated administration of zymosan induced pancreatitis dose dependently in both WT and IL-10-KO mice. Administration of LTA induced pancreatitis only in IL-10-KO mice. Adoptive transfer of splenocytes obtained from IL-10-KO mice with pancreatitis did not cause pancreatitis in recipient RAG2-KO mice. Pancreatitis was scarcely observed in RAG2-KO mice and was attenuated in T-cell-deficient and B-cell-deficient mice compared with WT mice. A single administration of zymosan significantly increased the serum level of monocyte chemoattractant protein 1 (MCP-1) in WT mice. CONCLUSIONS Repeated stimulation of TLR2 and dectin-1 induced nonautoimmune-mediated pancreatitis in mice. Participation of acquired immunity seems to play an important role in the pathogenesis of pancreatitis in association with the increase in serum MCP-1 level.
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Affiliation(s)
- Masahiro Takeo
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Akiyoshi Nishio
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan.
| | - Masataka Masuda
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Kazunori Aoi
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan
| | - Takashi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University Medical Center, 10-15 Fumizono-cho, Moriguchi, Osaka, 570-8507, Japan
| | - Toshiro Fukui
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kochi Medical School, 185-1 Kohasu Okocho, Nankoku, Kochi, Japan
| | - Makoto Naganuma
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, 2-5-1 Shinmachi, Hirakata, Osaka, Japan
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Alcohol Aggravates Acute Pancreatitis by Impairing Autophagic Flux Through Activation of AMPK Signaling Pathway. Dig Dis Sci 2022; 67:524-535. [PMID: 33555515 DOI: 10.1007/s10620-021-06870-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 01/20/2021] [Indexed: 12/09/2022]
Abstract
OBJECTIVE Alcohol consumption is always the main cause of acute pancreatitis (AP). It has been reported that alcohol exerts direct damage to the pancreas. However, the specific role of alcohol during AP needs to be investigated. This study aims to examine the effects of alcohol in cerulein-induced AP and the role of the AMPK pathway. METHODS Human subjects from operations, cerulein-induced AP rat, and cerulein-stimulated AR42J cell line were enrolled in this study. Electron microscopy was employed for observation of cell morphology, immunohistochemistry for identification of cells, ELISA for detection of inflammation factors, Annexin V/PI double staining for evaluation of cell apoptosis, immunofluorescence for assessment of autophagic flux, oil red O staining for examination of lipid droplet accumulation, and Western blot for measurement of expressions of proteins related to autophagy, apoptosis, and AMPK signal pathway. PI3K inhibitor 3-MA and AMPK inhibitor BML-275 were utilized for investigation of the relationship between impaired autophagic flux and the AMPK pathway by inhibiting or stimulating the formation of autophagosome. RESULTS Alcohol consumption caused lipid droplet accumulation in the pancreas, and it also activated AMPK signaling pathway, thus aggravating the autophagic flux during AP. Alcohol up-regulated the expressions of anti-apoptotic proteins during the induction of AP to inhibit cell apoptosis and enhance cell necrosis. Inhibition of autophagosome formation by AMPK inhibitor BML-275 ameliorated the decreased cell viability caused by alcohol and cerulein in vitro. CONCLUSION Alcohol aggravates AP progression by impairing autophagic flux and enhancing cell autophagy through the AMPK signaling pathway.
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8
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Li H, Wen W, Luo J. Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis. Biomedicines 2022; 10:biomedicines10010108. [PMID: 35052788 PMCID: PMC8773075 DOI: 10.3390/biomedicines10010108] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/04/2023] Open
Abstract
Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.
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Affiliation(s)
- Hui Li
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Wen Wen
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
| | - Jia Luo
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA; (H.L.); (W.W.)
- Iowa City VA Health Care System, Iowa City, IA 52246, USA
- Correspondence: ; Tel.: +1-319-335-2256
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9
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Whitcomb DC. Central role of the sentinel acute pancreatitis event (SAPE) model in understanding recurrent acute pancreatitis (RAP): Implications for precision medicine. Front Pediatr 2022; 10:941852. [PMID: 36046477 PMCID: PMC9421067 DOI: 10.3389/fped.2022.941852] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/21/2022] [Indexed: 11/13/2022] Open
Abstract
Traditional approaches to understanding the origins of chronic pancreatitis (CP) and find treatments led to abysmal failure. Thus, no drugs now exists to meet this need. Outdated concepts of the etiopathogenesis of CP have been replaced with new insights and disease models that provide the framework for early detection of the pathogenic pancreatitis process. Application of these principals require a new paradigm in disease definition and management, i.e. personalized / precision medicine. The key is acute pancreatitis (AP) starting with the first (sentinel) acute pancreatitis (AP) event (SAPE). This event sensitizes the pancreas to recurrent acute pancreatitis (RAP) as ongoing stressors drive various inflammatory responses to cause CP. The problem is the complex etiologies of AP and the additional genetic and environmental factors that promote progression to RAP and CP. This paper provides a background on the key conceptual changes that facilitate new approaches and the rationale for using mechanism-specific therapies to prevent RAP and CP.
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Affiliation(s)
- David C Whitcomb
- Cell Biology and Molecular Physiology, and Human Genetics, Division of Gastroenterology, Hepatology and Nutrition (Chief 1999-2016), University of Pittsburgh and UPMC, Pittsburgh, PA, United States.,Ariel Precision Medicine, Pittsburgh, PA, United States
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10
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Geisz A, Sahin-Tóth M. Sentinel Acute Pancreatitis Event Increases Severity of Subsequent Episodes in Mice. Gastroenterology 2021; 161:1692-1694. [PMID: 34139205 PMCID: PMC8545756 DOI: 10.1053/j.gastro.2021.06.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/17/2021] [Accepted: 06/07/2021] [Indexed: 12/19/2022]
Affiliation(s)
- Andrea Geisz
- Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts.
| | - Miklós Sahin-Tóth
- Department of Surgery, University of California Los Angeles, Los Angeles, California; Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, Massachusetts
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Gut microbiota in pancreatic diseases: possible new therapeutic strategies. Acta Pharmacol Sin 2021; 42:1027-1039. [PMID: 33093569 DOI: 10.1038/s41401-020-00532-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic diseases such as pancreatitis, type 1 diabetes and pancreatic cancer impose substantial health-care costs and contribute to marked morbidity and mortality. Recent studies have suggested a link between gut microbiota dysbiosis and pancreatic diseases; however, the potential roles and mechanisms of action of gut microbiota in pancreatic diseases remain to be fully elucidated. In this review, we summarize the evidence that supports relationship between alterations of gut microbiota and development of pancreatic diseases, and discuss the potential molecular mechanisms of gut microbiota dysbiosis in the pathogenesis of pancreatic diseases. We also propose current strategies toward gut microbiota to advance a developing research field that has clinical potential to reduce the cost of pancreatic diseases.
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12
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Abstract
Chronic pancreatitis is a clinical entity that results from the progressive inflammation and irreversible fibrosis of the pancreas resulting from the cumulative injury sustained by the pancreas over time. It is an illness with variable presentations that can severely impact quality of life, while its long-term complications such as exocrine pancreatic insufficiency (EPI), diabetes mellitus, and risk of pancreatic cancer can become life threatening. The diagnosis of chronic pancreatitis can be challenging as despite the recent advancements in imaging technology, the radiographic findings do not become prominent until late stages of disease. Thus, the physicians' clinical acumen in obtaining thorough history taking focusing on risk factors, clinical symptoms, in addition to high-quality imaging, often guide to the accurate diagnosis of chronic pancreatitis. Endoscopy also plays a pivotal role in the diagnosis and management of chronic pancreatitis. Endoscopic ultrasound (EUS) is believed to be the most sensitive modality for diagnosing chronic pancreatitis. Despite efforts, however, natural history studies have demonstrated that 61% of individuals with chronic pancreatitis will require at least one endoscopic intervention, while 31% will require a surgical procedure as part of their management strategy. Recent advancements in genomic studies have furthered our understanding of the genetic polymorphisms that are associated with the pathogenesis of chronic pancreatitis. Genetic testing offers the potential to reveal treatable pancreatitis-related disorders, and can inform decision making with regard to radical therapies for persistent or severe disease such as total pancreatectomy with islet autotransplantation (TPIAT). The management of patients suffering from chronic pancreatitis often requires a multi-disciplinary approach, addressing pertinent symptoms as well as the sequelae of chronic inflammation and fibrosis. Abdominal pain is the prevailing symptom and most common complication of chronic pancreatitis, and impairs quality of life. Although heavily dependent on a wide range of analgesia, endoscopic treatment such as endoscopic retrograde cholangiopancreatography (ERCP) and surgical intervention can offer long-lasting relief of symptoms. For EPI, treatment with pancreatic enzyme supplements offers marginal-to-moderate relief. The most feared complication of chronic pancreatitis-the development of pancreatic cancer-has no known prevention measure to date.
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Rajapriya S, Geetha A. Effect of luteolin on the gene level expression of apoptosis-associated speck-like protein containing a caspase recruitment domain of NLRP3 inflammasome and NF-κB in rats subjected to experimental pancreatitis - influence of HSP70. J Basic Clin Physiol Pharmacol 2021; 33:477-486. [PMID: 34167178 DOI: 10.1515/jbcpp-2020-0255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 04/14/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Nod-like receptor pyrin domain containing 3 (NLRP3) is one of the well characterized inflammasome that controls the maturation of pro-inflammatory cytokines and thereby the inflammation in pancreas which could be a promising target for anti-inflammatory drugs. The present study is aimed to explore whether luteolin can target the NLRP3 inflammasome and modulate its activity through the signaling protein, HSP70 in the ethanol-cerulein model of experimental pancreatitis. METHODS Male albino Wistar rats were divided into four groups. Groups 1 and 2 rats received normal diet. Groups 3 and 4 rats received isocalorically adjusted diet containing ethanol for 5 weeks and cerulein (20 μg/kg body weight i.p., thrice weekly for the last 3 weeks of the experimental period). Additionally, group 2 and 4 rats received 2 mg/kg body weight of luteolin orally from third week. RESULTS Luteolin co-administration decreased the serum levels of HSP70, oxidative stress markers, myeloperoxidase, GSH/GSSG and GST with concomitant downregulation in the mRNA expression of HSP70, caspase-1, ASC-NLRP3 and NF-κB. Spearman's rank correlation test showed that serum HSP70 has positive correlation with the expression of ASC-NLRP3, caspase-1, NF-κB and 4-hydroxynonenal and negative correlation with GSH:GSSG ratio. CONCLUSIONS The modulating effect of luteolin on the expression of HSP70, NF-κB and thereby on ASC-NLRP3 complex may be claimed for its pancreato-protective activity.
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Affiliation(s)
- Sadanandan Rajapriya
- Department of Biochemistry, Bharathi Women's College, Affiliated to University of Madras, Chennai, Tamil Nadu, India
| | - Arumugam Geetha
- Dr. Ambedkar Government Arts College, Chennai, Tamil Nadu, India
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14
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Chhatriya B, Sarkar P, Nath D, Ray S, Das K, Mohapatra SK, Goswami S. Pilot study identifying circulating miRNA signature specific to alcoholic chronic pancreatitis and its implication on alcohol-mediated pancreatic tissue injury. JGH OPEN 2020; 4:1079-1087. [PMID: 33319040 PMCID: PMC7731805 DOI: 10.1002/jgh3.12389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/15/2020] [Accepted: 06/28/2020] [Indexed: 11/12/2022]
Abstract
Background and Aim Alcohol exerts its effects on organs in multiple ways. Alcoholic chronic pancreatitis (ACP) is a disease in which alcohol triggers the pathological changes in pancreas, leading to chronic inflammation and fibrosis. The molecular mechanism behind these changes is not clear. Identification of key circulating miRNA changes in ACP patients and determination of the fraction that is secreted from diseased pancreas not only could serve as potential biomarker for assessing disease severity, but also could help identifying the molecular alterations prevailing in the organ precipitating the disease, to some extent. Methods We performed microRNA microarray using the Affymetrix miRNA 4.0 platform to identify differentially expressed miRNAs in serum of ACP patients as compared to alcoholic control individuals and then found out how many of them could be pancreas-specific and exosomally secreted. We further analyzed a pancreatitis-specific gene expression data set to find out the differentially expressed genes in diseased pancreas and explored the possible role of those selected miRNAs in regulation of gene expression in ACP. Results We identified 14 miRNAs differentially expressed in both serum and pancreas and also identified their experimentally validated targets. Transcription factors modulating the miRNA expression in an alcohol-dependent manner were also identified and characterized to derive the miRNA-gene-TF interaction network responsible for progression of the disease. Conclusions Differentially expressed miRNA signature demonstrated significant changes in both pro- and anti-inflammatory pathways probably balancing the chronic inflammation in the pancreas. Our findings also suggested possible involvement of pancreatic stellate cells in disease progression.
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Affiliation(s)
| | - Piyali Sarkar
- Department of Cytogenetics Tata Medical Centre Kolkata India
| | - Debashis Nath
- Department of Medicine Indira Gandhi Memorial Hospital Agartala India
| | - Sukanta Ray
- School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata India
| | - Kshaunish Das
- School of Digestive and Liver Diseases Institute of Post Graduate Medical Education and Research Kolkata India
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15
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Zhang Y, Huo X, Lu X, Zeng Z, Faas MM, Xu X. Exposure to multiple heavy metals associate with aberrant immune homeostasis and inflammatory activation in preschool children. CHEMOSPHERE 2020; 257:127257. [PMID: 32534297 DOI: 10.1016/j.chemosphere.2020.127257] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 05/26/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023]
Abstract
Heavy metals generate adverse health effects by interfering with immune homeostasis and promoting inflammation in individuals. Our objective was to explore the induction of immune and inflammatory responses by multiple heavy metals in children living in the e-waste contaminated area. A total of 147 preschool children were recruited, including 73 children from Guiyu, a typical e-waste recycling area, and 74 from a reference group. Blood levels of heavy metals, including lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As), were detected using an inductively coupled plasma mass spectrometry (ICP-MS). Immune cell counts (neutrophils, monocytes, lymphocytes) were determined by an automatic blood cell analyzer, pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and anti-inflammatory cytokines (IL-1RA, IL-4, IL-10, IL-13) were analyzed by a Luminex 200 multiplex immunoassay instrument. Multiple correspondences and linear regression analyses were applied to investigate the relationships between heavy metal exposure and relevant parameters. Results shows Guiyu children had higher levels of Pb, Cd, Hg, As, IL-1β and IL-6, but decreased lymphocyte, IL-1RA and IL-13. Neutrophil count was positively correlated with Pb, Cd and Hg exposure. Anti-inflammatory IL-1RA concentration was negatively related with Pb, Cd, Hg and As, while pro-inflammatory IL-1β and IL-6 were positively correlated with Pb. Guiyu children may have dysregulated immune response and high inflammation risk. Exposure to Pb, Cd, Hg and As could be harmful for immune response and inflammatory regulation. Our finding of decreased IL-RA production in children exposed to Pb, Cd, Hg, and As is novel and could be an opportunity for future research.
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Affiliation(s)
- Yu Zhang
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Provincial Key Laboratory of Infectious Diseases, Shantou University Medical College, Shantou, 515041, Guangdong, China; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ Groningen, the Netherlands
| | - Xia Huo
- School of Environment, Guangzhou Key Laboratory of Environmental Exposure and Health, Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou, 510632, Guangdong, China
| | - Xueling Lu
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Provincial Key Laboratory of Infectious Diseases, Shantou University Medical College, Shantou, 515041, Guangdong, China; Department of Epidemiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ Groningen, the Netherlands
| | - Zhijun Zeng
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Provincial Key Laboratory of Infectious Diseases, Shantou University Medical College, Shantou, 515041, Guangdong, China; Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ Groningen, the Netherlands
| | - Marijke M Faas
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ Groningen, the Netherlands
| | - Xijin Xu
- Laboratory of Environmental Medicine and Developmental Toxicology, Guangdong Provincial Key Laboratory of Infectious Diseases, Shantou University Medical College, Shantou, 515041, Guangdong, China; Department of Cell Biology and Genetics, Shantou University Medical College, Shantou, 515041, Guangdong, China.
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Alcohol and Smoking Mediated Modulations in Adaptive Immunity in Pancreatitis. Cells 2020; 9:cells9081880. [PMID: 32796685 PMCID: PMC7463831 DOI: 10.3390/cells9081880] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/05/2020] [Accepted: 08/06/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatitis is a condition of pancreatic inflammation driven by injury to the pancreatic parenchyma. The extent of acinar insult, intensity, and type of immune response determines the severity of the disease. Smoking, alcohol and autoimmune pancreatitis are some of the predominant risk factors that increase the risk of pancreatitis by differentially influencing the adaptive immune system. The overall decrease in peripheral lymphocyte (T-, B- and (natural killer T-) NKT-cell) count and increased infiltration into the damaged pancreatic tissue highlight the contribution of adaptive immunity in the disease pathology. Smoking and alcohol modulate the responsiveness and apoptosis of T- and B-cells during pancreatic insult. Acute pancreatitis worsens with smoking and alcohol, leading to the development of systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome, suggesting the critical role of adaptive immunity in fatal outcomes such as multiple organ dysfunction. The presence of CD4+ and CD8+ T-lymphocytes and perforin-expressing cells in the fibrotic tissue in chronic pancreatitis modulate the severity of the disease. Due to their important role in altering the severity of the disease, attempts to target adaptive immune mediators will be critical for the development of novel therapeutic interventions.
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17
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Park WG, Li L, Appana S, Wei W, Stello K, Andersen DK, Hughes SJ, Whitcomb DC, Brand RE, Yadav D, Habtezion A. Unique circulating immune signatures for recurrent acute pancreatitis, chronic pancreatitis and pancreatic cancer: A pilot study of these conditions with and without diabetes. Pancreatology 2020; 20:51-59. [PMID: 31791885 PMCID: PMC6983346 DOI: 10.1016/j.pan.2019.11.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 11/17/2019] [Accepted: 11/19/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This exploratory study seeks to identify distinct circulating immune signatures among patients having recurrent acute pancreatitis (RAP), chronic pancreatitis (CP), and pancreatic adenocarcinoma (PDAC). METHODS A retrospective analysis of human serum samples from collaborating institutions of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) was performed. Samples came from the North American Pancreatitis Studies 2 (NAPS2) cohort and the Pancreatic Adenocarcinoma Gene Environment Risk Study (PAGER) and were analyzed using a 62-plex Luminex assay in a blinded fashion. Group and pairwise comparisons were performed to identify unique immune signature panels and to calculate diagnostic utility using area under the curve analysis. RESULTS A total of 179 patients' samples were included: 41 controls, 40 CP, 78 PDAC and 20 RAP patients, of which 20 controls, 20 CP, and 58 PDAC patients had diabetes mellitus (DM). A unique immune signature panel could discriminate RAP, CP, and PDAC from controls with an AUC range from 0.77 to 0.86 (95% CI range: 0.64-0.94), RAP from CP, and CP from PDAC with an AUC of 0.77 (95% CI 0.64-0.90) and 0.76 (95% CI 0.67-0.86), respectively. Furthermore, an immune signature panel could also discriminate PDAC-DM from DM controls with an AUC of 0.96 (95% CI: 0.93-1.00) CONCLUSION: This study identifies unique immune analytes that may serve as novel diagnostic and predictive non-invasive biomarkers of RAP, CP, and PDAC. Further validation is warranted in prospective cohorts as developed by the CPDPC.
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Affiliation(s)
- Walter G Park
- Division of Gastroenterology & Hepatology, Department of Medicine, Stanford University, Stanford, CA, USA.
| | - Liang Li
- Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA
| | - Savitri Appana
- Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA
| | - Wei Wei
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Kimberly Stello
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Steven J Hughes
- Division of Surgical Oncology, Department of Surgery, University of Florida, Gainesville, FL, USA
| | - David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Randall E Brand
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Aida Habtezion
- Division of Gastroenterology & Hepatology, Department of Medicine, Stanford University, Stanford, CA, USA
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Malla RR, Kumari S, Amajala KC, Deepak KGK, Gugalavath S, Rokkam P. Methods and Models in Exploring Pancreatic Functions. EXPLORING PANCREATIC METABOLISM AND MALIGNANCY 2019:253-268. [DOI: 10.1007/978-981-32-9393-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Yuvaraj K, Geetha A. Effect of Morus alba root bark extract on gene-level expression of inflammatory markers in rats subjected to ethanol and cerulein induced pancreatitis- influence of heat shock protein 70. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2018; 16:/j/jcim.ahead-of-print/jcim-2017-0149/jcim-2017-0149.xml. [PMID: 30335608 DOI: 10.1515/jcim-2017-0149] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 07/17/2018] [Indexed: 12/15/2022]
Abstract
Background Chronic pancreatitis (CP) is a persistent inflammation of the pancreas clinically presented with severe abdominal pain, progressive fibrosis, and loss of exocrine and endocrine functions. Inflammasomes, cytosolic multiprotein complexes which regulate the formation of proinflammatory cytokines, are influenced by various factors including heat shock proteins (HSPs). Morus alba L., or white mulberry root bark is a valued traditional Asian medicine with a diverse array of phytochemicals. The aim of this investigation was to define the modulatory action of methanolic extract of Morus alba root bark (MEMARB) on NLRP3 inflammasome, and HSPs in pancreas subjected to inflammatory insult. Methods Pancreatitis was induced in male albino Wistar rats by ethanol (0-36%) and cerulein (20 µg/kg b.wt., i.p.) for 5 weeks with or without MEMARB administration. Serum lipase/amylase (L/A) ratio, oxidative stress index (OSI) and reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio in the pancreas were evaluated. Levels of serum HSP70 was quantified by ELISA. NF-kappa B, NLRP3-ASC, caspase-1, IL-1β, IL-18, and HSP70 gene expression was quantified by quantitative real-time polymerase chain reaction (qPCR). Results L/A ratio and oxidative stress determined in terms of OSI and GSH/GSSG ratio were elevated in pancreatitis-induced rats. The levels were restored in MEMARB co-administered animals. Serum level of HSP70 was increased in pancreatitis-induced animals and dropped significantly in MEMARB co-administrated rats. Pancreatitis-induced group showed increased expression of NF-kappa B, IL-1β, IL-18, caspase-1, NLRP3-ASC and HSP70 mRNA than in MEMARB treated group. Conclusions It can be concluded that the M. alba root extract modulates the expression of HSP70 and NLRP3-ASC which might be attributed to its pancreato-protective effect.
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Affiliation(s)
- Kavitha Yuvaraj
- Department of Biochemistry, Bharathi Women's College, Broadway, Chennai - 600 108, India
| | - Arumugam Geetha
- Department of Biochemistry, Bharathi Women's College, Broadway, Chennai - 600 108, India
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20
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Guo F, Zheng K, Benedé-Ubieto R, Cubero FJ, Nevzorova YA. The Lieber-DeCarli Diet-A Flagship Model for Experimental Alcoholic Liver Disease. Alcohol Clin Exp Res 2018; 42:1828-1840. [DOI: 10.1111/acer.13840] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 07/09/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Feifei Guo
- Department of Genetics, Physiology and Microbiology; Faculty of Biology; Complutense University of Madrid; Madrid Spain
| | - Kang Zheng
- Department of Immunology, Ophthalmology & ORL; School of Medicine; Complutense University of Madrid; Madrid Spain
- 12 de Octubre Health Research Institute (imas12); Madrid Spain
| | - Raquel Benedé-Ubieto
- Department of Genetics, Physiology and Microbiology; Faculty of Biology; Complutense University of Madrid; Madrid Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ORL; School of Medicine; Complutense University of Madrid; Madrid Spain
- 12 de Octubre Health Research Institute (imas12); Madrid Spain
| | - Yulia A. Nevzorova
- Department of Genetics, Physiology and Microbiology; Faculty of Biology; Complutense University of Madrid; Madrid Spain
- Department of Internal Medicine III; University Hospital RWTH Aachen; Aachen Germany
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21
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Whitcomb DC, Shimosegawa T, Chari ST, Forsmark CE, Frulloni L, Pramod G, Hegyi P, Hirooka Y, Irisawa A, Ishikawa T, Isaji S, Lerch MM, Levy P, Masamune A, Wilcox CM, Windsor J, Yadav D, Sheel A, Neoptolemos JP. International consensus statements on early chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group and European Pancreatic Club. Pancreatology 2018; 18:516-527. [PMID: 29793839 PMCID: PMC6748871 DOI: 10.1016/j.pan.2018.05.008] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 05/14/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic pancreatitis (CP) is a progressive inflammatory disorder currently diagnosed by morphologic features. In contrast, an accurate diagnosis of Early CP is not possible using imaging criteria alone. If this were possible and early treatment instituted, the later, irreversible features and complications of CP could possibly be prevented. METHOD An international working group supported by four major pancreas societies (IAP, APA, JPS, and EPC) and a PancreasFest working group sought to develop a consensus definition and diagnostic criteria for Early CP. Ten statements (S1-10) concerning Early CP were used to gauge consensus on the Early CP concept using anonymous voting with a 9 point Likert scale. Consensus required an alpha ≥0.80. RESULTS No consensus statement could be developed for a definition of Early-CP or diagnostic criteria. There was consensus on 5 statements: (S2) The word "Early" in early chronic pancreatitis is used to describe disease state, not disease duration. (S4) Early CP defines a stage of CP with preserved pancreatic function and potentially reversible features. (S8) Genetic variants are important risk factors for Early CP and can add specificity to the likely etiology, but they are neither necessary nor sufficient to make a diagnosis. (S9) Environmental risk factors can provide evidence to support the diagnosis of Early CP, but are neither necessary nor sufficient to make a diagnosis. (S10) The differential diagnosis for Early CP includes other disorders with morphological and functional features that overlap with CP. CONCLUSIONS Morphology based diagnosis of Early CP is not possible without additional information. New approaches to the accurate diagnosis of Early CP will require a mechanistic definition that considers risk factors, biomarkers, clinical context and new models of disease. Such a definition will require prospective validation.
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Affiliation(s)
- David C Whitcomb
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA. USA,Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA,Corresponding Author: David C Whitcomb MD PhD, University of Pittsburgh, Gastroenterology, Room 401.4, 3708 Fifth Ave, Pittsburgh PA 15213 412 578 9515; Fax 412 578-9537,
| | | | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. USA
| | - Christopher E. Forsmark
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainsville, FL USA
| | - Luca Frulloni
- Gastroenterology Unit, Department of Medicine and the Pancreas Institute, University of Verona, Verona, Italy
| | - Garg Pramod
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Peter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary and MTA-SZTE Translational Gastroenterology Research Group, Szeged, Hungary
| | - Yoshiki Hirooka
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Atsushi Irisawa
- Department of Gastroenterology, Dokkyo Medical University, Mibu, Tochigi, JAPAN
| | - Takuya Ishikawa
- Department of Gastroenterology, Nagoya University Hospital, Nagoya, Japan
| | - Shuiji Isaji
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University, Tsu, Japan
| | - Markus M. Lerch
- Division of Gastroenterology and Endocrinology, Ernst-Moritz-Arndt Universität Greifswald, Greifswald, Germany
| | - Philippe Levy
- Service de pancréatologie, Pôle des Maladies de l’Appareil Digestif, DHU UNITY, Centre de référence des maladies rares du pancréas (PAncreatic RAre DISeases), Centre de référence européen des tumeurs neuroendocrines digestives et pancréatiques, Hôpital Beaujon, Faculté Denis Diderot, APHP, Clichy, France
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Charles M. Wilcox
- Division of Gastroenterology & Hepatology, University of Alabama Birmingham, Birmingham, AL, USA
| | - John Windsor
- Department of Surgery, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - Dhiraj Yadav
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA. USA
| | - Andrea Sheel
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GE, UK
| | - John P Neoptolemos
- Department of General, Visceral and Transplantaion Surgery University of Heidelberg, Heidelberg, Germany
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Manohar M, Verma AK, Venkateshaiah SU, Mishra A. Role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Am J Physiol Gastrointest Liver Physiol 2018; 314:G211-G222. [PMID: 28935682 PMCID: PMC5866419 DOI: 10.1152/ajpgi.00210.2017] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/14/2017] [Accepted: 09/19/2017] [Indexed: 02/08/2023]
Abstract
Eosinophilic pancreatitis (EP) is reported in humans; however, the etiology and role of eosinophils in EP pathogenesis are poorly understood and not well explored. Therefore, it is interesting to examine the role of eosinophils in the initiation and progression of pancreatitis pathogenesis. Accordingly, we performed anti-major basic protein immunostaining, chloroacetate esterase, and Masson's trichrome analyses to detect eosinophils, mast cells, and collagen in the tissue sections of mouse and human pancreas. Induced eosinophils accumulation and degranulation were observed in the tissue sections of human pancreatitis, compared with no eosinophils in the normal pancreatic tissue sections. Similarly, we observed induced tissue eosinophilia along with mast cells and acinar cells atrophy in cerulein-induced mouse model of chronic pancreatitis. Additionally, qPCR and ELISA analyses detected induced transcript and protein levels of proinflammatory and profibrotic cytokines, chemokines like IL 5, IL-18, eotaxin-1, eotaxin-2, TGF-β1, collagen-1, collagen-3, fibronectin, and α-SMA in experimental pancreatitis. Mechanistically, we show that eosinophil-deficient GATA1 and endogenous IL-5-deficient mice were protected from the induction of proinflammatory and profibrotic cytokines, chemokines, tissue eosinophilia, and mast cells in a cerulein-induced murine model of pancreatitis. These human and experimental data indicate that eosinophil accumulation and degranulation may have a critical role in promoting pancreatitis pathogenesis including fibrosis. Taken together, eosinophil tissue accumulation needs appropriate attention to understand and restrict the progression of pancreatitis pathogenesis in humans. NEW & NOTEWORTHY The present study for the first time shows that eosinophils accumulate in the pancreas and promote disease pathogenesis, including fibrosis in earlier reported cerulein-induced experimental models of pancreatitis. Importantly, we show that GATA-1 and IL-5 deficiency protects mice form the induction of eosinophil active chemokines, and profibrotic cytokines, including accumulation of tissue collagen in an experimental model of pancreatitis. Additionally, we state that cerulein-induced chronic pancreatitis is independent of blood eosinophilia.
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Affiliation(s)
- Murli Manohar
- Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinophilic Disorders Centre, Tulane University School of Medicine , New Orleans, Louisiana
| | - Alok K Verma
- Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinophilic Disorders Centre, Tulane University School of Medicine , New Orleans, Louisiana
| | - Sathisha Upparahalli Venkateshaiah
- Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinophilic Disorders Centre, Tulane University School of Medicine , New Orleans, Louisiana
| | - Anil Mishra
- Section of Pulmonary Diseases, Department of Medicine, Tulane Eosinophilic Disorders Centre, Tulane University School of Medicine , New Orleans, Louisiana
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Gukovskaya AS, Gukovsky I, Algül H, Habtezion A. Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis. Gastroenterology 2017; 153:1212-1226. [PMID: 28918190 PMCID: PMC6338477 DOI: 10.1053/j.gastro.2017.08.071] [Citation(s) in RCA: 231] [Impact Index Per Article: 28.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 08/09/2017] [Accepted: 08/17/2017] [Indexed: 12/13/2022]
Abstract
Pancreatitis is a common disorder with significant morbidity and mortality, yet little is known about its pathogenesis, and there is no specific or effective treatment. Its development involves dysregulated autophagy and unresolved inflammation, demonstrated by studies in genetic and experimental mouse models. Disease severity depends on whether the inflammatory response resolves or amplifies, leading to multi-organ failure. Dysregulated autophagy might promote the inflammatory response in the pancreas. We discuss the roles of autophagy and inflammation in pancreatitis, mechanisms of deregulation, and connections among disordered pathways. We identify gaps in our knowledge and delineate perspective directions for research. Elucidation of pathogenic mechanisms could lead to new targets for treating or reducing the severity of pancreatitis.
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Affiliation(s)
- Anna S Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California.
| | - Ilya Gukovsky
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, California; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
| | - Hana Algül
- II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
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Manohar M, Verma AK, Venkateshaiah SU, Mishra A. Significance of Eosinophils in Promoting Pancreatic malignancy. ACTA ACUST UNITED AC 2017; 5. [PMID: 29756031 DOI: 10.15226/2374-815x/5/1/001109] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background Several reports indicate that eosinophils are induced in chronic pancreatitis including patients with pancreatic malignancy. However, significance of eosinophilic pancreatitis (EP) is poorly understood and unexplored. Aim Accumulation and degranulation of eosinophils promote pancreatic fibrosis and malignancy. Method Human pancreatic tissue biopsy samples including chronic pancreatitis (n=3), malignant (n=4), non-malignant (n=3), and normal (n=3) were used for H&E, anti-MBP staining, anti-tryptase staining, anti-IgE staining and Mason's trichrome staining. Results We show induced eosinophils and degranulated eosinophils indicated by the presence of anti-MBP stained extracellular granules in the malignant pancreatic (pancreatic cancer) and non-malignant human pancreatic tissues. A comparable number of eosinophils were observed in non-malignant and malignant pancreatic tissue sections, but the sections differed in degranulated eosinophils and the presence of extracellular granules. Additionally, induced mast cells and tissue-specific IgE positive cells were also detected in the tissue sections of malignant pancreatitis patients compared to non-malignant human pancreatic patients. Tissue-specific IgE induction is critical for the degranulation of eosinophils and mast cells that may lead to increased accumulation of collagen in malignant compared to non-malignant human pancreatic tissue samples. We show a large number of anti-tryptase stained extracellular granules in the tissue sections of malignant pancreatic cancer patients. Both IgE and eosinophil major basic proteins (MBP) are reported for the activation and degranulation of mast cells in tissues. Conclusion Taken together, our investigation concludes that eosinophils and mast cells accumulation and degranulation are critical in promoting pancreatitis pathogenesis that may lead to the development of pancreatic fibrosis and malignancy.
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Affiliation(s)
- Murli Manohar
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, USA
| | - Alok K Verma
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, USA
| | - Sathisha Upparahalli Venkateshaiah
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, USA
| | - Anil Mishra
- Department of Medicine, Tulane Eosinophilic Disorders Centre (TEDC), Section of Pulmonary Diseases, Tulane University School of Medicine, USA
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Abstract
Chronic pancreatitis is defined as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. Potential causes can include toxic factors (such as alcohol or smoking), metabolic abnormalities, idiopathic mechanisms, genetics, autoimmune responses and obstructive mechanisms. The pathophysiology of chronic pancreatitis is fairly complex and includes acinar cell injury, acinar stress responses, duct dysfunction, persistent or altered inflammation, and/or neuro-immune crosstalk, but these mechanisms are not completely understood. Chronic pancreatitis is characterized by ongoing inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Functional consequences include recurrent or constant abdominal pain, diabetes mellitus (endocrine insufficiency) and maldigestion (exocrine insufficiency). Diagnosing early-stage chronic pancreatitis is challenging as changes are subtle, ill-defined and overlap those of other disorders. Later stages are characterized by variable fibrosis and calcification of the pancreatic parenchyma; dilatation, distortion and stricturing of the pancreatic ducts; pseudocysts; intrapancreatic bile duct stricturing; narrowing of the duodenum; and superior mesenteric, portal and/or splenic vein thrombosis. Treatment options comprise medical, radiological, endoscopic and surgical interventions, but evidence-based approaches are limited. This Primer highlights the major progress that has been made in understanding the pathophysiology, presentation, prevalence and management of chronic pancreatitis and its complications.
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Lai Y, Yang H, Han W, Guo T, Lv H, Li J, Qian JM. Cigarette smoking associated with chronic pancreatitis: a case control study in China. Tob Induc Dis 2017. [DOI: 10.1186/s12971-017-0142-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Zator Z, Whitcomb DC. Insights into the genetic risk factors for the development of pancreatic disease. Therap Adv Gastroenterol 2017; 10:323-336. [PMID: 28246549 PMCID: PMC5305020 DOI: 10.1177/1756283x16684687] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 09/28/2016] [Indexed: 02/04/2023] Open
Abstract
Diseases of the exocrine pancreas such as recurrent acute pancreatitis (RAP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) represent syndromes defined according to traditional clinicopathologic criteria. The failure of traditional approaches to identify primary mechanisms underlying these progressive disorders illustrates a greater problem of failure of the germ theory of disease for complex disorders. Multiple genetic discoveries and new complex disease models force consideration of a new paradigm of 'precision medicine', requiring a new mechanistic definition of CP. Recognizing the advances in understanding complex gene and environment interactions, as well as the development of new strategies that limit or prevent the development of devastating end-stage diseases of the pancreas may lead to substantial improvements in patient care.
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Affiliation(s)
- Zachary Zator
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Poulsen JL, Olesen SS, Drewes AM, Ye B, Li WQ, Aghdassi AA, Sendler M, Mayerle J, Lerch MM. The Pathogenesis of Chronic Pancreatitis. CHRONIC PANCREATITIS 2017:29-62. [DOI: 10.1007/978-981-10-4515-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Zhan X, Wang F, Bi Y, Ji B. Animal models of gastrointestinal and liver diseases. Animal models of acute and chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol 2016; 311:G343-55. [PMID: 27418683 PMCID: PMC5076005 DOI: 10.1152/ajpgi.00372.2015] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 07/06/2016] [Indexed: 01/31/2023]
Abstract
Animal models of pancreatitis are useful for elucidating the pathogenesis of pancreatitis and developing and testing novel interventions. In this review, we aim to summarize the most commonly used animal models, overview their pathophysiology, and discuss their strengths and limitations. We will also briefly describe common animal study procedures and refer readers to more detailed protocols in the literature. Although animal models include pigs, dogs, opossums, and other animals, we will mainly focus on rodent models because of their popularity. Autoimmune pancreatitis and genetically engineered animal models will be reviewed elsewhere.
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Affiliation(s)
- Xianbao Zhan
- 1Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida and
| | - Fan Wang
- 1Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida and
| | - Yan Bi
- 2Department of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, Florida
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, Florida and
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Lee ATK, Xu Z, Pothula SP, Patel MB, Pirola RC, Wilson JS, Apte MV. Alcohol and cigarette smoke components activate human pancreatic stellate cells: implications for the progression of chronic pancreatitis. Alcohol Clin Exp Res 2015; 39:2123-33. [PMID: 26463405 DOI: 10.1111/acer.12882] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 08/16/2015] [Indexed: 12/30/2022]
Abstract
BACKGROUND Chronic pancreatitis, a known complication of alcohol abuse, is characterized histopathologically by prominent fibrosis. Pancreatic stellate cells (PSCs) are responsible for producing this fibrous tissue in chronic pancreatitis and are activated by alcohol. Progression of alcoholic chronic pancreatitis (as assessed by calcification and fibrosis) is thought to be facilitated by concurrent smoking, but the mechanisms are unknown. This study aimed to (a) determine whether human PSCs (hPSCs) and rat PSCs express nicotinic acetylcholine receptors (nAChRs), which are known to bind 2 important components of cigarette smoke, namely nicotine and nicotine-derived nitrosamine ketone (NNK), and (b) examine the effects of cigarette smoke components in the presence and absence of alcohol on PSC activation in vitro. METHODS Western blotting was used to detect the presence of nAChRs in primary cultures of PSCs. Clinically relevant concentrations of cigarette smoke components (either cigarette smoke extract [CSE], NNK, or nicotine) ± ethanol (EtOH) were used to treat primary cultures of PSCs, and stellate cell activation was assessed by cell migration, proliferation, collagen production, and apoptosis. RESULTS We demonstrate, for the first time, that PSCs express nAChRs (isoforms α3, α7, β, ε) and that the expression of the α7 isoform in hPSCs is induced by CSE + EtOH. We also provide novel findings that PSCs are activated by CSE and NNK (both alone and in combination with EtOH) as evidenced by an increase in cell migration and/or proliferation. Further, we demonstrate that activation of PSCs by CSE + EtOH and NNK + EtOH may be mediated via nAChRs on the cells. CONCLUSIONS PSCs are activated by clinically relevant concentrations of cigarette smoke components (CSE and NNK), alone and in combination with EtOH. Thus, in alcoholics who smoke, progression of pancreatic fibrosis may be facilitated by the combined effects of alcohol and cigarette smoke components on hPSC behavior.
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Affiliation(s)
- Alexandra T K Lee
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
- School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Srinivasa P Pothula
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Mishaal B Patel
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
- School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia
| | - Romano C Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Jeremy S Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
| | - Minoti V Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia
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Abstract
PURPOSE OF REVIEW This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis. RECENT FINDINGS Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation. SUMMARY Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.
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Xue J, Sharma V, Hsieh MH, Chawla A, Murali R, Pandol SJ, Habtezion A. Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nat Commun 2015; 6:7158. [PMID: 25981357 PMCID: PMC4632846 DOI: 10.1038/ncomms8158] [Citation(s) in RCA: 265] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 04/10/2015] [Indexed: 12/17/2022] Open
Abstract
Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.
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Affiliation(s)
- Jing Xue
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Vishal Sharma
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Michael H Hsieh
- Department of Urology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA
| | - Ajay Chawla
- Department of Physiology and Medicine, Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA
| | - Ramachandran Murali
- Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
| | - Stephen J Pandol
- Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
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Kim JY, Lee DY, Lee YJ, Park KJ, Kim KH, Kim JW, Kim WH. Chronic alcohol consumption potentiates the development of diabetes through pancreatic β-cell dysfunction. World J Biol Chem 2015; 6:1-15. [PMID: 25717351 PMCID: PMC4317634 DOI: 10.4331/wjbc.v6.i1.1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Revised: 10/29/2014] [Accepted: 12/10/2014] [Indexed: 02/05/2023] Open
Abstract
Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes (T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcohol consumption and the development of T2D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic β-cell and the exact mechanisms associated with ethanol-mediated β-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-to-moderate ethanol consumption may protect against T2D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2D, particularly with respect to pancreatic β-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanol-produced peroxynitrite contributes to pancreatic β-cell dysfunction and metabolic syndrome.
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The Common Chymotrypsinogen C (CTRC) Variant G60G (C.180T) Increases Risk of Chronic Pancreatitis But Not Recurrent Acute Pancreatitis in a North American Population. Clin Transl Gastroenterol 2015; 6:e68. [PMID: 25569187 PMCID: PMC4418406 DOI: 10.1038/ctg.2014.13] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 09/30/2014] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES: Recurrent acute pancreatitis (RAP) is a complex inflammatory disorder that may progress to fibrosis and other irreversible features recognized as chronic pancreatitis (CP). Chymotrypsinogen C (CTRC) protects the pancreas by degrading prematurely activated trypsinogen. Rare mutations are associated with CP in Europe and Asia. We evaluated the occurrence of CTRC variants in subjects with RAP, CP, and controls from the North American Pancreatitis Study II cohort. METHODS: CP (n=694), RAP (n=448), and controls (n=1017) of European ancestry were evaluated. Subgroup analysis included CFTR and SPINK1 variants, alcohol, and smoking. RESULTS: We identified previously reported rare pathogenic CTRC A73T, R254W, and K247_R254del variants, intronic variants, and G60G (c.180 C>T; rs497078). Compared with controls (minor allele frequency (MAF)=10.8%), c.180T was associated with CP (MAF=16.8%, P<0.00001) but not RAP (MAF=11.9% P=NS). Trend test indicated co-dominant risk for CP (CT odds ratio (OR)=1.36, 95% confidence interval (CI)=1.13–1.64, P=0.0014; TT OR=3.98, 95% CI=2.10–7.56, P<0.0001). The T allele was significantly more frequent with concurrent pathogenic CFTR variants and/or SPINK1 N34S (combined 22.9% vs. 16.1%, OR 1.92, 95% C.I. 1.26–2.94, P=0.0023) and with alcoholic vs. non-alcoholic CP etiologies (20.8% vs. 12.4%, OR=1.9, 95% CI=1.30–2.79, P=0.0009). Alcohol and smoking generally occurred together, but the frequency of CTRC c.180 T in CP, but not RAP, was higher among never drinkers–ever smokers (22.2%) than ever drinker–never smokers (10.8%), suggesting that smoking rather than alcohol may be the driving factor in this association. CONCLUSIONS: The common CTRC variant c.180T acts as disease modifier that promotes progression from RAP to CP, especially in patients with CFTR or SPINK1 variants, alcohol, or smoking.
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Fang F, Pan J, Xu L, Su G, Li G, Wang J. Association between chemokine (C-C motif) ligand 2 gene -2518 A/G polymorphism and pancreatitis risk: a meta-analysis. Pancreatology 2014; 15:53-8. [PMID: 25499426 DOI: 10.1016/j.pan.2014.11.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 11/13/2014] [Accepted: 11/15/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Many studies have focused on the relationship between chemokine (C-C motif) ligand 2 gene (CCL2) -2518 A/G polymorphism and pancreatitis risk, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between CCL2 -2518 A/G polymorphism and pancreatitis risk. METHODS Relevant publications were searched in several widely used databases and six studies were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between CCL2 -2518 A/G polymorphism and pancreatitis risk. RESULTS Significant associations between CCL2 -2518 A/G polymorphism and pancreatitis risk were observed in both overall meta-analysis (OR = 0.62, 95% CI = 0.43-0.89 for AA versus AG + GG; OR = 0.71, 95% CI = 0.51-0.98 for A allele versus G allele), and acute pancreatitis subgroup (OR = 0.56, 95% CI = 0.31-0.99 for AA versus AG + GG), especially severe acute pancreatitis subgroup when compared with controls (OR = 0.48, 95% CI = 0.24-0.97 for AG versus GG; OR = 0.35, 95% CI = 0.18-0.70 for AA + AG versus GG). However, no significant pancreatitis risk variation was detected for all genetic models in the severe acute pancreatitis versus mild acute pancreatitis subgroup and the subgroup analysis based on ethnicity. CONCLUSIONS The CCL2 -2518 A/G polymorphism probably associates with pancreatitis risk, especially severe acute pancreatitis risk when compared with controls, with the G allele acting as a risk factor.
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Affiliation(s)
- Fang Fang
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Jian Pan
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Lixiao Xu
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Guanghao Su
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Gang Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Jian Wang
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China.
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American Pancreatic Association Practice Guidelines in Chronic Pancreatitis: evidence-based report on diagnostic guidelines. Pancreas 2014; 43:1143-62. [PMID: 25333398 PMCID: PMC5434978 DOI: 10.1097/mpa.0000000000000237] [Citation(s) in RCA: 276] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The diagnosis of chronic pancreatitis remains challenging in early stages of the disease. This report defines the diagnostic criteria useful in the assessment of patients with suspected and established chronic pancreatitis. All current diagnostic procedures are reviewed, and evidence-based statements are provided about their utility and limitations. Diagnostic criteria for chronic pancreatitis are classified as definitive, probable, or insufficient evidence. A diagnostic (STEP-wise; survey, tomography, endoscopy, and pancreas function testing) algorithm is proposed that proceeds from a noninvasive to a more invasive approach. This algorithm maximizes specificity (low false-positive rate) in subjects with chronic abdominal pain and equivocal imaging changes. Furthermore, a nomenclature is suggested to further characterize patients with established chronic pancreatitis based on TIGAR-O (toxic, idiopathic, genetic, autoimmune, recurrent, and obstructive) etiology, gland morphology (Cambridge criteria), and physiologic state (exocrine, endocrine function) for uniformity across future multicenter research collaborations. This guideline will serve as a baseline manuscript that will be modified as new evidence becomes available and our knowledge of chronic pancreatitis improves.
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Aruna R, Geetha A, Suguna P. Rutin modulates ASC expression in NLRP3 inflammasome: a study in alcohol and cerulein-induced rat model of pancreatitis. Mol Cell Biochem 2014; 396:269-80. [PMID: 25060908 DOI: 10.1007/s11010-014-2162-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Accepted: 07/14/2014] [Indexed: 12/29/2022]
Abstract
Inflammasomes are protein complexes formed in response to tissue injury and inflammation to regulate the formation of proinflammatory cytokines. Nod-like receptor pyrin domain containing 3 (NLRP3) is one such inflammasome involved in pancreatic inflammation. Caspase activation recruitment domain (CARD) is an interaction motif found in all the major components of NLRP3 inflammasome such as apoptosis associated speck-like CARD containing protein (ASC) and procaspase-1. NLRP3 activates procaspase-1 with the concerted action of CARD domain of ASC. In the present study, the effect of rutin, a natural flavonoid on the expression of ASC of NLRP3, was investigated in rats treated with ethanol (EtOH) and cerulein (Cer). Male albino Wistar rats were divided into four groups. Groups 1 and 2 rats were fed normal diet, whereas groups 3 and 4 rats were fed EtOH (36 % of total calories) containing diet for a total period of 5 weeks and also administered Cer (20 µg/kg body weight i.p.) thrice weekly for the last 3 weeks. In addition, groups 2 and 4 rats received daily 100 mg/kg body weight of rutin from third week. Rutin co-administration significantly decreased the level of pancreatic marker enzymes, oxidative stress markers, inflammatory markers, mRNA expression of caspase-1, cytokines, ASC-NLRP3, and protein expression of caspase-1 and ASC in rats received EtOH-Cer. The results of the study revealed that rutin can reduce inflammation in pancreas probably by influencing the down regulation of ASC-NLRP3 which might result in the reduced activation of caspase-1 and controlled cytokine production.
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Affiliation(s)
- Ravikumar Aruna
- Department of Biochemistry, Bharathi Women's College, Affiliated to University of Madras, Broadway, Chennai, 600 108, Tamil Nadu, India
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Aruna R, Geetha A, Suguna P, Suganya V. Rutin rich Emblica officinalis Geart. fruit extract ameliorates inflammation in the pancreas of rats subjected to alcohol and cerulein administration. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2014; 11:9-18. [PMID: 24516008 DOI: 10.1515/jcim-2013-0023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Accepted: 01/13/2013] [Indexed: 06/03/2023]
Abstract
BACKGROUND The modulating effect of methanolic extract of Emblica officinalis (MEEO) on ethanol (EtOH)- and cerulein (Cer)-induced pancreatitis in rats was investigated in this study. METHODS Male albino Wistar rats were divided into four groups. Group 1 and 2 rats served as control and fed normal diet. Group 3 and 4 rats were fed isocalorically adjusted diet containing EtOH (36% of total calories) for 5 weeks and also subjected to intraperitoneal injection of Cer 20 µg/kg b.wt. thrice weekly for the last 3 weeks of the experimental period. In addition, group 2 and 4 rats received 200 mg/kg b.wt. of MEEO from 15th day till the experimental period. Serum levels of lipase (L), amylase (A), cytokines IL-1β, IL-18, caspase-1 and oxidative stress index (OSI) were determined. Levels of fecal trypsin, total collagen, caspase-1, myeloperoxidase (MPO), antioxidants and mRNA expression of caspase-1, IL-1β and IL-18 were determined in the pancreas. RESULTS HPLC analysis showed the presence of rutin in MEEO. We observed a significant elevation in serum L/A ratio, IL-1β, IL-18, caspase-1, OSI, collagen, MPO activity and the mRNA expression of IL-1β, IL-18 and caspase-1 and significant reduction in fecal trypsin and antioxidant status in EtOH- and Cer-administered rats. The inflammatory markers were found to be reduced and the antioxidant status of pancreas was maintained in MEEO-coadministered rats. CONCLUSIONS The rutin rich nature of E. officinalis can be claimed for its anti-inflammatory and pancreato protective effects.
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Acquired immunity plays an important role in the development of murine experimental pancreatitis induced by alcohol and lipopolysaccharide. Pancreas 2014; 43:28-36. [PMID: 24201778 DOI: 10.1097/mpa.0b013e3182a7c76b] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Although chronic alcohol ingestion is the major cause of chronic pancreatitis, less than 10% of alcohol abusers develop this disease. To address this issue, we created a murine model of pancreatitis induced by alcohol and lipopolysaccharide (LPS) and analyzed its immune responses. METHODS C57BL/6 mice were administered 20% ethanol (AL) in their drinking water and then injected intraperitoneally with LPS twice weekly for 4 weeks. Severe combined immunodeficient mice were reconstituted with splenocytes, CD4 cells, or CD8 T cells isolated from wild-type mice and then treated similarly. The severity of pancreatitis was graded histologically, and serum cytokine levels were measured. RESULTS Ethanol alone did not cause pancreatitis. However, the administration of AL+LPS or LPS alone induced pancreatitis. The histological scores were higher in the mice treated with AL+LPS than in those treated with LPS. Serum levels of interleukin 1β, interferon-γ, and tumor necrosis factor α were elevated in the AL+LPS-treated mice. The severe combined immunodeficient mice developed pancreatitis only after their reconstitution with splenocytes, CD4 cells, or CD8 T cells. CONCLUSIONS Repeated stimulation of the innate immune system is necessary, but not sufficient, to cause pancreatitis. The participation of the acquired immune response is essential for the development of the disease.
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Zhao JB, Liao DH, Nissen TD. Animal models of pancreatitis: Can it be translated to human pain study? World J Gastroenterol 2013; 19:7222-7230. [PMID: 24259952 PMCID: PMC3831203 DOI: 10.3748/wjg.v19.i42.7222] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 08/12/2013] [Accepted: 08/20/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis affects many individuals around the world, and the study of the underlying mechanisms leading to better treatment possibilities are important tasks. Therefore, animal models are needed to illustrate the basic study of pancreatitis. Recently, animal models of acute and chronic pancreatitis have been thoroughly reviewed, but few reviews address the important aspect on the translation of animal studies to human studies. It is well known that pancreatitis is associated with epigastric pain, but the understanding regarding to mechanisms and appropriate treatment of this pain is still unclear. Using animal models to study pancreatitis associated visceral pain is difficult, however, these types of models are a unique way to reveal the mechanisms behind pancreatitis associated visceral pain. In this review, the animal models of acute, chronic and un-common pancreatitis are briefly outlined and animal models related to pancreatitis associated visceral pain are also addressed.
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Whitcomb DC, Lowry LW. Genetic risk factors for pancreatic disorders. Gastroenterology 2013; 144:1292-302. [PMID: 23622139 PMCID: PMC3684061 DOI: 10.1053/j.gastro.2013.01.069] [Citation(s) in RCA: 195] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 01/15/2013] [Accepted: 01/17/2013] [Indexed: 02/06/2023]
Abstract
A combination of genetic, environmental, and metabolic factors contribute to the development and recurrence of acute and chronic pancreatitis; information on all of these is required to manage patients effectively. For example, variants that affect regulation of the protease, serine (PRSS)1-PRSS2, and claudin (CLDN)2 loci, rather than their coding sequences, interact with other genetic and environmental factors to affect disease development. New strategies are needed to use these data and determine their contribution to pathogenesis, because these variants differ from previously studied, rare variants in exons (coding regions) of genes such as PRSS1, SPINK1, cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin (CTR)C, and calcium-sensing receptor (CASR). Learning how various genetic factors affect pancreatic cells and systems could lead to etiology-based therapies rather than treatment of symptoms.
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Affiliation(s)
- David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
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Momi N, Kaur S, Krishn SR, Batra SK. Discovering the route from inflammation to pancreatic cancer. MINERVA GASTROENTERO 2012; 58:283-297. [PMID: 23207606 PMCID: PMC3556910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Pancreatic cancer (PC) remains a complex malignancy with the worst prognosis, lack of early diagnostic symptoms and resistance to conventional chemo- and radiotherapies. A better understanding of the etiology and early developmental events of PC requires profound attention. The evolution of fully blown PC from initial pancreatic injury is a multi-factorial phenomenon with a series of sequential events. The initial acute infection or tissue damage triggers inflammation that, in conjunction with innate immunity, establishes a state of homeostasis to limit harm to the body. Recurrent pancreatic injuries due to genetic susceptibility, smoking, unhealthy diet, and alcohol abuse induces a pro-inflammatory milieu, consisting of various types of immune cells, cytokines, chemokines, growth factors and restructured extracellular matrix, leading to prolonged inflammatory/chronic conditions. Cells having sustained DNA damage and/or mutagenic assault take advantage of this prolonged inflammatory response and aid in the initiation and development of neoplastic/fibrotic events. Eventually, many tumor-stromal interactions result in a chaotic environment accompanied by a loss of immune surveillance and repair response, thereby leading to PC. A better understanding of the inflammatory markers defining this "injury-inflammation-cancer" pathway would help to identify novel molecular targets for early screening and therapeutic intervention for this lethal malignancy.
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Affiliation(s)
- N Momi
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
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43
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Abstract
PURPOSE OF REVIEW To provide an expert review and expert perspective on important advances related to the genetics of acute and chronic pancreatitis. RECENT FINDINGS Provocative new studies highlight the interplay between genetic, developmental, and environmental factors. Key findings include the relationship between pancreas divisum and CFTR mutations, the role of trypsin in acute and recurrent acute pancreatitis, and the discovery of a pancreatitis modifier gene on the X chromosome that provides new clues to why the vast majority of patients with alcoholic pancreatitis are men. SUMMARY Pancreatic genetics is complex, linked to the multiplicative and modifying effects of multiple interacting genetic, structural, and environmental factors. Clinical interpretation will require disease modeling and simulation to understand the combined effect of risk factors that alone are neither sufficient nor necessary to cause disease, and to design treatment strategies that prevent the development of advanced chronic pancreatitis - which by definition is irreversible.
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Abstract
Personalized medicine is a new framework for medical care that involves modelling and simulation of a disease on the basis of its underlying mechanisms. This strategy must replace the 20(th) century paradigm of defining disease by pathology or associated signs and symptoms and conducting outcomes research that is based on the presence or absence of the disease syndrome. New technologies, including next-generation sequencing, the 'omics' and powerful computers provide massive amounts of accurate data. However, attempts to understand complex disorders by applying these new technologies within the 20(th) century framework have failed to produce the expected medical advances. To help physicians embrace a paradigm shift, the limitations of the old framework and major advantages of the new framework must be demonstrated. Chronic pancreatitis is an ideal complex disorder to study to consider the pros and cons of the two frameworks, because the pancreas is such a simple organ for disease modelling, and the advantages of personalized medicine are so profound.
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Affiliation(s)
- David C. Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Department of Cell Biology & Molecular Physiology, and Human Genetics, University of Pittsburgh, Medical Arts Building, 3708 Fifth Avenue, Suite 401.5, Pittsburgh, PA 15213, USA
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Yue F, Zhang X, Zhang H, Jiang X, Gao L, Zhao J. Association of alcohol consumption with the impaired β-cell function independent of body mass index among Chinese men. Endocr J 2012; 59:425-33. [PMID: 22447141 DOI: 10.1507/endocrj.ej12-0003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Alcohol consumption is associated with type 2 diabetes. However, the relationship between alcohol consumption and β-cell function is still unclear. The aim of this study is to investigate the association between them. 675 Chinese men aged 20-75 years were recruited. The subjects were first classified into never drinkers, abstainers, light drinkers (0.1-19.9 g/day) , moderate drinkers (20.0-39.9 g/day) and heavy drinkers (≥ 40.0 g/day) and then, were further divided into two subgroups according to body mass index (BMI) (BMI<25kg/m² and BMI ≥ 25kg/m²). Analysis procedure was adjusted by the confounders including age, smoking status, BMI, waist circumference (WC), blood pressure, lipids and blood uric acid. Compared with never drinkers, alcohol consumption was associated with decreased homeostasis model assessment of β-cell function (HOMA-β) independent of BMI. The homeostasis model assessment of insulin resistance (HOMA-IR) was significantly correlated with alcohol consumption history in the group of BMI<25kg/m² and was significantly correlated with alcohol consumption in the group of BMI ≥ 25kg/m². The results suggest that alcohol consumption is associated with the β-cell dysfunction independent of BMI in Chinese community dwelling men.
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Affiliation(s)
- Feng Yue
- Department of Endocrinology, Provincial Hospital Affiliated to Shandong University, Jinan 250021, China
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Aghdassi AA, Mayerle J, Christochowitz S, Weiss FU, Sendler M, Lerch MM. Animal models for investigating chronic pancreatitis. FIBROGENESIS & TISSUE REPAIR 2011; 4:26. [PMID: 22133269 PMCID: PMC3274456 DOI: 10.1186/1755-1536-4-26] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 12/01/2011] [Indexed: 02/06/2023]
Abstract
Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed.
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Affiliation(s)
- Alexander A Aghdassi
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
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Pandol SJ, Gorelick FS, Gerloff A, Lugea A. Alcohol abuse, endoplasmic reticulum stress and pancreatitis. Dig Dis 2011; 28:776-82. [PMID: 21525762 PMCID: PMC3211518 DOI: 10.1159/000327212] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Alcohol abuse is a common cause of both acute and chronic pancreatitis. There is a wide spectrum of pancreatic manifestations in heavy drinkers from no apparent disease in most individuals to acute inflammatory and necrotizing pancreatitis in a minority of individuals with some progressing to chronic pancreatitis characterized by replacement of the gland by fibrosis and chronic inflammation. Both smoking and African-American ethnicity are associated with increased risk of alcoholic pancreatitis. In this review we describe how our recent studies demonstrate that ethanol feeding in rodents causes oxidative stress in the endoplasmic reticulum (ER) of the digestive enzyme synthesizing acinar cell of the exocrine pancreas. This ER stress is attenuated by a robust unfolded protein response (UPR) involving X-box binding protein-1 (XBP1) in the acinar cell. When the UPR activation is prevented by genetic reduction in XBP1, ethanol feeding causes significant pathological responses in the pancreas. These results suggest that the reason most individuals who drink alcohol heavily do not get significant pancreatic disease is because the pancreas mounts an adaptive UPR to attenuate the ER stress that ethanol causes. We hypothesize that disease in the pancreas results when the UPR is insufficiently robust to alleviate the ER stress caused by alcohol abuse.
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Affiliation(s)
- Stephen J Pandol
- Southern California Research Center for Alcoholic Liver Pancreatic Diseases and Cirrhosis, UCLA Center for Excellence in Pancreatic Diseases, University of California, and VA Greater Los Angeles Health Care System, Los Angeles, Calif., USA.
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Abstract
There is an unacceptably high mortality in acute pancreatitis, which is due to the lack of specific treatments for the disease. A major reason stated to account for the inability to develop effective treatments is that there are multiple pathobiologic pathways activated in the acinar cell mediating pancreatitis making it difficult to choose molecular targets for therapeutic strategies. However, this reasoning limits opportunities for therapeutic development because it does include another important participant in pancreatitis - the pancreatic duct cells. The most recent advance in pancreatitis research is that depletion of both glycolytic and oxidative ATP synthesis is a common event in both acinar and ductal cells. Although ATP has a very short half-life in the blood and is hydrolysed to ADP, there is clear evidence that encapsulating ATP into liposomes can effectively drive ATP into the cells which can be effective in protecting them from necrosis. In this review, we will examine the effects of different insults associated with pancreatitis on both the acinar and ductal components of the exocrine pancreas pointing out the role of the ductal epithelial responses in both attenuating and increasing the severity of pancreatitis. In addition, we propose that exogenous ATP administration may restore ductal and acinar function providing therapeutic benefit.
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Affiliation(s)
- Péter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary.
| | - Stephen Pandol
- Department of Medicine, Veterans Affairs and University of California, Los Angeles, California, USA
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Zoltán Rakonczay
- First Department of Medicine, University of Szeged, Szeged, Hungary
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Li J, Zhou C, Wang R, Liu R, Huang Z, Tang C. Irreversible exocrine pancreatic insufficiency in alcoholic rats without chronic pancreatitis after alcohol withdrawal. Alcohol Clin Exp Res 2011; 34:1843-8. [PMID: 20662806 DOI: 10.1111/j.1530-0277.2010.01272.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Long-term alcohol consumption alone did not cause chronic pancreatitis (CP) but impaired exocrine pancreatic function. This study is to explore the reversibility of exocrine pancreatic insufficiency in the abstinent rats and its mechanism. METHODS Forty-eight healthy male Wistar rats were divided randomly into 4 groups: 6-month control, 6-month ethanol, 9-month control, and 9-month ethanol + withdrawal. Morphological changes of pancreatic acinar cells were observed. Pancreatic amylase and lipase were measured using an automatic biochemical analyzer. Free fatty acid (FFA) in rat intestinal chyme was measured. Cholecystokinin (CCK) levels were determined by radioimmunoassay. The expression of CCK-A receptors was quantitatively analyzed by Western blot. RESULTS Alcohol-induced ultramicrostructure changes of pancreatic acinar cells, including lipid droplets, myelinoid inclusion bodies, dilated rough endoplasmic reticulums, and diminished zymogen granules, were not attenuated after alcohol abstinence. The outputs of amylase and lipase, FFA content in intestinal chyme, and the intestinal and the pancreatic CCK levels in rats were reduced after chronic alcohol intake and were still lower than the control after cessation of alcohol use. Chronic ethanol intake or abstinence did not induce any change in the expression of CCK-A receptors. CONCLUSIONS Exocrine pancreatic insufficiency was irreversible in alcoholic rats without CP after alcohol withdrawal. It may be attributed to reduced pancreatic CCK, long-standing fatty infiltration, ultramicrostructure injuries in pancreatic acinar cells, and aging.
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Affiliation(s)
- Jing Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
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Whitcomb DC. Genetics and alcohol: a lethal combination in pancreatic disease? Alcohol Clin Exp Res 2011; 35:838-42. [PMID: 21303381 DOI: 10.1111/j.1530-0277.2010.01409.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
An association between alcohol consumption and pancreatic diseases has been recognized for decades, but the absolute risk for pancreatic disease for individuals who drink alcohol is low. Other than smoking, few additional environmental factors have been identified, which suggests that genetic risk factors may be important. Studies in our laboratory using the Lieber-DeCarli feeding technique demonstrate that alcohol causes oxidative stress and mitochondrial damage and alters neruohormonal regulation of the pancreas after a threshold dose is exceeded, which makes the pancreas susceptible to withdrawal hypersensitivity and acute pancreatitis. Alcohol also shifts cell death from apoptosis to necrosis and promotes fibrosis through anti-inflammatory immune mechanisms. Others have demonstrated that alcohol lowers the threshold for trypsin activation in acinar cells, which increases sensitivity to triggering pancreatitis. In addition, we used the Lieber-DeCarli diet plus recurrent acute pancreatitis insults to develop the first animal model of chronic pancreatitis that mimics human disease. Finally, our North American Pancreatitis Study 2 (NAPS2), which was built on insights from animal studies, confirmed the threshold effect predicted by Charles Lieber (>5 drinks per day and >35 drinks/week). These studies and others also defined distinctive roles of alcohol and genetics in the etiology and progression of chronic pancreatitis.
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Affiliation(s)
- David C Whitcomb
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh & UPMC, Pennsylvania 15213, USA.
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