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Sastre J, Pérez S, Sabater L, Rius-Pérez S. Redox signaling in the pancreas in health and disease. Physiol Rev 2025; 105:593-650. [PMID: 39324871 DOI: 10.1152/physrev.00044.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/27/2024] Open
Abstract
This review addresses oxidative stress and redox signaling in the pancreas under healthy physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione (GSH) in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, with PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the transsulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial reactive oxygen species (ROS), which trigger acinar-to-ductal metaplasia and progression to pancreatic intraepithelial neoplasia (PanIN). ROS are maintained at a sufficient level to promote cell proliferation, while avoiding cell death or senescence through formation of NADPH and GSH and activation of NRF2, HIF-1/2α, and CREB. Redox signaling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.
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Affiliation(s)
- Juan Sastre
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Salvador Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Liver, Biliary and Pancreatic Unit, Hospital Clínico, Department of Surgery, Faculty of Medicine, University of Valencia, Valencia, Spain
| | - Sergio Rius-Pérez
- Department of Physiology, Faculty of Pharmacy, University of Valencia, Valencia, Spain
- Department of Cell Biology, Functional Biology and Physical Anthropology, Faculty of Biology, University of Valencia, Valencia, Spain
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2
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Xing A, Wang F, Liu J, Zhang Y, He J, Zhao B, Sun B. The prospect and underlying mechanisms of Chinese medicine in treating periodontitis. Chin J Nat Med 2025; 23:269-285. [PMID: 40122658 DOI: 10.1016/s1875-5364(25)60842-9] [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: 03/22/2024] [Revised: 06/18/2024] [Accepted: 07/13/2024] [Indexed: 03/25/2025]
Abstract
Inflammation represents a critical immune response triggered by cellular activities and inflammatory mediators following tissue damage. It plays a central role in the pathological progression of diverse diseases, including psychiatric disorders, cancer, and immunological conditions, rendering it an essential target for therapeutic intervention. Periodontitis, a prevalent oral inflammatory disease, is a leading cause of tooth loss and poses significant health challenges globally. Traditionally, inflammatory diseases such as periodontitis have been treated with systemic administration of synthetic chemicals. However, recent years have witnessed challenges, including drug resistance and microbial dysbiosis associated with these treatments. In contrast, natural products derived from Chinese medicine offer numerous benefits, such as high safety profiles, minimal side effects, innovative pharmacological mechanisms, ease of extraction, and multiple targets, rendering them viable alternatives to conventional antibiotics for treating inflammatory conditions. Numerous effective anti-inflammatory natural products have been identified in traditional Chinese medicine (TCM), including alkaloids, flavonoids, terpenoids, lignans, and other natural products that exhibit inhibitory effects on inflammation and are potential therapeutic agents. Several studies have confirmed the substantial anti-inflammatory and immunomodulatory properties of these compounds. This comprehensive review examines the literature on the anti-inflammatory effects of TCM-derived natural products from databases such as PubMed, Web of Science, and CNKI, focusing on terms like "inflammation", "periodontitis", "pharmacology", and "traditional Chinese medicine". The analysis systematically summarizes the molecular pharmacology, chemical composition, and biological activities of these compounds in inflammatory responses, alongside their mechanisms of action. This research seeks to deepen understanding of the mechanisms and biological activities of herbal extracts in managing inflammatory diseases, potentially leading to the development of promising new anti-inflammatory drug candidates. Future applications could extend to the treatment of various inflammatory conditions, including periodontitis.
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Affiliation(s)
- Aili Xing
- Oral and Maxillofacial Surgery, Hospital of Stomatologyl, Jilin University, Changchun 130021, China
| | - Feng Wang
- Oral and Maxillofacial Surgery, Hospital of Stomatologyl, Jilin University, Changchun 130021, China
| | - Jinzhong Liu
- Preventive Dentistry, Hospital of Stomatologyl, Jilin University, Changchun 130021, China
| | - Yuan Zhang
- Oral and Maxillofacial Surgery, Hospital of Stomatologyl, Jilin University, Changchun 130021, China
| | - Jingya He
- Oral and Maxillofacial Surgery, Hospital of Stomatologyl, Jilin University, Changchun 130021, China
| | - Bin Zhao
- Periodontics, Hospital of Stomatologyl, Jilin University, Changchun 130021, China.
| | - Bin Sun
- Oral and Maxillofacial Surgery, Hospital of Stomatologyl, Jilin University, Changchun 130021, China.
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Luo M, Jin T, Fang Y, Chen F, Zhu L, Bai J, Ding J. Signaling Pathways Involved in Acute Pancreatitis. J Inflamm Res 2025; 18:2287-2303. [PMID: 40230438 PMCID: PMC11995411 DOI: 10.2147/jir.s485804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Accepted: 01/25/2025] [Indexed: 04/16/2025] Open
Abstract
Acute pancreatitis (AP) is a common digestive emergency with high morbidity and mortality. Over the past decade, significant progress has been made in understanding the mechanisms of AP, including oxidative stress, disruptions in calcium homeostasis, endoplasmic reticulum stress, inflammatory responses, and various forms of cell death. This review provides an overview of the typical signaling pathways involved and proposes the latest clinical translation prospects. These strategies are important for the early management of AP, preventing multi-organ injury, and improving the overall prognosis of the disease.
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Affiliation(s)
- Mengchen Luo
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Ting Jin
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Yi Fang
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Feng Chen
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Lujian Zhu
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Jin Bai
- Cancer Institute, Xuzhou Medical University, Xuzhou, People’s Republic of China
| | - Jin Ding
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
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Gukovskaya AS, Lerch MM, Mayerle J, Sendler M, Ji B, Saluja AK, Gorelick FS, Gukovsky I. Trypsin in pancreatitis: The culprit, a mediator, or epiphenomenon? World J Gastroenterol 2024; 30:4417-4438. [PMID: 39534420 PMCID: PMC11551668 DOI: 10.3748/wjg.v30.i41.4417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/19/2024] [Accepted: 07/16/2024] [Indexed: 10/23/2024] Open
Abstract
Pancreatitis is a common, life-threatening inflammatory disease of the exocrine pancreas. Its pathogenesis remains obscure, and no specific or effective treatment is available. Gallstones and alcohol excess are major etiologies of pancreatitis; in a small portion of patients the disease is hereditary. Pancreatitis is believed to be initiated by injured acinar cells (the main exocrine pancreas cell type), leading to parenchymal necrosis and local and systemic inflammation. The primary function of these cells is to produce, store, and secrete a variety of enzymes that break down all categories of nutrients. Most digestive enzymes, including all proteases, are secreted by acinar cells as inactive proforms (zymogens) and in physiological conditions are only activated when reaching the intestine. The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens. It was proposed that pancreatitis results from proteolytic autodigestion of the gland, mediated by premature/inappropriate trypsinogen activation within acinar cells. The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis, and in human disease. On the basis of these observations, it has been considered the central pathogenic mechanism of pancreatitis - a concept with a century-old history. This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis, particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis; analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its' damaging effects; discusses the gaps in our knowledge, potential therapeutic approaches, and directions for future research. We conclude that trypsin is not the culprit in the disease pathogenesis but, at most, a mediator of some pancreatitis responses. Therefore, the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes, such as defective autophagy leading to parenchymal cell death and unrelenting inflammation.
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Affiliation(s)
- Anna S Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90073, United States
- Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
| | - Markus M Lerch
- Department of Medicine, Ludwig Maximilian University Hospital, Munich 81377, Germany
| | - Julia Mayerle
- Department of Medicine II, Ludwig Maximilian University of Munich, Munich 81377, Germany
| | - Matthias Sendler
- Department of Medicine A, University of Greifswald, Greifswald 17475, Germany
| | - Baoan Ji
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, United States
| | - Ashok K Saluja
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Fred S Gorelick
- Departments of Cell Biology and Internal Medicine, Yale University School of Medicine and VA West Haven, New Haven, CT 06519, United States
| | - Ilya Gukovsky
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90073, United States
- Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States
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5
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Mai W, Shang Y, Wang Y, Chen Y, Mu B, Zheng Q, Liu H. 1-DNJ Alleviates Obesity-Induced Testicular Inflammation in Mice Model by Inhibiting IKKβ/ NF-kB Pathway. Reprod Sci 2024; 31:2103-2113. [PMID: 38453770 PMCID: PMC11217107 DOI: 10.1007/s43032-024-01502-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/14/2024] [Indexed: 03/09/2024]
Abstract
Obesity is associated with chronic inflammation that affects various organs in the body, including the reproductive system, which is a key factor in male infertility. 1-Deoxynojirimycin (1-DNJ) is a natural alkaloid in mulberry leaves, which has anti-inflammatory capabilities, yet, it's effects on obesity-induced inflammation-related male infertility remain unclear. Therefore, this research investigates the underlying mechanism by which 1-DNJ may mitigate fertility impairment in male mice caused by obesity-related inflammation. Male mice with high-fat diet (HFD)-induced obesity were treated with 1-DNJ or metformin for 8 weeks. Metabolic profiles were evaluated by enzyme method. Reproductive capacity was assessed by sperm viability, motility and counts, immunohistochemistry was performed to evaluate the testicular damage caused by obesity and inflammation. The inflammation was assessed by measuring the levels of tumor necrosis factor α (TNFα), interleukin 1β (IL-1β), and interleukin 6 (IL-6). The activation of IκB kinase β (IKKβ) and nuclear factor κB (NF-κB) was examined using western blot and immunohistochemistry. HFD induced obesity in mice with obvious lipid metabolism disorder. The obese male mice had a decreased testosterone level, impaired sperm motility, and increased inflammatory factors. 1-DNJ treatment improved the testosterone level in the obese mice, ameliorated the testicular structure damage and improve sperm viability. In addition, 1-DNJ treatment inhibited IKKβ/NF-kB signaling pathway and reduced inflammation in obese mice. 1-DNJ can improve the fertility of obese men by reducing obesity as well as obesity-induced inflammation. These findings provide new insights for 1-DNJ to alleviate inflammation caused by obesity and provide future possibilities for treating male infertility.
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Affiliation(s)
- Wenli Mai
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Sichuan, 637000, China
| | - Yi Shang
- The Second Affiliated Hospital of North Sichuan Medical College, Sichuan, 637000, China
| | - Yibin Wang
- Department of Imaging Medicine, North Sichuan Medical College, Sichuan, 637000, China
| | - Ying Chen
- Department of Clinical Medicine, North Sichuan Medical College, Sichuan, 637000, China
| | - Bo Mu
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Sichuan, 637000, China
| | - Qian Zheng
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Sichuan, 637000, China
| | - Hua Liu
- Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Sichuan, 637000, China.
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6
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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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Niu M, Zhang X, Wu Z, Li B, Bao J, Dai J, Yang Z, Zeng Y, Li L, Pandol S, Sutton R, Wen L. Neutrophil-specific ORAI1 Calcium Channel Inhibition Reduces Pancreatitis-associated Acute Lung Injury. FUNCTION 2023; 5:zqad061. [PMID: 38020066 PMCID: PMC10666672 DOI: 10.1093/function/zqad061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 10/19/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Acute pancreatitis is initiated within pancreatic exocrine cells and sustained by dysregulated systemic inflammatory responses mediated by neutrophils. Store-operated Ca2+ entry (SOCE) through ORAI1 channels in pancreatic acinar cells triggers acute pancreatitis, and ORAI1 inhibitors ameliorate experimental acute pancreatitis, but the role of ORAI1 in pancreatitis-associated acute lung injury has not been determined. Here, we showed mice with pancreas-specific deletion of Orai1 (Orai1ΔPdx1, ∼70% reduction in the expression of Orai1) are protected against pancreatic tissue damage and immune cell infiltration, but not pancreatitis-associated acute lung injury, suggesting the involvement of unknown cells that may cause such injury through SOCE via ORAI1. Genetic (Orai1ΔMRP8) or pharmacological inhibition of ORAI1 in murine and human neutrophils decreased Ca2+ influx and impaired chemotaxis, reactive oxygen species production, and neutrophil extracellular trap formation. Unlike pancreas-specific Orai1 deletion, mice with neutrophil-specific deletion of Orai1 (Orai1ΔMRP8) were protected against pancreatitis- and sepsis-associated lung cytokine release and injury, but not pancreatic injury in experimental acute pancreatitis. These results define critical differences between contributions from different cell types to either pancreatic or systemic organ injury in acute pancreatitis. Our findings suggest that any therapy for acute pancreatitis that targets multiple rather than single cell types is more likely to be effective.
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Affiliation(s)
- Mengya Niu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Xiuli Zhang
- Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
| | - Zengkai Wu
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Bin Li
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Jingpiao Bao
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Juanjuan Dai
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Zihan Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
| | - Yue Zeng
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Liang Li
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201600, China
| | - Stephen Pandol
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Robert Sutton
- Liverpool Pancreatitis Research Group, Liverpool University Hospitals NHS Foundation Trust and Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK
| | - Li Wen
- Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
- State Key Laboratory of Complex, Severe, and Rare Diseases, Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
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8
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Glaubitz J, Asgarbeik S, Lange R, Mazloum H, Elsheikh H, Weiss FU, Sendler M. Immune response mechanisms in acute and chronic pancreatitis: strategies for therapeutic intervention. Front Immunol 2023; 14:1279539. [PMID: 37881430 PMCID: PMC10595029 DOI: 10.3389/fimmu.2023.1279539] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 10/02/2023] [Indexed: 10/27/2023] Open
Abstract
Acute pancreatitis (AP) is one of the most common inflammatory diseases of the gastrointestinal tract and a steady rising diagnosis for inpatient hospitalization. About one in four patients, who experience an episode of AP, will develop chronic pancreatitis (CP) over time. While the initiating causes of pancreatitis can be complex, they consistently elicit an immune response that significantly determines the severity and course of the disease. Overall, AP is associated with a significant mortality rate of 1-5%, which is caused by either an excessive pro-inflammation, or a strong compensatory inhibition of bacterial defense mechanisms which lead to a severe necrotizing form of pancreatitis. At the time-point of hospitalization the already initiated immune response is the only promising common therapeutic target to treat or prevent a severe disease course. However, the complexity of the immune response requires fine-balanced therapeutic intervention which in addition is limited by the fact that a significant proportion of patients is in danger of development or progress to recurrent and chronic disease. Based on the recent literature we survey the disease-relevant immune mechanisms and evaluate appropriate and promising therapeutic targets for the treatment of acute and chronic pancreatitis.
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Affiliation(s)
| | | | | | | | | | | | - Matthias Sendler
- Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany
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Thiel FG, Asgarbeik S, Glaubitz J, Wilden A, Lerch MM, Weiss FU, Sendler M. IRAK3-mediated suppression of pro-inflammatory MyD88/IRAK signaling affects disease severity in acute pancreatitis. Sci Rep 2023; 13:10833. [PMID: 37402858 DOI: 10.1038/s41598-023-37930-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 06/29/2023] [Indexed: 07/06/2023] Open
Abstract
Acute pancreatitis (AP), which is characterized by self-digestion of the pancreas by its own prematurely activated digestive proteases, is a major reason for hospitalization. The autodigestive process causes necrotic cell death of pancreatic acinar cells and the release of damage associated molecular pattern which activate macrophages and drive the secretion of pro-inflammatory cytokines. The MYD88/IRAK signaling pathway plays an important role for the induction of inflammatory responses. Interleukin-1 receptor associated kinase-3 (IRAK3) is a counter-regulator of this pathway. In this study, we investigated the role of MYD88/IRAK using Irak3-/- mice in two experimental animal models of mild and severe AP. IRAK3 is expressed in macrophages as well as pancreatic acinar cells where it restrains NFκB activation. Deletion of IRAK3 enhanced the migration of CCR2+ monocytes into the pancreas and triggered a pro-inflammatory type 1 immune response characterized by significantly increased serum levels of TNFα, IL-6, and IL-12p70. Unexpectedly, in a mild AP model this enhanced pro-inflammatory response resulted in decreased pancreatic damage, whereas in a severe AP model, induced by partial pancreatic duct ligation, the increased pro-inflammatory response drives a severe systemic inflammatory response syndrome (SIRS) and is associated with an increased local and systemic damage. Our results indicate that complex immune regulation mechanism control the course of AP, where moderate pro-inflammation not necessarily associates with increased disease severity but also drives tissue regenerative processes through a more effective clearance of necrotic acinar cells. Only when the pro-inflammation exceeds a certain systemic level, it fuels SIRS and increases disease severity.
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Affiliation(s)
- Franziska G Thiel
- Department of Medicine A, University Medicine, University of Greifswald, Fleischmannstr. 41, 17475, Greifswald, Germany
| | - Saeedeh Asgarbeik
- Department of Medicine A, University Medicine, University of Greifswald, Fleischmannstr. 41, 17475, Greifswald, Germany
| | - Juliane Glaubitz
- Department of Medicine A, University Medicine, University of Greifswald, Fleischmannstr. 41, 17475, Greifswald, Germany
| | - Anika Wilden
- Department of Medicine A, University Medicine, University of Greifswald, Fleischmannstr. 41, 17475, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine, University of Greifswald, Fleischmannstr. 41, 17475, Greifswald, Germany
| | - Frank Ulrich Weiss
- Department of Medicine A, University Medicine, University of Greifswald, Fleischmannstr. 41, 17475, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine, University of Greifswald, Fleischmannstr. 41, 17475, Greifswald, Germany.
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10
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N 6-methyladenosine of Spi2a attenuates inflammation and sepsis-associated myocardial dysfunction in mice. Nat Commun 2023; 14:1185. [PMID: 36864027 PMCID: PMC9979126 DOI: 10.1038/s41467-023-36865-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 02/17/2023] [Indexed: 03/04/2023] Open
Abstract
Bacteria-triggered sepsis is characterized by systemic, uncontrolled inflammation in affected individuals. Controlling the excessive production of pro-inflammatory cytokines and subsequent organ dysfunction in sepsis remains challenging. Here, we demonstrate that Spi2a upregulation in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages reduces the production of pro-inflammatory cytokines and myocardial impairment. In addition, exposure to LPS upregulates the lysine acetyltransferase, KAT2B, to promote METTL14 protein stability through acetylation at K398, leading to the increased m6A methylation of Spi2a in macrophages. m6A-methylated Spi2a directly binds to IKKβ to impair IKK complex formation and inactivate the NF-κB pathway. The loss of m6A methylation in macrophages aggravates cytokine production and myocardial damage in mice under septic conditions, whereas forced expression of Spi2a reverses this phenotype. In septic patients, the mRNA expression levels of the human orthologue SERPINA3 negatively correlates with those of the cytokines, TNF, IL-6, IL-1β and IFNγ. Altogether, these findings suggest that m6A methylation of Spi2a negatively regulates macrophage activation in the context of sepsis.
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11
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Functional IKK/NF-κB signaling in pancreatic stellate cells is essential to prevent autoimmune pancreatitis. Commun Biol 2022; 5:509. [PMID: 35624133 PMCID: PMC9142538 DOI: 10.1038/s42003-022-03371-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 04/14/2022] [Indexed: 01/07/2023] Open
Abstract
Pancreatic stellate cells (PSCs) are resident cells in the exocrine pancreas which contribute to pancreatic fibrogenesis and inflammation. Studies on NF-κB in pancreatitis so far focused mainly on the parenchymal and myeloid compartments. Here we show a protective immunomodulatory function of NF-κB in PSCs. Conditional deletion of NEMO (IKKγ) in PSCs leads to spontaneous pancreatitis with elevated circulating IgM, IgG and antinuclear autoantibodies (ANA) within 18 weeks. When further challenged with caerulein, NEMOΔCol1a2 mice show an exacerbated autoimmune phenotype characterized by increased infiltration of eosinophils, B and T lymphocytes with reduced latency period. Transcriptomic profiling shows that NEMOΔCol1a2 mice display molecular signatures resembling autoimmune pancreatitis patients. Mechanistically, we show that PSCΔNEMO cells produce high levels of CCL24 ex vivo which contributes to eosinophil recruitment, as neutralization with a CCL24 antibody abolishes the transwell migration of eosinophils. Our findings uncover an unexpected immunomodulatory role specifically of NF-κB in PSCs during pancreatitis. A model of autoimmune pancreatitis is developed by blocking the activation of NF-κB in pancreatic stellate cells, via conditional deletion of NEMO (IKKγ), which presents strong pancreatic inflammation with eosinophilia after the induction of chronic pancreatitis by repeated caerulein challenges.
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12
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Cridge H, Lim SY, Algül H, Steiner JM. New insights into the etiology, risk factors, and pathogenesis of pancreatitis in dogs: Potential impacts on clinical practice. J Vet Intern Med 2022; 36:847-864. [PMID: 35546513 PMCID: PMC9151489 DOI: 10.1111/jvim.16437] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 04/08/2022] [Accepted: 04/12/2022] [Indexed: 12/11/2022] Open
Abstract
While most cases of pancreatitis in dogs are thought to be idiopathic, potential risk factors are identified. In this article we provide a state‐of‐the‐art overview of suspected risk factors for pancreatitis in dogs, allowing for improved awareness and detection of potential dog‐specific risk factors, which might guide the development of disease prevention strategies. Additionally, we review important advances in our understanding of the pathophysiology of pancreatitis and potential areas for therapeutic manipulation based thereof. The outcome of pathophysiologic mechanisms and the development of clinical disease is dependent on the balance between stressors and protective mechanisms, which can be evaluated using the critical threshold theory.
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Affiliation(s)
- Harry Cridge
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Sue Yee Lim
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, Texas, USA
| | - Hana Algül
- Gastrointestinal Cancer and Inflammatory Research Laboratory, Technical University of Munich, Munich, Germany
| | - Jörg M Steiner
- Gastrointestinal Laboratory, Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, Texas, USA
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13
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Li G, Chen H, Liu L, Xiao P, Xie Y, Geng X, Zhang T, Zhang Y, Lu T, Tan H, Li L, Sun B. Role of Interleukin-17 in Acute Pancreatitis. Front Immunol 2021; 12:674803. [PMID: 34594321 PMCID: PMC8476864 DOI: 10.3389/fimmu.2021.674803] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 08/31/2021] [Indexed: 11/24/2022] Open
Abstract
Acute pancreatitis (AP) is a leading cause of death and is commonly accompanied by systemic manifestations that are generally associated with a poor prognosis. Many cytokines contribute to pancreatic tissue damage and cause systemic injury. Interleukin-17 (IL-17) is a cytokine that may play a vital role in AP. Specifically, IL-17 has important effects on the immune response and causes interactions between different inflammatory mediators in the AP-related microenvironment. In this literature review, we will discuss the existing academic understanding of IL-17 and the impacts of IL-17 in different cells (especially in acinar cells and immune system cells) in AP pathogenesis. The clinical significance and potential mechanisms of IL-17 on AP deterioration are emphasized. The evidence suggests that inhibiting the IL-17 cytokine family could alleviate the pathogenic process of AP, and we highlight therapeutic strategies that directly or indirectly target IL-17 cytokines in acute pancreatitis.
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Affiliation(s)
- Guanqun Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongze Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Liwei Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Peng Xiao
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yu Xie
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinglong Geng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tao Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yang Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tianqi Lu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongtao Tan
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
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14
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Silke J, O’Reilly LA. NF-κB and Pancreatic Cancer; Chapter and Verse. Cancers (Basel) 2021; 13:4510. [PMID: 34572737 PMCID: PMC8469693 DOI: 10.3390/cancers13184510] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/29/2021] [Accepted: 08/30/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the world's most lethal cancers. An increase in occurrence, coupled with, presently limited treatment options, necessitates the pursuit of new therapeutic approaches. Many human cancers, including PDAC are initiated by unresolved inflammation. The transcription factor NF-κB coordinates many signals that drive cellular activation and proliferation during immunity but also those involved in inflammation and autophagy which may instigate tumorigenesis. It is not surprising therefore, that activation of canonical and non-canonical NF-κB pathways is increasingly recognized as an important driver of pancreatic injury, progression to tumorigenesis and drug resistance. Paradoxically, NF-κB dysregulation has also been shown to inhibit pancreatic inflammation and pancreatic cancer, depending on the context. A pro-oncogenic or pro-suppressive role for individual components of the NF-κB pathway appears to be cell type, microenvironment and even stage dependent. This review provides an outline of NF-κB signaling, focusing on the role of the various NF-κB family members in the evolving inflammatory PDAC microenvironment. Finally, we discuss pharmacological control of NF-κB to curb inflammation, focussing on novel anti-cancer agents which reinstate the process of cancer cell death, the Smac mimetics and their pre-clinical and early clinical trials.
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Affiliation(s)
- John Silke
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC 3052, Australia;
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
| | - Lorraine Ann O’Reilly
- Inflammation Division, Walter and Eliza Hall Institute of Medical Research (WEHI), Parkville, VIC 3052, Australia;
- Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia
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15
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Forman MA, Steiner JM, Armstrong PJ, Camus MS, Gaschen L, Hill SL, Mansfield CS, Steiger K. ACVIM consensus statement on pancreatitis in cats. J Vet Intern Med 2021; 35:703-723. [PMID: 33587762 PMCID: PMC7995362 DOI: 10.1111/jvim.16053] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 12/16/2022] Open
Abstract
Background Pancreatitis in cats, although commonly diagnosed, still presents many diagnostic and management challenges. Objective To summarize the current literature as it relates to etiology, pathogenesis, diagnosis, and management of pancreatitis in cats and to arrive at clinically relevant suggestions for veterinary clinicians that are based on evidence, and where such evidence is lacking, based on consensus of experts in the field. Animals None. Methods A panel of 8 experts in the field (5 internists, 1 radiologist, 1 clinical pathologist, and 1 anatomic pathologist), with support from a librarian, was formed to assess and summarize evidence in the peer reviewed literature and complement it with consensus clinical recommendations. Results There was little literature on the etiology and pathogenesis of spontaneous pancreatitis in cats, but there was much in the literature about the disease in humans, along with some experimental evidence in cats and nonfeline species. Most evidence was in the area of diagnosis of pancreatitis in cats, which was summarized carefully. In contrast, there was little evidence on the management of pancreatitis in cats. Conclusions and Clinical Importance Pancreatitis is amenable to antemortem diagnosis by integrating all clinical and diagnostic information available, and recognizing that acute pancreatitis is far easier to diagnose than chronic pancreatitis. Although both forms of pancreatitis can be managed successfully in many cats, management measures are far less clearly defined for chronic pancreatitis.
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Affiliation(s)
- Marnin A Forman
- Cornell University Veterinary Specialists, Stamford, Connecticut, USA
| | - Joerg M Steiner
- Gastrointestinal Laboratory, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA
| | - P Jane Armstrong
- College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, USA
| | - Melinda S Camus
- Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA
| | - Lorrie Gaschen
- Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Louisiana, USA
| | - Steve L Hill
- Flagstaff Veterinary Internal Medicine Consulting, Flagstaff, Arizona, USA
| | | | - Katja Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
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16
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Thiruvengadam NR, Kochman ML. Emerging Therapies to Prevent Post-ERCP Pancreatitis. Curr Gastroenterol Rep 2020; 22:59. [PMID: 33188441 DOI: 10.1007/s11894-020-00796-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW The aim of this review is to evaluate emerging, novel therapies for the prevention of post-ERCP pancreatitis. RECENT FINDINGS Rectal indomethacin reduces the risk of pancreatitis in low- and average-risk patients, who comprise the majority of patients undergoing ERCP. An 8-h protocol of aggressive lactated Ringer's reduces the risk of pancreatitis in average-risk patients. Sublingual nitrate may provide additional benefit to rectal NSAIDs in preventing PEP. A tacrolimus trough > 2.5 ng/mL was recently shown to be associated with a lower risk of PEP in liver transplant patients undergoing ERCP. Routine usage of rectal indomethacin in all patients undergoing ERCP reduces the risk of PEP. Pancreatic-duct stents reduce the risk of PEP in high-risk patients. There is emerging data that aggressive hydration with lactated Ringer's and nitrates may further reduce PEP. Tacrolimus is a promising potential agent to prevent PEP but needs further clinical study.
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Affiliation(s)
- Nikhil R Thiruvengadam
- Division of Gastroenterology and Hepatology, University of California San Francisco, 513 Parnassus Avenue, S-357, Box 0538, San Francisco, CA, 94143-0538, USA. .,Gastroenterology Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
| | - Michael L Kochman
- Gastroenterology Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center for Endoscopic Innovation, Research and Training, Perelman School of Medicine, Philadelphia, PA, USA
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17
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Heath H, Britton G, Kudo H, Renney G, Ward M, Hutchins R, Foster GR, D Goldin R, Alazawi W. Stat2 loss disrupts damage signalling and is protective in acute pancreatitis. J Pathol 2020; 252:41-52. [PMID: 32506441 DOI: 10.1002/path.5481] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 05/16/2020] [Accepted: 05/29/2020] [Indexed: 12/15/2022]
Abstract
The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage-sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon-independent roles in murine lipopolysaccharide-induced NF-κB-mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non-infective inflammation in the pancreas. Wild type (WT) and Stat2-/- mice were injected i.p. with caerulein or l-arginine. Specific cytokine-blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h post l-arginine. Whole-tissue phosphoproteomic changes were assessed using label-free mass spectrometry. Tissue-specific Stat2 effects were studied in WT/Stat2-/- bone marrow chimera and using Cre-lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. Stat2-/- mice were protected from caerulein- and l-arginine-induced pancreatitis. Protection was independent of type I interferon signalling. Stat2-/- mice had lower cytokine levels, including TNF-α and IL-10, and reduced NF-κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF-α improved (inhibition of IL-10 worsened) caerulein-induced pancreatitis in WT but not Stat2-/- mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412-phosphorylated Tak1. Stat2 deletion in Pdx1-expressing acinar cells (Stat2flox/Pdx1-cre ) reduced pancreatic TNF-α expression, but not histological injury or serum amylase. WT/Stat2-/- bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF-κB in non-acinar and/or bone marrow-derived cells. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Helen Heath
- Blizard Institute, Queen Mary, University of London, London, UK
| | - Gary Britton
- Blizard Institute, Queen Mary, University of London, London, UK
| | - Hiromi Kudo
- Department of Cellular Pathology, Imperial College, London, UK
| | - George Renney
- Proteomics, Institute of Psychiatry, Kings College London, London, UK
| | - Malcolm Ward
- Proteomics, Institute of Psychiatry, Kings College London, London, UK
| | - Robert Hutchins
- Hepatopancreaticobiliary Unit, Barts Health NHS Trust, London, UK
| | - Graham R Foster
- Blizard Institute, Queen Mary, University of London, London, UK
| | - Robert D Goldin
- Department of Cellular Pathology, Imperial College, London, UK
| | - William Alazawi
- Blizard Institute, Queen Mary, University of London, London, UK
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18
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Qian W, Xiao Q, Wang L, Qin T, Xiao Y, Li J, Yue Y, Zhou C, Duan W, Ma Q, Ma J. Resveratrol slows the tumourigenesis of pancreatic cancer by inhibiting NFκB activation. Biomed Pharmacother 2020; 127:110116. [PMID: 32428833 DOI: 10.1016/j.biopha.2020.110116] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 03/17/2020] [Accepted: 03/19/2020] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumour with an extremely poor prognosis due to its insidious initiation and a lack of therapeutic strategies. Resveratrol suppresses pancreatic cancer progression and attenuates pancreatitis by modulating multiple targets, including nuclear factor kappa B (NFκB) signalling pathways. However, the effect of resveratrol on pancreatic cancer initiation and its mechanisms remain unclear. In this study, we utilised the LSL-KrasG12D/+; Pdx1-Cre (KC) spontaneous pancreatic precancerous lesion mouse model to explore the anti-tumourigenesis mechanisms of resveratrol in vivo. In vitro acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasias (PanINs) formation assays were performed by pancreatic acinar cell 3-dimensional (3D) culture. Histopathological analysis was used to examine the pathological morphology of pancreatic tissues. Resveratrol prevented the progression of pancreatic precancerous lesions and inhibited the activation of NFκB signalling pathway-related molecules in KC mouse pancreatic tissues. In addition, resveratrol reduced the severity of cerulein-induced pancreatitis and the formation of ADM/PanINs in vivo and in vitro, which may be related to its effect on NFκB inactivation. Furthermore, pancreatic acinar 3D culture demonstrated that activation of the NFκB signalling pathway promoted the formation of ADM/PanINs in vitro, and this initiating effect of NFκB was blocked by resveratrol. Resveratrol slowed the tumourigenesis of pancreatic cancer by inhibiting NFκB activation.
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Affiliation(s)
- Weikun Qian
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Qigui Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Lin Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Tao Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Ying Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Jie Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Yangyang Yue
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Cancan Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Wanxing Duan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Jiguang Ma
- Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
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19
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Mayerle J, Sendler M, Hegyi E, Beyer G, Lerch MM, Sahin-Tóth M. Genetics, Cell Biology, and Pathophysiology of Pancreatitis. Gastroenterology 2019; 156:1951-1968.e1. [PMID: 30660731 PMCID: PMC6903413 DOI: 10.1053/j.gastro.2018.11.081] [Citation(s) in RCA: 224] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/14/2018] [Accepted: 11/16/2018] [Indexed: 02/07/2023]
Abstract
Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.
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Affiliation(s)
- Julia Mayerle
- Medical Department II, University Hospital, LMU, Munich, Germany,Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Eszter Hegyi
- Institute for Translational Medicine, University of Pécs, Hungary
| | - Georg Beyer
- Medical Department II, University Hospital, LMU, Munich, Germany
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Miklós Sahin-Tóth
- Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA 02118
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20
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Garg PK, Singh VP. Organ Failure Due to Systemic Injury in Acute Pancreatitis. Gastroenterology 2019; 156:2008-2023. [PMID: 30768987 PMCID: PMC6486861 DOI: 10.1053/j.gastro.2018.12.041] [Citation(s) in RCA: 356] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/07/2018] [Accepted: 12/29/2018] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis may be associated with both local and systemic complications. Systemic injury manifests in the form of organ failure, which is seen in approximately 20% of all cases of acute pancreatitis and defines "severe acute pancreatitis." Organ failure typically develops early in the course of acute pancreatitis, but also may develop later due to infected pancreatic necrosis-induced sepsis. Organ failure is the most important determinant of outcome in acute pancreatitis. We review here the current understanding of the risk factors, pathophysiology, timing, impact on outcome, and therapy of organ failure in acute pancreatitis. As we discuss the pathophysiology of severe systemic injury, the distinctions between markers and mediators of severity are highlighted based on evidence supporting their causality in organ failure. Emphasis is placed on clinically relevant end points of organ failure and the mechanisms underlying the pathophysiological perturbations, which offer insight into potential therapeutic targets to treat.
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21
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Diakopoulos KN, Algül H. New wine into old wineskins: PGC-1α and NF-κB in obesity and acute pancreatitis. J Pathol 2019; 248:6-8. [PMID: 30570131 DOI: 10.1002/path.5220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 12/17/2018] [Indexed: 11/08/2022]
Abstract
Obesity and acute pancreatitis are both proinflammatory conditions. Importantly, obesity increases severity in acute pancreatitis by enhancing inflammation. In a recent issue of The Journal of Pathology, Pérez and Ruiz-Pérez et al connected obesity and pancreatitis for the first time, through the transcriptional regulator PPARγ coactivator 1α (PGC-1α). Obesity reduces pancreatic PGC-1α levels and potentiates not only oxidative but also IL-6-mediated inflammatory damage during acute pancreatitis by relieving the binding of PGC-1α to the NF-κB subunit p65. Blockade of the IL-6 receptor subunit gp130 ameliorated tissue injury, substantiating the importance of deregulated PGC-1α/p65/IL-6 signaling in obesity and acute pancreatitis. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Kalliope N Diakopoulos
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Hana Algül
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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22
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Tao L, Lin X, Tan S, Lei Y, Liu H, Guo Y, Zheng F, Wu B. β-Arrestin1 alleviates acute pancreatitis via repression of NF-κBp65 activation. J Gastroenterol Hepatol 2019; 34:284-292. [PMID: 30144357 DOI: 10.1111/jgh.14450] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 08/10/2018] [Accepted: 08/10/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM β-Arrestins (β-arrs) are regulators and mediators of G protein-coupled receptor signaling that are functionally involved in inflammation. Nuclear factor-κB p65 (NF-κBp65) activation has been observed early in the onset of pancreatitis. However, the effect of β-arrs in acute pancreatitis (AP) is unclear. The aim of this study is to investigate whether β-arrs are involved in AP through activation of NF-κBp65. METHODS Acute pancreatitis was induced by either caerulein injection or choline-deficient supplemented with ethionine diet (CDE). β-arr1 wild-type and β-arr1 knockout mice were used in the experiment. The survival rate was calculated in the CDE model mice. Histological and western blot analyses were performed in the caerulein model. Inflammatory mediators were detected by real-time polymerase chain reaction in the caerulein-induced AP mice. Furthermore, AR42J and PANC-1 cell lines were used to further study the effects of β-arr1 in caerulein-induced pancreatic cells. RESULTS β-Arr1 but not β-arr2 is significantly downregulated in caerulein-induced AP in mice. Targeted deletion of β-arr1 notably upregulated expression of the pancreatic inflammatory mediators including tumor necrosis factor α and interleukin 1β as well as interleukin 6 and aggravated AP in caerulein-induced mice. β-Arr1 deficiency increased mortality in mice with CDE-induced AP. Further, β-arr1 deficiency enhanced caerulein-induced phosphorylation of NF-κBp65 both in vivo and in vitro. CONCLUSION β-Arr1 alleviates AP via repression of NF-κBp65 activation, and it is a potentially therapeutic target for AP.
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Affiliation(s)
- Li Tao
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xianyi Lin
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Siwei Tan
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yiming Lei
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Huiling Liu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuwei Guo
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fengping Zheng
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Bin Wu
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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23
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Regel I, Raulefs S, Benitz S, Mihaljevic C, Rieder S, Leinenkugel G, Steiger K, Schlitter AM, Esposito I, Mayerle J, Kong B, Kleeff J, Michalski CW. Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis. Pancreatology 2019; 19:149-157. [PMID: 30583980 DOI: 10.1016/j.pan.2018.12.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/06/2018] [Accepted: 12/14/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Acute pancreatitis is accompanied by acinar cell damage releasing potential toll-like receptor 3 (TLR3) ligands. So far, TLR3 is known as a pattern recognition receptor in the immune signaling cascade triggering a type I interferon response. In addition, TLR3 signaling contributes to programmed cell death through the activation of caspase 8. However, the functional role of TLR3 and its downstream toll-like receptor adaptor molecule 1 (TICAM1) in the inflamed pancreas is unknown. METHODS To uncover the role of TLR3 signaling in acute pancreatitis, we induced a cerulein-mediated pancreatitis in Tlr3 and Ticam1 knockout (KO) mice and in wildtype animals. The exocrine damage was determined by blood serum analysis and histological examination. Immunohistochemistry, gene expression and immunoblot analysis were conducted to study TLR3 function. RESULTS After the induction of an acute pancreatitis, wildtype mice showed a high endosomal TLR3 expression in acinar cells. In comparison to wildtype and Ticam1 KO mice, Tlr3 KO mice exhibited the highest severity of pancreatitis with an increased NF-κB activation and elevated expression of the pro-inflammatory cytokines Il6 and Tnf, although the amount of infiltrating immune cells was unaffected. Additionally, we detected a strong elevation of acinar cell necrosis and reduced levels of cleaved caspase 8 in Tlr3 and Ticam1 KO mice. CONCLUSIONS TLR3 and its downstream adaptor TICAM1 are important mediators of acinar cell damage in acute pancreatitis. They possess a critical role in programmed cell death and our data suggest that TLR3 signaling controls the onset and severity of acute pancreatitis.
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Affiliation(s)
- Ivonne Regel
- Department of Medicine II, University Hospital, LMU Munich, Germany.
| | - Susanne Raulefs
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
| | - Simone Benitz
- Department of Medicine II, University Hospital, LMU Munich, Germany
| | - Charlotte Mihaljevic
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany; Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany
| | - Simon Rieder
- Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Georg Leinenkugel
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University Munich, Germany
| | | | - Irene Esposito
- Institute of Pathology, Heinrich-Heine University and University Hospital, Duesseldorf, Germany
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, Germany
| | - Bo Kong
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Germany
| | - Jörg Kleeff
- Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Christoph W Michalski
- Department of Surgery, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany
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Pérez S, Rius‐Pérez S, Finamor I, Martí‐Andrés P, Prieto I, García R, Monsalve M, Sastre J. Obesity causes PGC‐1α deficiency in the pancreas leading to marked IL‐6 upregulation via NF‐κB in acute pancreatitis. J Pathol 2018; 247:48-59. [DOI: 10.1002/path.5166] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 08/05/2018] [Accepted: 09/04/2018] [Indexed: 01/15/2023]
Affiliation(s)
- Salvador Pérez
- Department of Physiology, Faculty of PharmacyUniversity of Valencia Valencia Spain
| | - Sergio Rius‐Pérez
- Department of Physiology, Faculty of PharmacyUniversity of Valencia Valencia Spain
| | - Isabela Finamor
- Department of Physiology, Faculty of PharmacyUniversity of Valencia Valencia Spain
| | - Pablo Martí‐Andrés
- Department of Physiology, Faculty of PharmacyUniversity of Valencia Valencia Spain
| | - Ignacio Prieto
- Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM) Madrid Spain
| | - Raquel García
- Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM) Madrid Spain
| | - María Monsalve
- Instituto de Investigaciones Biomédicas ‘Alberto Sols’ (CSIC‐UAM) Madrid Spain
| | - Juan Sastre
- Department of Physiology, Faculty of PharmacyUniversity of Valencia Valencia Spain
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Barrera K, Stanek A, Okochi K, Niewiadomska Z, Mueller C, Ou P, John D, Alfonso AE, Tenner S, Huan C. Acinar cell injury induced by inadequate unfolded protein response in acute pancreatitis. World J Gastrointest Pathophysiol 2018; 9:37-46. [PMID: 30283709 PMCID: PMC6163129 DOI: 10.4291/wjgp.v9.i2.37] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 07/24/2018] [Accepted: 08/21/2018] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodigestion theory of AP is now facing challenges, since inhibiting protease activation has negligible effectiveness for AP treatment despite numerous efforts. Furthermore, accumulating evidence supports a new concept that malfunction of a self-protective mechanism, the unfolded protein response (UPR), is the driving force behind the pathogenesis of AP. The UPR is induced by endoplasmic reticulum (ER) stress, a disturbance frequently found in acinar cells, to prevent the aggravation of ER stress that can otherwise lead to cell injury. In addition, the UPR's signaling pathways control NFκB activation and autophagy flux, and these dysregulations cause acinar cell inflammatory injury in AP, but with poorly understood mechanisms. We therefore summarize the protective role of the UPR in AP, propose mechanistic models of how inadequate UPR could promote NFκB's pro-inflammatory activity and impair autophagy's protective function in acinar cells, and discuss its relevance to current AP treatment. We hope that insight provided in this review will help facilitate the research and management of AP.
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Affiliation(s)
- Kaylene Barrera
- Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Albert Stanek
- Department of Surgery and Pathology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Kei Okochi
- College of Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Zuzanna Niewiadomska
- Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Cathy Mueller
- Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Peiqi Ou
- School of Graduate Studies, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Devon John
- Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Antonio E Alfonso
- Department of Surgery, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
| | - Scott Tenner
- Greater New York Endoscopy Surgical Center, State University of New York, Brooklyn, NY 11235, United States
| | - Chongmin Huan
- Department of Surgery and Cell Biology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, United States
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26
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Sendler M, Weiss FU, Golchert J, Homuth G, van den Brandt C, Mahajan UM, Partecke LI, Döring P, Gukovsky I, Gukovskaya AS, Wagh PR, Lerch MM, Mayerle J. Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice. Gastroenterology 2018; 154:704-718.e10. [PMID: 29079517 PMCID: PMC6663074 DOI: 10.1053/j.gastro.2017.10.018] [Citation(s) in RCA: 186] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 10/04/2017] [Accepted: 10/17/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Acute pancreatitis is characterized by premature intracellular activation of digestive proteases within pancreatic acini and a consecutive systemic inflammatory response. We investigated how these processes interact during severe pancreatitis in mice. METHODS Pancreatitis was induced in C57Bl/6 wild-type (control), cathepsin B (CTSB)-knockout, and cathepsin L-knockout mice by partial pancreatic duct ligation with supramaximal caerulein injection, or by repetitive supramaximal caerulein injections alone. Immune cells that infiltrated the pancreas were characterized by immunofluorescence detection of Ly6g, CD206, and CD68. Macrophages were isolated from bone marrow and incubated with bovine trypsinogen or isolated acinar cells; the macrophages were then transferred into pancreatitis control or cathepsin-knockout mice. Activities of proteases and nuclear factor (NF)-κB were determined using fluorogenic substrates and trypsin activity was blocked by nafamostat. Cytokine levels were measured using a cytometric bead array. We performed immunohistochemical analyses to detect trypsinogen, CD206, and CD68 in human chronic pancreatitis (n = 13) and acute necrotizing pancreatitis (n = 15) specimens. RESULTS Macrophages were the predominant immune cell population that migrated into the pancreas during induction of pancreatitis in control mice. CD68-positive macrophages were found to phagocytose acinar cell components, including zymogen-containing vesicles, in pancreata from mice with pancreatitis, as well as human necrotic pancreatic tissues. Trypsinogen became activated in macrophages cultured with purified trypsinogen or co-cultured with pancreatic acini and in pancreata of mice with pancreatitis; trypsinogen activation required macrophage endocytosis and expression and activity of CTSB, and was sensitive to pH. Activation of trypsinogen in macrophages resulted in translocation of NF-kB and production of inflammatory cytokines; mice without trypsinogen activation (CTSB-knockout mice) in macrophages developed less severe pancreatitis compared with control mice. Transfer of macrophage from control mice to CTSB-knockout mice increased the severity of pancreatitis. Inhibition of trypsin activity in macrophages prevented translocation of NF-κB and production of inflammatory cytokines. CONCLUSIONS Studying pancreatitis in mice, we found activation of digestive proteases to occur not only in acinar cells but also in macrophages that infiltrate pancreatic tissue. Activation of the proteases in macrophage occurs during endocytosis of zymogen-containing vesicles, and depends on pH and CTSB. This process involves macrophage activation via NF-κB-translocation, and contributes to systemic inflammation and severity of pancreatitis.
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MESH Headings
- Adoptive Transfer
- Animals
- Cathepsin B/deficiency
- Cathepsin B/genetics
- Cathepsin B/metabolism
- Cathepsin L/deficiency
- Cathepsin L/genetics
- Cells, Cultured
- Ceruletide
- Coculture Techniques
- Cytokines/metabolism
- Disease Models, Animal
- Endocytosis
- Enzyme Activation
- Genetic Predisposition to Disease
- Humans
- Hydrogen-Ion Concentration
- Inflammation Mediators/metabolism
- Macrophages/enzymology
- Macrophages/immunology
- Macrophages/pathology
- Macrophages/transplantation
- Mice, Inbred C57BL
- Mice, Knockout
- NF-kappa B/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein/deficiency
- NLR Family, Pyrin Domain-Containing 3 Protein/genetics
- Necrosis
- Pancreas/enzymology
- Pancreas/immunology
- Pancreas/pathology
- Pancreatectomy
- Pancreatitis, Acute Necrotizing/chemically induced
- Pancreatitis, Acute Necrotizing/enzymology
- Pancreatitis, Acute Necrotizing/immunology
- Pancreatitis, Acute Necrotizing/pathology
- Phagocytosis
- Phenotype
- Severity of Illness Index
- Time Factors
- Trypsinogen/metabolism
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Affiliation(s)
- Matthias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Frank-Ulrich Weiss
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Janine Golchert
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | | | - Ujjwal M Mahajan
- Medizinische Klinik und Poliklinik II, Universitätsklinikum der Ludwig-Maximilians-Universität, Klinikum Grosshadern, Munich, Germany
| | - Lars-Ivo Partecke
- Department of Surgery, University Medicine Greifswald, Greifswald, Germany
| | - Paula Döring
- Institute of Pathology, University Medicine Greifswald, Greifswald, Germany
| | - Ilya Gukovsky
- VA Greater Los Angeles Healthcare System; David Geffen School of Medicine, University of California at Los Angeles, California
| | - Anna S Gukovskaya
- VA Greater Los Angeles Healthcare System; David Geffen School of Medicine, University of California at Los Angeles, California
| | - Preshit R Wagh
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Markus M Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Julia Mayerle
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Medizinische Klinik und Poliklinik II, Universitätsklinikum der Ludwig-Maximilians-Universität, Klinikum Grosshadern, Munich, Germany.
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27
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Martinelli P, Real FX. Animal Modeling of Pancreatitis-to-Cancer Progression. PANCREATIC CANCER 2018:313-347. [DOI: 10.1007/978-1-4939-7193-0_66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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28
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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: 248] [Impact Index Per Article: 31.0] [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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29
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Chan LK, Gerstenlauer M, Konukiewitz B, Steiger K, Weichert W, Wirth T, Maier HJ. Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis. Gut 2017; 66:1995-2007. [PMID: 27464707 DOI: 10.1136/gutjnl-2015-311028] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 07/01/2016] [Accepted: 07/03/2016] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Inhibitory κB kinase (IKK)/nuclear factor κB (NF-κB) signalling has been implicated in the pathogenesis of pancreatitis, but its precise function has remained controversial. Here, we analyse the contribution of IKK/NF-κB signalling in epithelial cells to the pathogenesis of pancreatitis by targeting the IKK subunit NF-κB essential modulator (NEMO) (IKKγ), which is essential for canonical NF-κB activation. DESIGN Mice with a targeted deletion of NEMO in the pancreas were subjected to caerulein pancreatitis. Pancreata were examined at several time points and analysed for inflammation, fibrosis, cell death, cell proliferation, as well as cellular differentiation. Human samples were used to corroborate findings established in mice. RESULTS In acute pancreatitis, NEMO deletion in the pancreatic parenchyma resulted in minor changes during the early phase but led to the persistence of inflammatory and fibrotic foci in the recovery phase. In chronic pancreatitis, NEMO deletion aggravated inflammation and fibrosis, inhibited compensatory acinar cell proliferation, and enhanced acinar atrophy and acinar-ductal metaplasia. Gene expression analysis revealed sustained activation of profibrogenic genes and the CXCL12/CXCR4 axis in the absence of epithelial NEMO. In human chronic pancreatitis samples, the CXCL12/CXCR4 axis was activated as well, with CXCR4 expression correlating with the degree of fibrosis. The aggravating effects of NEMO deletion were attenuated by the administration of the CXCR4 antagonist AMD3100. CONCLUSIONS Our results suggest that NEMO in epithelial cells exerts a protective effect during pancreatitis by limiting inflammation and fibrosis and improving acinar cell regeneration. The CXCL12/CXCR4 axis is an important mediator of that effect and may also be of importance in human chronic pancreatitis.
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Affiliation(s)
- Lap Kwan Chan
- Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
| | | | - Björn Konukiewitz
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany
| | - Katja Steiger
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University of Munich (TUM), Munich, Germany
| | - Thomas Wirth
- Institute of Physiological Chemistry, University of Ulm, Ulm, Germany
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30
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Wu J, Mulatibieke T, Ni J, Han X, Li B, Zeng Y, Wan R, Wang X, Hu G. Dichotomy between Receptor-Interacting Protein 1– and Receptor-Interacting Protein 3–Mediated Necroptosis in Experimental Pancreatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1035-1048. [DOI: 10.1016/j.ajpath.2016.12.021] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 12/28/2016] [Accepted: 12/29/2016] [Indexed: 12/21/2022]
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Kanak MA, Shahbazov R, Yoshimatsu G, Levy MF, Lawrence MC, Naziruddin B. A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis. J Gastroenterol 2017; 52:352-365. [PMID: 27418337 DOI: 10.1007/s00535-016-1238-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 06/24/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND The underlying molecular mechanism that leads to development of chronic pancreatitis remains elusive. The aim of this study is to understand the downstream inflammatory signaling involved in progression of chronic pancreatitis, and to use withaferin A (WA), a small molecule inhibitor of nuclear factor κB (NFκB), to prevent progression of chronic pancreatitis. METHODS Two different protocols were used to induce pancreatitis in mice: standard and stringent administration of cerulein. The severity of pancreatitis was assessed by means of pancreatic histology and serum amylase levels. Immunohistochemistry and flow-cytometric analysis was performed to visualize immune cell infiltration into the pancreas. Real-time PCR and Western blot were used to analyze the downstream signaling mechanism involved in the development of chronic pancreatitis. RESULTS The severity of cerulein-induced pancreatitis was reduced significantly by WA, used as either preventive or curative treatment. Immune cell infiltration into the pancreas and acinar cell death were efficiently reduced by WA treatment. Expression of proinflammatory and proapoptotic genes regulated by NFκB activation was increased by cerulein treatment, and WA suppressed these genes significantly. Sustained endoplasmic reticulum stress activation by cerulein administration was reduced. NLRP3 inflammasome activation in cerulein-induced pancreatitis was identified, and this was also potently blocked by WA. The human pancreatitis tissue gene signature correlated with the mouse model. CONCLUSIONS Our data provide evidence for the role of NFκB in the pathogenesis of chronic pancreatitis, and strongly suggest that WA could be used as a potential therapeutic drug to alleviate some forms of chronic pancreatitis.
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Affiliation(s)
- Mazhar A Kanak
- Institute of Biomedical Studies, Baylor University, Waco, TX, USA.
- Department of Surgery, Transplantation Division, Virginia Commonwealth University, Richmond, VA, USA.
| | - Rauf Shahbazov
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | | | - Marlon F Levy
- Department of Surgery, Transplantation Division, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Bashoo Naziruddin
- Islet Cell Laboratory, Baylor Research Institute, Dallas, TX, USA.
- Baylor Annette C. and Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX, USA.
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32
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Neesse A, Ellenrieder V. NEMO-CXCL12/CXCR4 axis: a novel vantage point for antifibrotic therapies in chronic pancreatitis? Gut 2017; 66:211-212. [PMID: 27590996 DOI: 10.1136/gutjnl-2016-312874] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 08/15/2016] [Indexed: 12/08/2022]
Affiliation(s)
- Albrecht Neesse
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany
| | - Volker Ellenrieder
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany
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Abstract
OBJECTIVES Inflammation plays a key role in pancreatitis. Earlier studies from our laboratory showed that experimental pancreatitis activated the pancreatic apelin-APJ axis robustly in mice. Apelin signaling reduced neutrophil invasion and the activation of pancreatic nuclear factor (NF)-κB in mice with experimental pancreatitis. METHODS The aim of this study was to assess whether apelin-induced inhibition of pancreatic NF-κB activation was linked mechanistically to apelin's inhibition of pancreatic inflammatory mediator up-regulation in mice with cerulein-induced chronic pancreatitis (CP). Whether apelin's inhibitory effects were associated with the inhibition of NF-κB binding to the promoter region of IL-1β was examined. The effects of apelin exposure on pancreatic IκB degradation/replenishment and membrane levels of phosphorylated protein kinase C were measured. RESULTS Results demonstrated that apelin inhibited the up-regulation of pancreatic tumor necrosis factor α, macrophage inflammatory protein-1 α/β, and IL-1β expression significantly in mice with CP. Chromatin immunoprecipitation assay findings showed that apelin inhibited NF-κB binding to a putative NF-κB binding site in the IL-1β promoter. Apelin exposure reduced the pancreatic membrane levels of phosphorylated protein kinase C-δ and enhanced the replenishment of pancreatic IκB proteins. CONCLUSIONS Together, these findings indicated that the inhibition of NF-κB activation by apelin was a mechanism behind the reduced pancreatic levels of inflammatory mediators in CP mice exposed to apelin.
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34
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Yang ZW, Meng XX, Zhang C, Xu P. CARD9 gene silencing with siRNA protects rats against severe acute pancreatitis: CARD9-dependent NF-κB and P38MAPKs pathway. J Cell Mol Med 2016; 21:1085-1093. [PMID: 27957800 PMCID: PMC5431129 DOI: 10.1111/jcmm.13040] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 10/20/2016] [Indexed: 01/05/2023] Open
Abstract
We previously reported the up‐regulation of caspase recruitment domain 9 (CARD9) expressions in severe acute pancreatitis (SAP) patients, but little is known about its regulation. In this study, small interfering RNA (siRNA) was used to reduce the levels of CARD9 expression in sodium taurocholate‐stimulated SAP rats. CARD9 was overexpressed in SAP rats, which correlated with the severity of pancreatitis. When compared to the untreated group, the cohort that received the siRNA treatment demonstrated a significant reduction in pancreatic injury, neutrophil infiltration, myeloperoxidase activity and pro‐inflammatory cytokines. Furthermore, siRNAs showed that the reduction of CARD9 in SAP rats down‐regulated the expression of NF‐κBp65 and P38MAPK which are involved in the transcription and release of a wide variety of inflammatory cytokines. These findings provide evidence that CARD9 is up‐regulated in SAP rats and acts as a potential therapeutic target for the treatment thereof. Blocking the activation of NF‐κB and P38MAPK via siRNA‐mediated gene knock‐down of CARD9 appears to reduce the inflammatory response in pancreatic tissue.
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Affiliation(s)
- Zhi-Wen Yang
- Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Xiao-Xiao Meng
- Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Chun Zhang
- Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Ping Xu
- Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.,Shanghai Songjiang Hospital Affiliated to Nanjing Medical University, Nanjing, China
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35
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He Z, Hua J, Qian D, Gong J, Lin S, Xu C, Wei G, Meng H, Yang T, Zhou B, Song Z. Intravenous hMSCs Ameliorate Acute Pancreatitis in Mice via Secretion of Tumor Necrosis Factor-α Stimulated Gene/Protein 6. Sci Rep 2016; 6:38438. [PMID: 27917949 PMCID: PMC5137159 DOI: 10.1038/srep38438] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 11/08/2016] [Indexed: 01/12/2023] Open
Abstract
The administration of mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs) to enhance tissue repair is currently undergoing clinical trials. Some studies, including our previous work, have also revealed the beneficial effect of MSCs in severe acute pancreatitis (SAP); however, their mechanisms or mode of action remain controversial. In this study, we demonstrated that intravenously (i.v.)-administered human MSCs (hMSCs) remarkably promoted recovery from experimental SAP without significant engraftment of hMSCs in the damaged pancreas. Interestingly, we found that i.v.-administered hMSCs with knockdown of TSG-6 expression lost most of their anti-inflammatory effects and thus could not significantly ameliorate SAP. As expected, the effects of hMSCs were also duplicated by i.v. infusion of recombinant TSG-6. Furthermore, our results showed that the increase of oxidative stress, activation of the NLRP3 inflammasome and NF-κB signaling in SAP was substantially inhibited following administration of hMSCs or TSG-6, which was dependent on the presence of CD-44 receptors in acinar cells. In conclusion, our study, for the first time, revealed that novel mechanisms are responsible for the immunomodulatory effect of i.v. hMSCs.
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Affiliation(s)
- Zhigang He
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jie Hua
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Daohai Qian
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jian Gong
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shengping Lin
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Chenglei Xu
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ge Wei
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hongbo Meng
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Tingsong Yang
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bo Zhou
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhenshun Song
- Department of Hepatobiliary and Pancreatic Surgery, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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Diao HY, Shao JG, Bian ZL, Chen L, Ju LL, Zhang Y. Role of phosphoinositide-3 kinase signaling pathways in pathogenesis of acute pancreatitis. Shijie Huaren Xiaohua Zazhi 2016; 24:3002-3008. [DOI: 10.11569/wcjd.v24.i19.3002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis (AP) as a common acute disease poses a great threat to people's health. According to statistics, about one-fifth of cases develop acute respiratory distress syndrome and multiple organ dysfunction, which result in high mortality. The early understanding of the pathogenesis of this disease is limited to an inflammatory response resulting in autodigestion, edema, hemorrhage and necrosis of pancreatic tissue after the abnormal activation of trypsin. In recent years, researchers have focused their research on the role of immune inflammatory response in the pathogenesis of AP. Here we discuss the relationship between the immune inflammation and PI3K signaling pathways in AP.
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Abstract
Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas frequently associated with metabolic causes, contributing factors, or consequences, including hypertriglyceridemia, obesity, and disorders of intermediary metabolism, respectively. To date, there is no specific therapy for this disease. Future optimal therapy should correct both inflammatory and metabolic components of the disease. Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that control inflammatory and metabolic pathways via ligand-dependent and ligand-independent mechanisms. There are 3 known subtypes, PPAR-α, PPAR-β/δ, and PPAR-γ, which are differentially expressed in various tissues. The PPARs interact closely with other transcription factors such as nuclear factor κB and signal tranducers and activators of transcription that have pivotal roles in the pathobiology of AP. In this comprehensive review, we summarize the role of PPARs in AP, highlighting important in vitro and in vivo experimental findings. Finally, we propose future research directions as well as potential translational use of PPAR agonists in the treatment of AP.
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38
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Song L, Wörmann S, Ai J, Neuhöfer P, Lesina M, Diakopoulos KN, Ruess D, Treiber M, Witt H, Bassermann F, Halangk W, Steiner JM, Esposito I, Rosendahl J, Schmid RM, Riemann M, Algül H. BCL3 Reduces the Sterile Inflammatory Response in Pancreatic and Biliary Tissues. Gastroenterology 2016; 150:499-512.e20. [PMID: 26526716 DOI: 10.1053/j.gastro.2015.10.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 10/13/2015] [Accepted: 10/19/2015] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Under conditions of inflammation in the absence of micro-organisms (sterile inflammation), necrotic cells release damage-associated molecular patterns that bind to Toll-like receptors on immune cells to activate a signaling pathway that involves activation of IκB kinase and nuclear factor κB (NF-κB). Little is known about the mechanisms that control NF-κB activity during sterile inflammation. We analyzed the contribution of B-cell CLL/lymphoma 3 (BCL3), a transcription factor that associates with NF-κB, in control of sterile inflammation in the pancreas and biliary system of mice. METHODS Acute pancreatitis (AP) was induced in C57BL/6 (control) and Bcl3(-/-) mice by intraperitoneal injection of cerulein or pancreatic infusion of sodium taurocholate. We also studied Mdr2(-/-) mice, which develop spontaneous biliary inflammation, as well as Bcl3(-/-)Mdr2(-/-) mice. We performed immunohistochemical analyses of inflamed and noninflamed regions of pancreatic tissue from patients with AP or primary sclerosing cholangitis (PSC), as well as from mice. Immune cells were characterized by fluorescence-activated cell sorting analysis. Control or Bcl3(-/-) mice were irradiated, injected with bone marrow from Bcl3(-/-) or control mice, and AP was induced. RESULTS Pancreatic or biliary tissues from patients with AP or PSC had higher levels of BCL3 and phosphorylated RelA and IκBα in inflamed vs noninflamed regions. Levels of BCL3 were higher in pancreata from control mice given cerulein than from mice without AP, and were higher in biliary tissues from Mdr2(-/-) mice than from control mice. Bcl3(-/-) mice developed more severe AP after administration of cerulein or sodium taurocholate than control mice; pancreata from the Bcl3(-/-) mice with AP had greater numbers of macrophages, myeloid-derived suppressor cells, dendritic cells, and granulocytes than control mice with AP. Activation of NF-κB was significantly prolonged in Bcl3(-/-) mice with AP, compared with control mice with AP. Bcl3(-/-)Mdr2(-/-) mice developed more severe cholestasis and had increased markers of liver injury and increased proliferation of biliary epithelial cells and hepatocytes than Mdr2(-/-) mice. In experiments with bone marrow chimeras, expression of BCL3 by acinar cells, but not myeloid cells, was required for reduction of inflammation during development of AP. BCL3 inhibited ubiquitination and proteasome-mediated degradation of p50 homodimers, which prolonged binding of NF-κB heterodimers to DNA. CONCLUSIONS BCL3 is up-regulated in inflamed pancreatic or biliary tissues from mice and patients with AP or cholangitis. Its production appears to reduce the inflammatory response in these tissues via blocking ubiquitination and proteasome-mediated degradation of p50 homodimers.
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Affiliation(s)
- Liang Song
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Sonja Wörmann
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Jiaoyu Ai
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Patrick Neuhöfer
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Marina Lesina
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Kalliope N Diakopoulos
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Dietrich Ruess
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Matthias Treiber
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Heiko Witt
- Department of Pediatrics, Technische Universität München, Munich, Germany
| | - Florian Bassermann
- Department of Medicine III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Walter Halangk
- Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Jörg M Steiner
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Irene Esposito
- Department of Pathology, Heinrich Heine University, Düsseldorf, Germany
| | - Jonas Rosendahl
- Department of Gastroenterology, University Hospital Leipzig, Leipzig, Germany
| | - Roland M Schmid
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Marc Riemann
- Leibniz-Institut für Altersforschung, Fritz-Lipmann-Institut, Jena, Germany
| | - Hana Algül
- Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
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Steele CW, Karim SA, Foth M, Rishi L, Leach JDG, Porter RJ, Nixon C, Jeffry Evans TR, Carter CR, Nibbs RJB, Sansom OJ, Morton JP. CXCR2 inhibition suppresses acute and chronic pancreatic inflammation. J Pathol 2015; 237:85-97. [PMID: 25950520 PMCID: PMC4833178 DOI: 10.1002/path.4555] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Revised: 04/01/2015] [Accepted: 04/28/2015] [Indexed: 12/18/2022]
Abstract
Pancreatitis is a significant clinical problem and the lack of effective therapeutic options means that treatment is often palliative rather than curative. A deeper understanding of the pathogenesis of both acute and chronic pancreatitis is necessary to develop new therapies. Pathological changes in pancreatitis are dependent on innate immune cell recruitment to the site of initial tissue damage, and on the coordination of downstream inflammatory pathways. The chemokine receptor CXCR2 drives neutrophil recruitment during inflammation, and to investigate its role in pancreatic inflammation, we induced acute and chronic pancreatitis in wild-type and Cxcr2(-/-) mice. Strikingly, Cxcr2(-/-) mice were strongly protected from tissue damage in models of acute pancreatitis, and this could be recapitulated by neutrophil depletion or by the specific deletion of Cxcr2 from myeloid cells. The pancreata of Cxcr2(-/-) mice were also substantially protected from damage during chronic pancreatitis. Neutrophil depletion was less effective in this model, suggesting that CXCR2 on non-neutrophils contributes to the development of chronic pancreatitis. Importantly, pharmacological inhibition of CXCR2 in wild-type mice replicated the protection seen in Cxcr2(-/-) mice in acute and chronic models of pancreatitis. Moreover, acute pancreatic inflammation was reversible by inhibition of CXCR2. Thus, CXCR2 is critically involved in the development of acute and chronic pancreatitis in mice, and its inhibition or loss protects against pancreatic damage. CXCR2 may therefore be a viable therapeutic target in the treatment of pancreatitis.
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MESH Headings
- Acute Disease
- Animals
- Anti-Inflammatory Agents/pharmacology
- Ceruletide
- Cytoprotection
- Disease Models, Animal
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Neutrophil Infiltration/drug effects
- Neutrophils/drug effects
- Neutrophils/immunology
- Neutrophils/metabolism
- Pancreas/drug effects
- Pancreas/immunology
- Pancreas/metabolism
- Pancreas/pathology
- Pancreatitis/chemically induced
- Pancreatitis/genetics
- Pancreatitis/immunology
- Pancreatitis/metabolism
- Pancreatitis/pathology
- Pancreatitis/prevention & control
- Pancreatitis, Chronic/chemically induced
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/immunology
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Pancreatitis, Chronic/prevention & control
- Peptides/pharmacology
- Receptors, Interleukin-8B/antagonists & inhibitors
- Receptors, Interleukin-8B/deficiency
- Receptors, Interleukin-8B/genetics
- Receptors, Interleukin-8B/immunology
- Signal Transduction/drug effects
- Time Factors
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Affiliation(s)
- Colin W Steele
- Cancer Research UK Beatson Institute, Glasgow, UK
- Department of Surgery, Glasgow Royal Infirmary, Glasgow, UK
| | | | - Mona Foth
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Loveena Rishi
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Joshua D G Leach
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - T R Jeffry Evans
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - C Ross Carter
- Department of Surgery, Glasgow Royal Infirmary, Glasgow, UK
| | - Robert J B Nibbs
- Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, UK
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
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40
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Jin S, Orabi AI, Le T, Javed TA, Sah S, Eisses JF, Bottino R, Molkentin JD, Husain SZ. Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin. Gastroenterology 2015; 149:753-64.e11. [PMID: 25980752 PMCID: PMC4550538 DOI: 10.1053/j.gastro.2015.05.004] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Revised: 05/05/2015] [Accepted: 05/06/2015] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Radiocontrast agents are required for radiographic procedures, but these agents can injure tissues by unknown mechanisms. We investigated whether exposure of pancreatic tissues to radiocontrast agents during endoscopic retrograde cholangiopancreatography (ERCP) causes pancreatic inflammation, and studied the effects of these agents on human cell lines and in mice. METHODS We exposed mouse and human acinar cells to the radiocontrast agent iohexol (Omnipaque; GE Healthcare, Princeton, NJ) and measured intracellular release of Ca(2+), calcineurin activation (using a luciferase reporter), activation of nuclear factor-κB (NF-κB, using a luciferase reporter), and cell necrosis (via propidium iodide uptake). We infused the radiocontrast agent into the pancreatic ducts of wild-type mice (C57BL/6) to create a mouse model of post-ERCP pancreatitis; some mice were given intraperitoneal injections of the calcineurin inhibitor FK506 before and after infusion of the radiocontrast agent. CnAβ(-/-) mice also were used. This experiment also was performed in mice given infusions of adeno-associated virus 6-NF-κB-luciferase, to assess activation of this transcription factor in vivo. RESULTS Incubation of mouse and human acinar cells, but not HEK293 or COS7 cells, with iohexol led to a peak and then plateau in Ca(2+) signaling, along with activation of the transcription factors NF-κB and nuclear factor of activated T cells. Suppressing Ca(2+) signaling or calcineurin with BAPTA, cyclosporine A, or FK506 prevented activation of NF-κB and acinar cell injury. Calcineurin Aβ-deficient mice were protected against induction of pancreatic inflammation by iohexol. The calcineurin inhibitor FK506 prevented contrast-induced activation of NF-κB in pancreata of mice, this was observed by live imaging of mice given infusions of adeno-associated virus 6-NF-κB-luciferase. CONCLUSIONS Radiocontrast agents cause pancreatic inflammation in mice, via activation of NF-κB, Ca(2+) signaling, and calcineurin. Calcineurin inhibitors might be developed to prevent post-ERCP pancreatitis in patients.
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Affiliation(s)
- Shunqian Jin
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224
| | - Abrahim I. Orabi
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224
| | - Tianming Le
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224
| | - Tanveer A. Javed
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224
| | - Swati Sah
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224
| | - John F. Eisses
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224
| | - Rita Bottino
- Institute of Cellular Therapeutics, Allegheny General Hospital, Pittsburgh, PA, 15212
| | - Jeffery D. Molkentin
- Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Howard Hughes Medical Institute, Cincinnati, OH, 45229
| | - Sohail Z. Husain
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224
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41
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Orabi AI, Sah S, Javed TA, Lemon KL, Good ML, Guo P, Xiao X, Prasadan K, Gittes GK, Jin S, Husain SZ. Dynamic imaging of pancreatic nuclear factor κB (NF-κB) activation in live mice using adeno-associated virus (AAV) infusion and bioluminescence. J Biol Chem 2015; 290:11309-20. [PMID: 25802340 PMCID: PMC4416837 DOI: 10.1074/jbc.m115.647933] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Indexed: 12/19/2022] Open
Abstract
Nuclear factor κB (NF-κB) is an important signaling molecule that plays a critical role in the development of acute pancreatitis. Current methods for examining NF-κB activation involve infection of an adenoviral NF-κB-luciferase reporter into cell lines or electrophoretic mobility shift assay of lysate. The use of adeno-associated viruses (AAVs) has proven to be an effective method of transfecting whole organs in live animals. We examined whether intrapancreatic duct infusion of AAV containing an NF-κB-luciferase reporter (AAV-NF-κB-luciferase) can reliably measure pancreatic NF-κB activation. We confirmed the infectivity of the AAV-NF-κB-luciferase reporter in HEK293 cells using a traditional luciferase readout. Mice were infused with AAV-NF-κB-luciferase 5 weeks before induction of pancreatitis (caerulein, 50 μg/kg). Unlike transgenic mice that globally express NF-κB-luciferase, AAV-infused mice showed a 15-fold increase in pancreas-specific NF-κB bioluminescence following 12 h of caerulein compared with baseline luminescence (p < 0.05). The specificity of the NF-κB-luciferase signal to the pancreas was confirmed by isolating the pancreas and adjacent organs and observing a predominant bioluminescent signal in the pancreas compared with liver, spleen, and stomach. A complementary mouse model of post-ERCP-pancreatitis also induced pancreatic NF-κB signals. Taken together these data provide the first demonstration that NF-κB activation can be examined in a live, dynamic fashion during pancreatic inflammation. We believe this technique offers a valuable tool to study real-time activation of NF-κB in vivo.
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Affiliation(s)
| | - Swati Sah
- From the Department of Pediatrics and
| | | | | | | | - Ping Guo
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Xiangwei Xiao
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - Krishna Prasadan
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
| | - George K Gittes
- Surgery, Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224
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42
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Kang R, Lotze MT, Zeh HJ, Billiar TR, Tang D. Cell death and DAMPs in acute pancreatitis. Mol Med 2014; 20:466-77. [PMID: 25105302 PMCID: PMC4277549 DOI: 10.2119/molmed.2014.00117] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 08/04/2014] [Indexed: 12/18/2022] Open
Abstract
Cell death and inflammation are key pathologic responses of acute pancreatitis (AP), the leading cause of hospital admissions for gastrointestinal disorders. It is becoming increasingly clear that damage-associated molecular pattern molecules (DAMPs) play an important role in the pathogenesis of AP by linking local tissue damage to systemic inflammation syndrome. Endogenous DAMPs released from dead, dying or injured cells initiate and extend sterile inflammation via specific pattern recognition receptors. Inhibition of the release and activity of DAMPs (for example, high mobility group box 1, DNA, histones and adenosine triphosphate) provides significant protection against experimental AP. Moreover, increased serum levels of DAMPs in patients with AP correlate with disease severity. These findings provide novel insight into the mechanism, diagnosis and management of AP. DAMPs might be an attractive therapeutic target in AP.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Timothy R Billiar
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
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43
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Abstract
Pancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme-producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases.
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Affiliation(s)
- L Charles Murtaugh
- Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112;
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44
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Autophagy in alcohol-induced multiorgan injury: mechanisms and potential therapeutic targets. BIOMED RESEARCH INTERNATIONAL 2014; 2014:498491. [PMID: 25140315 PMCID: PMC4124834 DOI: 10.1155/2014/498491] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 06/29/2014] [Indexed: 12/21/2022]
Abstract
Autophagy is a genetically programmed, evolutionarily conserved intracellular degradation pathway involved in the trafficking of long-lived proteins and cellular organelles to the lysosome for degradation to maintain cellular homeostasis. Alcohol consumption leads to injury in various tissues and organs including liver, pancreas, heart, brain, and muscle. Emerging evidence suggests that autophagy is involved in alcohol-induced tissue injury. Autophagy serves as a cellular protective mechanism against alcohol-induced tissue injury in most tissues but could be detrimental in heart and muscle. This review summarizes current knowledge about the role of autophagy in alcohol-induced injury in different tissues/organs and its potential molecular mechanisms as well as possible therapeutic targets based on modulation of autophagy.
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45
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Lerch MM, Conwell DL, Mayerle J. The anti-inflammasome effect of lactate and the lactate GPR81-receptor in pancreatic and liver inflammation. Gastroenterology 2014; 146:1602-5. [PMID: 24780214 DOI: 10.1053/j.gastro.2014.04.025] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Markus M Lerch
- Department of Medicine A, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany.
| | - Darwin L Conwell
- Division of Gastroenterology, Hepatology and Nutrition, Ohio State University, Columbus, Ohio
| | - Julia Mayerle
- Department of Medicine A, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany
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46
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Kang R, Zhang Q, Hou W, Yan Z, Chen R, Bonaroti J, Bansal P, Billiar TR, Tsung A, Wang Q, Bartlett DL, Whitcomb DC, Chang EB, Zhu X, Wang H, Lu B, Tracey KJ, Cao L, Fan XG, Lotze MT, Zeh HJ, Tang D. Intracellular Hmgb1 inhibits inflammatory nucleosome release and limits acute pancreatitis in mice. Gastroenterology 2014; 146:1097-107. [PMID: 24361123 PMCID: PMC3965592 DOI: 10.1053/j.gastro.2013.12.015] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 12/08/2013] [Accepted: 12/09/2013] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS High mobility group box 1 (HMGB1) is an abundant protein that regulates chromosome architecture and also functions as a damage-associated molecular pattern molecule. Little is known about its intracellular roles in response to tissue injury or during subsequent local and systemic inflammatory responses. We investigated the function of Hmgb1 in mice after induction of acute pancreatitis. METHODS We utilized a Cre/LoxP system to create mice with pancreas-specific disruption in Hmbg1 (Pdx1-Cre; HMGB1(flox/flox) mice). Acute pancreatitis was induced in these mice (HMGB1(flox/flox) mice served as controls) after injection of l-arginine or cerulein. Pancreatic tissues and acinar cells were collected and analyzed by histologic, immunoblot, and immunohistochemical analyses. RESULTS After injection of l-arginine or cerulein, Pdx1-Cre; HMGB1(flox/flox) mice developed acute pancreatitis more rapidly than controls, with increased mortality. Pancreatic tissues of these mice also had higher levels of serum amylase, acinar cell death, leukocyte infiltration, and interstitial edema than controls. Pancreatic tissues and acinar cells collected from the Pdx1-Cre; HMGB1(flox/flox) mice after l-arginine or cerulein injection demonstrated nuclear catastrophe with greater nucleosome release when compared with controls, along with increased phosphorylation/activation of RELA nuclear factor κB, degradation of inhibitor of κB, and phosphorylation of mitogen-activated protein kinase. Inhibitors of reactive oxygen species (N-acetyl-l-cysteine) blocked l-arginine-induced DNA damage, necrosis, apoptosis, release of nucleosomes, and activation of nuclear factor κB in pancreatic tissues and acinar cells from Pdx1-Cre; HMGB1(flox/flox) and control mice. Exogenous genomic DNA and recombinant histone H3 proteins significantly induced release of HMGB1 from mouse macrophages; administration of antibodies against H3 to mice reduced serum levels of HMGB1 and increased survival after l-arginine injection. CONCLUSIONS In 2 mouse models of acute pancreatitis, intracellular HMGB1 appeared to prevent nuclear catastrophe and release of inflammatory nucleosomes to block inflammation. These findings indicate a role for the innate immune response in tissue damage.
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Affiliation(s)
- Rui Kang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
| | - Qiuhong Zhang
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Wen Hou
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Zhenwen Yan
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA, Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Ruochan Chen
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Jillian Bonaroti
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Preeti Bansal
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Timothy R. Billiar
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Allan Tsung
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Qingde Wang
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - David L. Bartlett
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - David C Whitcomb
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA
| | - Eugene B. Chang
- Department of Medicine, University of Chicago; Chicago, IL 60637, USA
| | - Xiaorong Zhu
- Department of Medicine, University of Chicago; Chicago, IL 60637, USA
| | - Haichao Wang
- Department of Emergency Medicine, North Shore University Hospital, Manhasset, New York 11030, USA
| | - Ben Lu
- Laboratory of Biomedical Science, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Kevin J. Tracey
- Laboratory of Biomedical Science, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Lizhi Cao
- Department of Pediatrics Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xue-Gong Fan
- Department of Infectious Diseases and State Key Lab of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Michael T. Lotze
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA,Correspondence should be directed to Dr. Daolin Tang (), Dr. Rui Kang (), Dr. Michael T. Lotze (), or Dr. Herbert J. Zeh ()
| | - Herbert J. Zeh
- Department of Surgery University of Pittsburgh, Pittsburgh, PA 15219, USA,Correspondence should be directed to Dr. Daolin Tang (), Dr. Rui Kang (), Dr. Michael T. Lotze (), or Dr. Herbert J. Zeh ()
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
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47
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Lesina M, Wörmann SM, Neuhöfer P, Song L, Algül H. Interleukin-6 in inflammatory and malignant diseases of the pancreas. Semin Immunol 2014; 26:80-7. [DOI: 10.1016/j.smim.2014.01.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2013] [Accepted: 01/06/2014] [Indexed: 02/07/2023]
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48
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Kui B, Balla Z, Végh ET, Pallagi P, Venglovecz V, Iványi B, Takács T, Hegyi P, Rakonczay Z. Recent advances in the investigation of pancreatic inflammation induced by large doses of basic amino acids in rodents. J Transl Med 2014; 94:138-149. [PMID: 24365745 DOI: 10.1038/labinvest.2013.143] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 11/13/2013] [Accepted: 11/19/2013] [Indexed: 12/16/2022] Open
Abstract
It has been known for approximately 30 years that large doses of the semi-essential basic amino acid L-arginine induce severe pancreatic inflammation in rats. Recently, it has been demonstrated that L-arginine can also induce pancreatitis in mice. Moreover, other basic amino acids like L-ornithine and L-lysine can cause exocrine pancreatic damage without affecting the endocrine parenchyma and the ducts in rats. The utilization of these noninvasive severe basic amino acid-induced pancreatitis models is becoming increasingly popular and appreciated as these models nicely reproduce most laboratory and morphological features of human pancreatitis. Consequently, the investigation of basic amino acid-induced pancreatitis may offer us a better understanding of the pathogenesis and possible treatment options of the human disease.
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Affiliation(s)
- Balázs Kui
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zsolt Balla
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Eszter T Végh
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Petra Pallagi
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Béla Iványi
- Department of Pathology, University of Szeged, Szeged, Hungary
| | - Tamás Takács
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Péter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zoltán Rakonczay
- First Department of Medicine, University of Szeged, Szeged, Hungary
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Kolodecik T, Shugrue C, Ashat M, Thrower EC. Risk factors for pancreatic cancer: underlying mechanisms and potential targets. Front Physiol 2014; 4:415. [PMID: 24474939 PMCID: PMC3893685 DOI: 10.3389/fphys.2013.00415] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Accepted: 12/30/2013] [Indexed: 12/16/2022] Open
Abstract
PURPOSE OF THE REVIEW Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer. RECENT FINDINGS Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer. SUMMARY Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.
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Affiliation(s)
- Thomas Kolodecik
- Digestive Diseases Section, Department of Internal Medicine, Yale UniversityNew Haven, CT, USA
- VA HealthcareWest Haven, CT, USA
| | - Christine Shugrue
- Digestive Diseases Section, Department of Internal Medicine, Yale UniversityNew Haven, CT, USA
- VA HealthcareWest Haven, CT, USA
| | - Munish Ashat
- Digestive Diseases Section, Department of Internal Medicine, Yale UniversityNew Haven, CT, USA
- VA HealthcareWest Haven, CT, USA
| | - Edwin C. Thrower
- Digestive Diseases Section, Department of Internal Medicine, Yale UniversityNew Haven, CT, USA
- VA HealthcareWest Haven, CT, USA
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Abstract
PURPOSE OF REVIEW In this article, we review important advances in our understanding of the mechanisms of pancreatitis. RECENT FINDINGS The relative contributions of intrapancreatic trypsinogen activation and nuclear factor kappa B (NFκB) activation, the two major early independent cellular events in pancreatitis, have been investigated using novel genetic models. Trypsinogen activation has traditionally held the spotlight for many decades as the central pathogenic event of pancreatitis. However, recent experimental evidence points to the role of trypsin activation in early acinar cell damage but not in the inflammatory response of acute pancreatitis, which was shown to be induced by NFκB activation. Further, chronic pancreatitis developed independently of trypsinogen activation in the caerulein model. Sustained NFκB activation, but not persistent intra-acinar expression of active trypsin, was shown to result in chronic pancreatitis. Calcineurin-NFAT (nuclear factor of activated T-cells) signaling was shown to mediate downstream effects of pathologic rise in intracellular calcium. Interleukin-6 was identified as a key cytokine mediating pancreatitis-associated lung injury. SUMMARY Recent advances challenge the long-believed trypsin-centered understanding of pancreatitis. It is becoming increasingly clear that activation of intense inflammatory signaling mechanisms in acinar cells is crucial to the pathogenesis of pancreatitis, which may explain the strong systemic inflammatory response in pancreatitis.
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