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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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Xu Y, Song J, Gao J, Zhang H. Identification of Biomarkers Associated with Oxidative Stress and Immune Cells in Acute Pancreatitis. J Inflamm Res 2024; 17:4077-4091. [PMID: 38948197 PMCID: PMC11214539 DOI: 10.2147/jir.s459044] [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: 01/11/2024] [Accepted: 06/14/2024] [Indexed: 07/02/2024] Open
Abstract
Purpose Oxidative stress promotes disease progression by stimulating the humoral and cellular immune responses. However, the molecular mechanisms underlying oxidative stress and immune responses in acute pancreatitis (AP) have not been extensively studied. Patients and Methods We analyzed the GSE194331 dataset and oxidative stress-related genes (OSRGs). We identified differentially expressed immune cell-associated OSRGs (DE-ICA-OSRGs) by overlapping key module genes from weighted gene co-expression network analysis, OSRGs, and DEGs between AP and normal samples. Functional enrichment analysis was performed to investigate the functions of DE-ICA-OSRGs. We then filtered diagnostic genes using receiver operating characteristic curves and investigated their molecular mechanisms using single-gene set enrichment analysis (GSEA). We also explored the correlation between diagnostic genes and differential immune cells. Finally, we constructed a transcription factor-microRNA-messenger RNA (TF-miRNA-mRNA) network of biomarkers. Results In this study, three DE-ICA-OSRGs (ARG1, NME8 and VNN1) were filtered by overlapping key module genes, OSRGs and DEGs. Functional enrichment results revealed that DE-ICA-OSRGs were involved in the cellular response to reactive oxygen species and arginine biosynthesis. Latterly, a total of two diagnostic genes (ARG1 and VNN1) were derived and their expression was higher in the AP group than in the normal group. The single-gene GSEA enrichment results revealed that diagnostic genes were mainly enriched in macroautophagy and Toll-like receptor signaling pathways. Correlation analysis revealed that CD8 T cells, resting memory T CD4 cells, and resting NK cells were negatively correlated with ARG1, and neutrophils were positively correlated with ARG1, which was consistent with that of VNN1. The TF-miRNA-mRNA regulatory network included 11 miRNAs, 2 mRNAs, 10 transcription factors (TFs), and 26 pairs of regulatory relationships, like NFKB1-has-miR-2909-VNN1. Conclusion In this study, two immune cell oxidative stress-related AP diagnostic genes (ARG1 and VNN1) were screened to offer a new reference for the diagnosis of patients with AP.
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Affiliation(s)
- Yuan Xu
- Department of Gastroenterology, Dongying People’s Hospital(Dongying Hospital of Shandong Provincial Hospital Group), Dongying, Shandong, People’s Republic of China
| | - Jie Song
- Department of Gastroenterology, Dongying People’s Hospital(Dongying Hospital of Shandong Provincial Hospital Group), Dongying, Shandong, People’s Republic of China
| | - Jie Gao
- Department of Gastroenterology, Dongying People’s Hospital(Dongying Hospital of Shandong Provincial Hospital Group), Dongying, Shandong, People’s Republic of China
| | - Hongjing Zhang
- Community Health Service Center in Hekou District, Dongying, Shandong, People’s Republic of China
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Konarska-Bajda K, Ceranowicz P, Cieszkowski J, Ginter G, Stempniewicz A, Gałązka K, Kuśnierz-Cabala B, Dumnicka P, Bonior J, Warzecha Z. Administration of Warfarin Inhibits the Development of Cerulein-Induced Edematous Acute Pancreatitis in Rats. Biomolecules 2023; 13:948. [PMID: 37371528 DOI: 10.3390/biom13060948] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 05/19/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Acute pancreatitis (AP) is a severe disease with high morbidity and mortality in which inflammation and coagulation play crucial roles. The development of inflammation leads to vascular injury, endothelium and leukocytes stimulation, and an increased level of tissue factor, which results in the activation of the coagulation process. For this reason, anticoagulants may be considered as a therapeutic option in AP. Previous studies have shown that pretreatment with heparin, low-molecular-weight heparin (LMWH), or acenocoumarol inhibits the development of AP. The aim of the present study was to check if pretreatment with warfarin affects the development of edematous pancreatitis evoked by cerulein. Warfarin (90, 180, or 270 µg/kg/dose) or saline were administered intragastrically once a day for 7 days consecutively before the induction of AP. AP was evoked by the intraperitoneal administration of cerulein. The pre-administration of warfarin at doses of 90 or 180 µg/kg/dose reduced the histological signs of pancreatic damage in animals with the induction of AP. Additionally, other parameters of AP, such as an increase in the serum activity of lipase and amylase, the plasma concentration of D-dimer, and interleukin-1β, were decreased. In addition, pretreatment with warfarin administered at doses of 90 or 180 µg/kg/dose reversed the limitation of pancreatic blood flow evoked by AP development. Warfarin administered at a dose of 270 µg/kg/dose did not exhibit a preventive effect in cerulein-induced AP. Conclusion: Pretreatment with low doses of warfarin inhibits the development of AP evoked by the intraperitoneal administration of cerulein.
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Affiliation(s)
- Katarzyna Konarska-Bajda
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland
- Department of Pediatric Cardiology, University Children's Hospital in Cracow, 30-663 Kraków, Poland
| | - Piotr Ceranowicz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland
| | - Jakub Cieszkowski
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland
| | - Grzegorz Ginter
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland
| | - Agnieszka Stempniewicz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland
| | - Krystyna Gałązka
- Department of Pathology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland
| | - Beata Kuśnierz-Cabala
- Chair of Clinical Biochemistry/Chair of Medical Biochemistry, Jagiellonian University Medical College, 31-034 Kraków, Poland
| | - Paulina Dumnicka
- Chair of Clinical Biochemistry/Chair of Medical Biochemistry, Jagiellonian University Medical College, 31-034 Kraków, Poland
| | - Joanna Bonior
- Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, 31-126 Kraków, Poland
| | - Zygmunt Warzecha
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, 31-531 Kraków, Poland
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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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Mohamed MZ, Mohammed HH, Khalaf HM. Therapeutic effect of rupatadine against l-arginine-induced acute pancreatitis in rats: role of inflammation. Can J Physiol Pharmacol 2022; 100:176-183. [PMID: 35050802 DOI: 10.1139/cjpp-2021-0330] [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] [Indexed: 11/22/2022]
Abstract
Acute pancreatitis (AP) is an abrupt inflammatory disorder causing high morbidity and mortality. As AP is an insidious medical emergency, a curative modality is required instead of a preventive measure. Thus, we investigated the possible curative effect of rupatadine on a rat model of AP. Rupatadine is a potent histamine receptor 1 (H1R) and platelet-activating factor (PAF) blocker. We used four groups of six Wistar rats as follows: the control group received vehicle; the rupatadine control group received rupatadine as 6 mg/kg orally; the AP group received l-arginine intraperitoneally, and the treatment group received rupatadine at 1, 6, and 24 h after l-arginine injection. The levels of serum amylase, pancreatic oxidative parameters, and pancreatic cytokines were measured. PAF, histamine, and myeloperoxidase levels were determined in the pancreas. Histopathological and immunohistochemical examinations were performed to determine nuclear factor kappa-B (NF-κB) and caspase 3 expressions. Oxidative damage and severe inflammation were detected in the pancreas of the AP group. Rupatadine reduced the oxidative damage and the levels of proinflammatory cytokines, PAF, histamine, myeloperoxidase, NF-κB, and caspase 3 expressions. It restored the pancreatic acini to almost normal condition. Rupatadine induced important anti-inflammatory and antiapoptotic effects against l-arginine-induced AP.
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Affiliation(s)
- Mervat Z Mohamed
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Hanaa H Mohammed
- Department of Histology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
| | - Hanaa M Khalaf
- Department of Pharmacology, Faculty of Medicine, Minia University, 61511 Minia, Egypt
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Ma X, Yamaguchi A, Maeshige N, Uemura M, Noguchi H, Kondo H, Fujino H. Enhancement of astaxanthin incorporation by pulsed high-intensity ultrasound in LPS-stimulated macrophages. J Med Ultrason (2001) 2022; 49:125-132. [PMID: 35089476 DOI: 10.1007/s10396-022-01189-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/22/2021] [Indexed: 01/23/2023]
Abstract
PURPOSE Ultrasound (US) has been reported to improve the permeability of cell membranes to pharmaceuticals by causing cavitation. Astaxanthin (AX) potently terminates the induction of inflammation, but it has low oral bioavailability, which limits its incorporation in local cells and organs and its therapeutic potential. In this study, we aimed to investigate the contribution of US to AX incorporation to compensate for the limited incorporation of AX, and regulation of the pro-inflammatory factor interleukin-1β (IL-1β) by AX. METHODS Murine bone marrow-derived macrophages were stimulated by lipopolysaccharide (LPS). After 2 h, cells were treated with 10 μM AX and/or pulsed high-intensity US irradiation. The cells were then incubated for another 3 h and harvested. AX incorporation in cells was measured by absorbance, and the expression of IL-1β was measured by qPCR. All values are expressed as means ± standard error of the mean. RESULTS The combination of AX and US significantly increased AX incorporation in cells compared to AX alone (p < 0.05). In addition, this combination further suppressed the expression of IL-1β compared to AX alone (p < 0.05). CONCLUSION Pulsed high-intensity US irradiation combined with AX treatment promoted AX incorporation in cells and enhanced the anti-inflammatory effect on macrophages.
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Affiliation(s)
- Xiaoqi Ma
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Kobe, Hyogo, 654-0142, Japan
| | - Atomu Yamaguchi
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Kobe, Hyogo, 654-0142, Japan
| | - Noriaki Maeshige
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Kobe, Hyogo, 654-0142, Japan.
| | - Mikiko Uemura
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Kobe, Hyogo, 654-0142, Japan
| | - Hikari Noguchi
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Kobe, Hyogo, 654-0142, Japan
| | - Hiroyo Kondo
- Department of Food Science and Nutrition, Nagoya Women's University, Nagoya, Japan
| | - Hidemi Fujino
- Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10-2 Tomogaoka, Kobe, Hyogo, 654-0142, Japan
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7
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Schmuck RB, Lippens E, Wulsten D, Garske DS, Strönisch A, Pratschke J, Sauer IM, Duda GN, Bahra M, Cipitria A. Role of extracellular matrix structural components and tissue mechanics in the development of postoperative pancreatic fistula. J Biomech 2021; 128:110714. [PMID: 34534790 DOI: 10.1016/j.jbiomech.2021.110714] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 06/28/2021] [Accepted: 08/23/2021] [Indexed: 01/04/2023]
Abstract
Radical resection remains the only curative treatment option in pancreatic cancer. Postoperative pancreatic fistulas (POPF) occur in up to 30% of patients leading to prolonged hospital-stay, increased cost of care and morbidity and mortality. Mechanical properties of the pancreas are associated with POPF. The aim of this study is to analyze the role of extracellular matrix (ECM) and tissue mechanics in the risk of POPF. Biopsies of 41 patients receiving a partial pancreas-resection are analyzed. Clinical data, ECM components and mechanical properties are correlated with POPF. Preoperative cholestasis is correlated with reduced risk of POPF, which comes along with a dilatation of the pancreatic duct and significantly higher content of collagen I. Patients developing POPF exhibited a degenerated tissue integrity, with significantly lower content of fibronectin and a trend for lower collagen I, III, IV and hyaluronic acid. This correlated with a soft tactile sensation of the surgeon during the intervention. However, this was not reflected with tissue mechanics evaluated by ex vivo uniaxial compression testing, where a significantly higher elastic modulus and no effect on the stress relaxation time were found. In conclusion, patients with cholestasis seem to have a lower risk for POPF, and an increase in collagen I. A degenerated matrix with lower content of structural ECM components correlates with increased risk of POPF. However, ex vivo uniaxial compression testing failed to clearly explain the link of ECM properties and POPF.
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Affiliation(s)
- Rosa B Schmuck
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte I Campus Virchow-Klinikum, Berlin 10117, Germany.
| | - Evi Lippens
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, Berlin 13353, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, GermanyBerlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Dag Wulsten
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, Berlin 13353, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, GermanyBerlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Daniela S Garske
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, Berlin 13353, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, GermanyBerlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany; Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam 14476, Germany
| | - Annika Strönisch
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte I Campus Virchow-Klinikum, Berlin 10117, Germany
| | - Johann Pratschke
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte I Campus Virchow-Klinikum, Berlin 10117, Germany
| | - Igor M Sauer
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte I Campus Virchow-Klinikum, Berlin 10117, Germany
| | - Georg N Duda
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, Berlin 13353, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, GermanyBerlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany
| | - Marcus Bahra
- Department of Surgery, Charité - Universitätsmedizin Berlin, Campus Charité Mitte I Campus Virchow-Klinikum, Berlin 10117, Germany
| | - Amaia Cipitria
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Julius Wolff Institute, Augustenburger Platz 1, Berlin 13353, Germany; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Charitéplatz 1, 10117 Berlin, GermanyBerlin Institute of Health Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Berlin 13353, Germany; Max Planck Institute of Colloids and Interfaces, Department of Biomaterials, Potsdam 14476, Germany
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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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9
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Bläuer M, Sand J, Laukkarinen J. Regulation of p38 MAPK and glucocorticoid receptor activation by hydrocortisone in mono-and co-cultured pancreatic acinar and stellate cells. Pancreatology 2021; 21:384-389. [PMID: 33454208 DOI: 10.1016/j.pan.2020.12.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/17/2020] [Accepted: 12/29/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES Acute pancreatitis develops as an inflammatory response to pancreatic tissue injury. Postoperative pancreatitis has recently been associated with increased occurrence of complications. Activation of the mitogen-activated protein kinase p38 (p38 MAPK) pathway occurs early in acute pancreatitis and its inhibition has been suggested to alleviate pancreatic inflammation. Glucocorticoids are potent anti-inflammatory steroids whose use in the management of acute pancreatitis remains controversial. Our aim was to examine the effect of crosstalk between pancreatic acinar cells (PACs) and stellate cells (PSCs) on p38 MAPK and glucocorticoid receptor (GR) activation and to assess the impact of hydrocortisone on these events. METHODS The long-term co-culture setting for mouse PACs and PSCs developed in our laboratory was used. Parallel 4d mono- and co-cultures with or without 10 nM hydrocortisone were performed followed by immunocytochemical analysis of nuclear GR and phospho-p38 MAPK (pp38 MAPK). RESULTS Hydrocortisone inhibited pp38 MAPK up-regulation evoked by co-culture in PACs and PSCs and increased nuclear translocation of GR in PAC monocultures and in co-cultured PACs and PSCs. In PSC monocultures and co-cultured PACs, ligand-independent expression of nuclear GR was observed. In the former no change in nuclear GR but a significant decrease in total GR as analyzed by Western blot was caused by hydrocortisone. CONCLUSIONS Cellular microenvironment plays a significant role on p38 MAPK and GR activation in PACs and PSCs. Hydrocortisone is an effective means to inhibit p38 MAPK activation in PACs and PSCs. Both ligand-dependent and -independent regulatory roles for GR are suggested in the exocrine pancreas.
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Affiliation(s)
- Merja Bläuer
- Tampere Pancreas Laboratory and Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Juhani Sand
- Tampere Pancreas Laboratory and Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Johanna Laukkarinen
- Tampere Pancreas Laboratory and Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
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10
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Barreto SG, Habtezion A, Gukovskaya A, Lugea A, Jeon C, Yadav D, Hegyi P, Venglovecz V, Sutton R, Pandol SJ. Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis. Gut 2021; 70:194-203. [PMID: 32973069 PMCID: PMC7816970 DOI: 10.1136/gutjnl-2020-322163] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/01/2020] [Accepted: 08/19/2020] [Indexed: 12/11/2022]
Abstract
Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? (c) Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.
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Affiliation(s)
- Savio George Barreto
- Division of Surgery and Perioperative Medicine, Flinders Medical Center, Bedford Park, Adelaide, South Australia, Australia
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Anna Gukovskaya
- Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA
- Department of Medicine, West Los Angeles VA Healthcare Center, Los Angeles, California, USA
| | - Aurelia Lugea
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Christie Jeon
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Dhiraj Yadav
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Peter Hegyi
- First Department of Medicine, Faculty of Medicine, University of Szeged, Szeged, Hungary
- Institute for Translational Medicine and First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
- Szentágothai Research Center, University of Pécs, Pécs, Hungary
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Robert Sutton
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Stephen J Pandol
- Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, California, USA
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11
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Jiang X, Zheng YW, Bao S, Zhang H, Chen R, Yao Q, Kou L. Drug discovery and formulation development for acute pancreatitis. Drug Deliv 2020; 27:1562-1580. [PMID: 33118404 PMCID: PMC7598990 DOI: 10.1080/10717544.2020.1840665] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Acute pancreatitis is a sudden inflammation and only last for a short time, but might lead to a life-threatening emergency. Traditional drug therapy is an essential supportive method for acute pancreatitis treatment, yet, failed to achieve satisfactory therapeutic outcomes. To date, it is still challenging to develop therapeutic medicine to redress the intricate microenvironment promptly in the inflamed pancreas, and more importantly, avoid multi-organ failure. The understanding of the acute pancreatitis, including the causes, mechanism, and severity judgment, could help the scientists bring up more effective intervention and treatment strategies. New formulation approaches have been investigated to precisely deliver therapeutics to inflammatory lesions in the pancreas, and some even could directly attenuate the pancreatic damages. In this review, we will briefly introduce the involved pathogenesis and underlying mechanisms of acute pancreatitis, as well as the traditional Chinese medicine and the new drug option. Most of all, we will summarize the drug delivery strategies to reduce inflammation and potentially prevent the further development of pancreatitis, with an emphasis on the bifunctional nanoparticles that act as both drug delivery carriers and therapeutics.
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Affiliation(s)
- Xue Jiang
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.,Central Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ya-Wen Zheng
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Shihui Bao
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Hailin Zhang
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Children's Respiration Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ruijie Chen
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qing Yao
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Longfa Kou
- Municipal Key Laboratory of Paediatric Pharmacy, Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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12
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Xue BH, Liu Y, Chen H, Sun Y, Yu WL. A novel function of IRF9 in acute pancreatitis by modulating cell apoptosis, proliferation, migration, and suppressing SIRT1-p53. Mol Cell Biochem 2020; 472:125-134. [PMID: 32577948 DOI: 10.1007/s11010-020-03791-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023]
Abstract
Acute pancreatitis (AP) is an inflammatory disease caused by the abnormal activation of pancreatic enzymes in the pancreas, with a considerably high morbidity and mortality. However, the etiological factor and pathogenesis of AP are still unclear. This study was aimed to explore the role and mechanism of interferon regulatory factor 9 (IRF9) in the occurrence of AP and to provide experimental and theoretical foundation for AP diagnosis and treatment. AP model in vitro was established by caerulein-induced group. Small interfering RNA (siRNA) was designed and constructed to silence IRF9 gene. After siRNA transfected and caerulein treated successfully, the expression levels of IRF9, SIRT1, and acetylated p53 (Ac-p53) were determined by qRT-PCR and Western blot. The apoptosis, proliferation, and migration of AR42J cells were checked by flow cytometry, MTT, and transwell assay. Dual-luciferase reporter assay was implemented to validate the regulatory effect of IRF9 on SIRT1. Here, our study showed that the expression of IRF9 and Ac-p53 was increased, SIRT1 was decreased, and cell apoptosis, proliferation, and migration of AR42J cells were increased after caerulein induced. IRF9 gene silencing upregulated SIRT1, downregulated Ac-p53, and inhibited cell apoptosis, proliferation, and migration. Dual-Luciferase reporter assay showed that IRF9 could negatively regulate SIRT1. The potential mechanism was that IRF9 could modulate cell apoptosis, proliferation, migration, and bind the promoter of SIRT1 to repress SIRT1-p53. It hinted that IRF9 showed a novel function in AP by modulating cell apoptosis, proliferation, migration, and suppressing SIRT1-p53. IRF9 might be a good potential treatment target for AP.
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Affiliation(s)
- Bin-Hua Xue
- Department of Intensive Care Unit, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Yi Liu
- Department of Intensive Care Unit, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Hu Chen
- Department of Intensive Care Unit, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Yun Sun
- Department of Intensive Care Unit, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China
| | - Wei-Li Yu
- Department of Intensive Care Unit, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, Anhui, China.
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13
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Abstract
OBJECTIVE We clarified clinicopathological characteristics of acute pancreatitis in terminal patients. METHODS Pathological changes in the entire pancreas from serial autopsies (N = 183) classified lesions into the following 3 categories: focal neutrophil infiltration, focal necrotizing pancreatitis, and diffuse necrotizing pancreatitis. The former two are possible precursors of diffuse necrotizing pancreatitis. Immunohistochemical staining was performed to analyze pancreatic stellate cells and inflammatory cells. RESULTS There were pathologically acute pancreatitis in 45 patients (24.6%), and no patients were diagnosed with it before autopsy. Focal neutrophil infiltration was present in 22 cases, focal necrotizing pancreatitis in 18 cases, and diffuse necrotizing pancreatitis in 5 cases. Severe inflammatory disease and surgery were associated with acute pancreatitis. Sepsis due to viral or bacterial infection was the most common cause of acute pancreatitis. Patients with diffuse necrotizing pancreatitis showed low white blood cell counts, while amylase levels were not increased. Increase in α-smooth muscle actin and nestin-positive stellate cell numbers in acute pancreatitis was correlated to increase in numbers of CD34-positive vascular endothelium, CD68- or CD163-positive macrophages, CD138-positive plasmacytes, CD3-positive T lymphocytes, and myeloperoxidase-positive leucocytes. CONCLUSIONS Necrotizing pancreatitis without typical clinical signs was frequently detected in autopsy samples. Clinicians must be mindful of necrotizing pancreatitis in terminal patients.
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Jian J, Li S, Fang N, Cao YZ, Zhen L, Qin JB, Li B. Pim-3 alleviates lipopolysaccharide-stimulated AR42J pancreatic acinar cell injury via improving the inflammatory microenvironment. Exp Ther Med 2019; 18:4427-4435. [PMID: 31777546 PMCID: PMC6862483 DOI: 10.3892/etm.2019.8094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 09/24/2019] [Indexed: 12/12/2022] Open
Abstract
Acute pancreatitis (AP) is a common acute abdominal disease characterized by pancreatic aseptic inflammation, with ~20% of patients progressing to severe AP (SAP) with a high mortality rate. The aim of this study was to explore the protective effects of Pim-3 proto-oncogene, serine/threonine kinase (Pim-3) on rat pancreatic acinar AR4-2J cells damaged by lipopolysaccharide (LPS). The recombinant plasmid p-enhanced green fluorescent protein (pEGFP)-N2/Pim-3 was transiently transfected into AR42J cells and the AR42J cells were then treated with 2 µg/ml LPS. Subsequently, the proliferation of AR42J cells was detected using MTT assay. The cell cycle progression and apoptosis rate of the AR42J cells were examined using flow cytometry. AR42J cell migration was assessed using wound healing assays. Additionally, RT-semi quantitative PCR and western blot analyses were used to detect the mRNA and protein expression levels, respectively, of Pim-3, interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, intercellular adhesion molecule (ICAM)-1 and Occludin in AR42J cells. The results revealed that proliferation of AR42J cells was significantly enhanced and cell apoptosis was markedly reduced in the pEGFP-N2/Pim-3 + LPS group. The proportion of AR42J cells in G1 phase in the pEGFP-N2/Pim-3 + LPS group was decreased, whereas the proportion of cells in the G2 and S phases was increased. The wound healing assays demonstrated that AR42J cell migration was significantly increased in the pEGFP-N2/Pim-3 + LPS group. Finally, the expression levels of IL-6, IL-1β, TNF-α and ICAM-1 were significantly decreased in the pEGFP-N2/Pim-3 + LPS group, whereas the expression of Occludin was significantly increased. The present study demonstrated that raised expression levels of Pim-3 can protect AR42J cells from LPS-induced injury by modifying the inflammatory microenvironment, suggesting that Pim-3 may be a potential target for AP or SAP therapy.
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Affiliation(s)
- Jie Jian
- Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Shuang Li
- Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Nian Fang
- Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - You-Zhao Cao
- Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Li Zhen
- Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Jian-Bin Qin
- Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Bin Li
- Department of Gastroenterology, The Third Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
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15
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Siriviriyakul P, Chingchit T, Klaikeaw N, Chayanupatkul M, Werawatganon D. Effects of curcumin on oxidative stress, inflammation and apoptosis in L-arginine induced acute pancreatitis in mice. Heliyon 2019; 5:e02222. [PMID: 31485503 PMCID: PMC6717142 DOI: 10.1016/j.heliyon.2019.e02222] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/21/2019] [Accepted: 07/31/2019] [Indexed: 02/07/2023] Open
Abstract
Background and purpose Curcumin, an active constituent of rhizomes of Curcuma longa Linn, exhibits a variety of biological activities such as anti-inflammation and anti-oxidant. The present study aims to examine the effects of curcumin on oxidative stress, inflammation and apoptosis in L-arginine induced acute pancreatitis (AP) in mice. Methods Male ICR mice were randomly divided into 4 groups. Control group received intraperitoneal injection (i.p.) of 1% DMSO as a vehicle. AP group received two doses of i.p. L-arginine (L-Arg) 450 mg/100 g body weight (BW) at 1-hour interval. AP plus low-dose curcumin group received i.p. curcumin 50 mg/kg BW 1 hour before L-Arg injection and then once daily for 3 days. AP plus high-dose curcumin group received i.p. curcumin 200 mg/kg BW 1 hour before L-Arg injection and then once daily for 3 days. All mice were sacrificed at 72 hours. Pancreatic tissue was obtained for histological evaluation, immunohistochemical studies for nuclear factor-kappa beta (NF-kβ), apoptosis and myeloperoxidase (MPO), and Western blot analyses for 4-Hydroxynonenal (4-HNE). Blood samples were collected for amylase analysis. Results Mean body weight was significantly lower in AP group than in control group, while in curcumin group, body weight was maintained. The serum amylase, number of MPO positive cells, NF-kB positive cells, TUNEL positive cells, and 4-HNE expression significantly increased in AP group when compared with control group, but decreased in low and high-dose curcumin groups. Mice in AP group developed severe pancreatic inflammation, edema and fat necrosis. While mice in low and high-dose curcumin groups showed a significant improvement in histopathological scores. There was no significant difference between low and high doses of curcumin. Conclusion Curcumin could attenuate acute pancreatitis via anti-oxidant, anti-inflammation and anti-apoptosis property leading to the improvement in pancreatic damage.
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Affiliation(s)
- Prasong Siriviriyakul
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Thidarat Chingchit
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Naruemon Klaikeaw
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Maneerat Chayanupatkul
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
| | - Duangporn Werawatganon
- Alternative and Complementary Medicine for Gastrointestinal and Liver Diseases Research Unit, Department of Physiology, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Road, Pathumwan, Bangkok, 10330, Thailand
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16
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Gulla A, Gulbinas A, Dambrauskas Z, Strupas K. Heme Oxygenase-1 Polymorphism Is Associated With the Development of Necrotic Acute Pancreatitis Via Vascular Cell Adhesion Molecule-1 and the E-Selectin Expression Regulation Pathway. Pancreas 2019; 48:787-791. [PMID: 31210657 DOI: 10.1097/mpa.0000000000001328] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Severe acute pancreatitis can lead to systemic complications. Here, we explore the mechanisms based on our previous study associated with the deregulation of heme oxygenase-1 (HO-1) and development of severe acute pancreatitis. METHODS Acute pancreatitis patients (n = 135) and age- and sex-matched healthy controls (n = 108) were studied. The polymerase chain reaction products were analyzed with an ABI 3130 genetic analyzer and GeneMapper software. A short allele was defined ≤27 dinucleotide (GT) repeats, whereas a long allele was defined >27 GT. Levels of 12 different cytokines in blood serum were measured by enzyme-linked immunosorbent assay. All samples in this study were consistently stored in -80°C. RESULTS Patients with the long long genotype expressed E-selectin and vascular cell adhesion molecule-1 at statistically significantly higher levels in serum compared with short short genotype or short long genotypes. Vascular cell adhesion molecule-1 and E-selectin serum levels significantly correlate with the total allele length of the HO-1 promoter region. CONCLUSION Polymorphism of the GT repeats in the HO-1 promoter region may be a risk factor for developing acute necrotizing pancreatitis due to deregulation of the immune response.
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Affiliation(s)
| | - Antanas Gulbinas
- Department of Surgery, Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Zilvinas Dambrauskas
- Department of Surgery, Hospital of Lithuanian University of Health Sciences, Kaunas, Lithuania
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17
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Fonteh P, Smith M, Brand M. Adaptive Immune Cell Dysregulation and Role in Acute Pancreatitis Disease Progression and Treatment. Arch Immunol Ther Exp (Warsz) 2018; 66:199-209. [PMID: 29189884 DOI: 10.1007/s00005-017-0495-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 08/31/2017] [Indexed: 12/18/2022]
Abstract
Acute pancreatitis (AP) is an inflammation of the pancreas caused by various stimuli including excessive alcohol consumption, gallstone disease and certain viral infections. Managing specifically the severe form of AP is limited due to lack of an understanding of the complex immune events that occur during AP involving immune cells and inflammatory molecules such as cytokines. The relative abundance of various immune cells resulting from the immune dysregulation drives disease progression. In this review, we examine the literature on the adaptive immune cells in AP, the prognostic value of these cells in stratifying patients into appropriate care and treatment strategies based on cell frequency in different AP severities are discussed.
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Affiliation(s)
- Pascaline Fonteh
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa.
| | - Martin Smith
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
| | - Martin Brand
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
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18
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Shen Y, Wen L, Zhang R, Wei Z, Shi N, Xiong Q, Xia Q, Xing Z, Zeng Z, Niu H, Huang W. Dihydrodiosgenin protects against experimental acute pancreatitis and associated lung injury through mitochondrial protection and PI3Kγ/Akt inhibition. Br J Pharmacol 2018; 175:1621-1636. [PMID: 29457828 DOI: 10.1111/bph.14169] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 01/22/2018] [Accepted: 01/25/2018] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND AND PURPOSE Acute pancreatitis (AP) is a painful and distressing disorder of the exocrine pancreas with no specific treatment. Diosgenyl saponins extracted from from Dioscorea zingiberensis C. H. Wright have been reported to protect against experimental models of AP. Diosgenin, or its derivatives are anti-inflammatory in various conditions. However, the effects of diosgenin and its spiroacetal ring opened analogue, dihydrodiosgenin (Dydio), on AP have not been determined. EXPERIMENTAL APPROACH Effects of diosgenin and Dydio on sodium taurocholate hydrate (Tauro)-induced necrosis were tested, using freshly isolated murine pancreatic acinar cells. Effects of Dydio on mitochondrial dysfunction in response to Tauro, cholecystokinin-8 and palmitoleic acid ethyl ester were also assessed. Dydio (5 or 10 mg·kg-1 ) was administered after the induction in vivo of Tauro-induced AP (Wistar rats), caerulein-induced AP and palmitoleic acid plus ethanol-induced AP (Balb/c mice). Pancreatitis was assessed biochemically and histologically. Activation of pancreatic PI3Kγ/Akt was measured by immunoblotting. KEY RESULTS Dydio inhibited Tauro-induced activation of the necrotic cell death pathway and prevented pancreatitis stimuli-induced mitochondrial dysfunction. Therapeutic administration of Dydio ameliorated biochemical and histopathological responses in all three models of AP through pancreatic mitochondrial protection and PI3Kγ/Akt inactivation. Moreover, Dydio improved pancreatitis-associated acute lung injury through preventing excessive inflammatory responses. CONCLUSION AND IMPLICATIONS These data provide in vitro and in vivo mechanistic evidence that the diosgenin analogue, Dydio could be potential treatment for AP. Further medicinal optimization of diosgenin and its analogue might be a useful strategy for identifying lead candidates for inflammatory diseases.
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Affiliation(s)
- Yan Shen
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Li Wen
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China.,Department of Pediatric Gastroenterology, Children's Hospital of Pittsburgh of UPMC and School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Rui Zhang
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Zeliang Wei
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Na Shi
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Qiuyang Xiong
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Qing Xia
- Department of Integrated Traditional Chinese and Western Medicine, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Zhihua Xing
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Zhi Zeng
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
| | - Hai Niu
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China.,College of Mathematics, Sichuan University, Chengdu, Sichuan, China
| | - Wen Huang
- Laboratory of Ethnopharmacology/Regenerative Medicine Research Center, West China Hospital/West China Medical School, Sichuan University, Chengdu, Sichuan, China
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Abstract
OBJECTIVES Inflammation in the setting of acute pancreatitis (AP) is partially driven by pathogen recognition receptors that recognize damage-associated molecular patterns. Interleukin (IL)-8 is a chemotactic factor produced by pathogen recognition receptor-expressing cells. A single-nucleotide polymorphism in IL8 promoter region (-251 A/T) has been implicated in inflammatory diseases. We examined whether this IL8 polymorphism confers susceptibility to AP. METHODS Patients with AP (n = 357) were prospectively recruited. Clinical data and blood were collected in subjects and controls (n = 347). Severity was defined following the Revised Atlanta Classification. Genotypes were assessed by quantitative polymerase chain reaction using TaqMan probes. RESULTS Patients and controls had similar demographics and had no difference in Hardy-Weinberg (patients, P = 0.29; controls, P = 0.66). Twenty-five percent of patients developed severe AP. Compared with controls, the A/A genotype was more common in AP (P = 0.041; odds ratio, 1.42; 95% confidence interval, 1-1.99). Obese patients with the A/A genotype were more likely to develop mild AP (P = 0.047). CONCLUSIONS The -251 polymorphism confers susceptibility to AP and disease severity in obese patients. However, its effect is moderate. One potential mechanism for this susceptibility is via increased IL8 production by innate cells, with subsequent enhanced neutrophil influx and pancreatic injury.
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20
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Manohar M, Verma AK, Upparahalli Venkateshaiah S, Goyal H, Mishra A. Food-Induced Acute Pancreatitis. Dig Dis Sci 2017; 62:3287-3297. [PMID: 29086330 PMCID: PMC5718054 DOI: 10.1007/s10620-017-4817-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 10/19/2017] [Indexed: 12/24/2022]
Abstract
Food allergy, a commonly increasing problem worldwide, defined as an adverse immune response to food. A variety of immune-related effector cells such as mast cells, eosinophils, neutrophils, and T cells are involved in food-related allergic responses categorized as IgE mediated, non-IgE mediated, and mixed (IgE and non-IgE) depending upon underlying immunological mechanisms. The dietary antigens mainly target the gastrointestinal tract including pancreas that gets inflamed due to food allergy and leads acute pancreatitis. Reports indicate several food proteins induce pancreatitis; however, detailed underlying mechanism of food-induced pancreatitis is unexplored. The aim of the review is to understand and update the current scenario of food-induced pancreatitis. A comprehensive literature search of relevant research articles has been performed through PubMed, and articles were chosen based on their relevance to food allergen-mediated pancreatitis. Several cases in the literature indicate that acute pancreatitis has been provoked after the consumption of mustard, milk, egg, banana, fish, and kiwi fruits. Food-induced pancreatitis is an ignored and unexplored area of research. The review highlights the significance of food in the development of pancreatitis and draws the attention of physicians and scientists to consider food allergies as a possible cause for initiation of pancreatitis pathogenesis.
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Affiliation(s)
- Murli Manohar
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Alok K Verma
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Sathisha Upparahalli Venkateshaiah
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA
| | - Hemant Goyal
- Department of Internal Medicine, Mercer University School of Medicine, 707 Pine St., Macon, GA, 31201, USA
| | - Anil Mishra
- Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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21
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Umazume T, Thomas WM, Campbell S, Aluri H, Thotakura S, Zoukhri D, Makarenkova HP. Lacrimal Gland Inflammation Deregulates Extracellular Matrix Remodeling and Alters Molecular Signature of Epithelial Stem/Progenitor Cells. Invest Ophthalmol Vis Sci 2016; 56:8392-402. [PMID: 26747770 DOI: 10.1167/iovs.15-17477] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
PURPOSE The adult lacrimal gland (LG) is highly regenerative and is able to repair itself even after substantial damage; however, this ability to regenerate is lost with the development of dry eye conditions in chronically inflamed LGs.This study compares changes in the cell adhesion and cell matrix molecules and stem cell transcription factors in the LGs of healthy mice and of two mouse models of Sjögren's syndrome: nonobese diabetic (NOD) and MRL-lpr/lpr (MRL/lpr) mice during the early stage of inflammation. METHODS The LGs from 12- to 13-week-old female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for quantitative (q) RT-PCR and qRT-PCR Arrays, histology, immunohistochemistry, and Western blotting. RESULTS The extracellular matrix (ECM) and adhesion molecules RT2-PCR array combined with protein expression data revealed changes in the expression of integrins, matrix metalloproteinases, and other molecules, which are associated largely with invasion, attachment, and expansion of the lymphocytic cells, whereas changes in the stem cell transcription factors revealed substantial decrease in expression of transcription factors associated with epithelial stem/progenitor cell lineage. CONCLUSIONS We concluded that the expression of several important ECM components is significantly deregulated in the LG of two murine models of Sjögren's syndrome, suggesting an alteration of the epithelial stem/progenitor cell niche. This may result in profound effects on localization, activation, proliferation, and differentiation of the LG stem/progenitor cells and, therefore, LG regeneration.
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Affiliation(s)
- Takeshi Umazume
- Department of Cell and Molecular Biology The Scripps Research Institute, La Jolla, California, United States
| | - William M Thomas
- Department of Cell and Molecular Biology The Scripps Research Institute, La Jolla, California, United States
| | - Sabrina Campbell
- Department of Cell and Molecular Biology The Scripps Research Institute, La Jolla, California, United States
| | - Hema Aluri
- Department of Diagnosis and Health Promotion, Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Suharika Thotakura
- Department of Diagnosis and Health Promotion, Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Driss Zoukhri
- Department of Diagnosis and Health Promotion, Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Helen P Makarenkova
- Department of Cell and Molecular Biology The Scripps Research Institute, La Jolla, California, United States
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22
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García-Hernández V, Sarmiento N, Sánchez-Bernal C, Coveñas R, Hernández-Hernández A, Calvo JJ, Sánchez-Yagüe J. Changes in the expression of LIMP-2 during cerulein-induced pancreatitis in rats: Effect of inhibition of leukocyte infiltration, cAMP and MAPKs early on in its development. Int J Biochem Cell Biol 2016; 72:109-117. [PMID: 26794464 DOI: 10.1016/j.biocel.2016.01.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 12/28/2015] [Accepted: 01/15/2016] [Indexed: 12/26/2022]
Abstract
Lysosomal integral membrane protein-2 (LIMP-2) is an important protein in lysosomal biogenesis and function and also plays a role in the tissue inflammatory response. It is known that lysosomes play a central role in acute pancreatitis, with inflammatory cell infiltration triggering the disease early on. In this study we report increases in pancreatic LIMP-2 protein and mRNA levels as early events that occur during the development of cerulein (Cer)-induced acute pancreatitis (AP) in rats. GdCl3, a macrophage inhibitor, but not FK506, a T lymphocyte inhibitor, was able to reverse the increase in LIMP-2 expression after Cer treatment, although such reversion was abolished if the animals were depleted of neutrophils due to a vinblastine sulfate pre-treatment. Immunostaining revealed that the cellular source of LIMP-2 was mainly acinar cells. Additionally, pre-treatments with the MAPKs inhibitors SP600125 and PD98059, inhibitors of JNK and ERK½ activation, respectively, but not of rolipram, a type IV phosphodiesterase inhibitor, suppressed the increase in the expression of LIMP-2 after Cer administration. Together, these results indicate that neutrophils are able to drive a macrophage activation that would regulate the increase in LIMP-2 expression during the early phase of Cer-induced AP, with the stress kinases JNK and ERK½ also playing a coordinated role in the increase of LIMP-2 expression due to Cer.
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Affiliation(s)
- Violeta García-Hernández
- Department of Biochemistry and Molecular Biology, University of Salamanca, IBSAL (Instituto de Investigación Biomédica de Salamanca), Spain
| | - Nancy Sarmiento
- Department of Biochemistry and Molecular Biology, University of Salamanca, IBSAL (Instituto de Investigación Biomédica de Salamanca), Spain
| | - Carmen Sánchez-Bernal
- Department of Biochemistry and Molecular Biology, University of Salamanca, IBSAL (Instituto de Investigación Biomédica de Salamanca), Spain
| | - Rafael Coveñas
- Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, Spain
| | - Angel Hernández-Hernández
- Department of Biochemistry and Molecular Biology, University of Salamanca, IBSAL (Instituto de Investigación Biomédica de Salamanca), Spain
| | - José J Calvo
- Department of Physiology and Pharmacology, University of Salamanca, IBSAL (Instituto de Investigación Biomédica de Salamanca), Spain
| | - Jesús Sánchez-Yagüe
- Department of Biochemistry and Molecular Biology, University of Salamanca, IBSAL (Instituto de Investigación Biomédica de Salamanca), Spain.
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23
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Barreto SG. How does cigarette smoking cause acute pancreatitis? Pancreatology 2016; 16:157-163. [PMID: 26419886 DOI: 10.1016/j.pan.2015.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 08/22/2015] [Accepted: 09/03/2015] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Acute Pancreatitis (AP) is an emerging health problem world-wide and it is a major cause of admissions for gastrointestinal disease in many countries. Amongst the more common causes (alcohol and gallstones), recent evidence has emerged indicating that smoking is an independent risk factor for AP. However, the mechanisms involved in smoking-induced AP have not been completely elucidated. This review puts together all the published evidence in literature to present the clinical and laboratory evidence relating smoking to the causation of AP. DISCUSSION The two main metabolites from cigarette smoke, namely nicotine and NNK are able to induce functional and histological changes within the pancreas consistent with AP. The major mechanisms involved include their action on acinar cells and zymogen secretion through pathways involving CCK and the nicotinic preganglionic receptors. Effects on the pancreatic microvasculature may be mediated through the nitric oxide pathway. There is indirect evidence to suggest that nicotine and acrolein may lead to CFTR dysfunction thereby influencing ductal secretion. However, direct evidence for this effect is needed. The effect of cigarette smoke metabolites on stellate cells and the islets warrants further investigation in the context of pathogenesis of AP. CONCLUSION Using a step-wise approach, the review revisits the effects of the various metabolites of cigarette smoke on the constituents of the pancreas (exocrine, endocrine, neurohormonal, stellate cells, ductal system) and highlights their proven, and potential, mechanisms in triggering off an attack of AP.
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Affiliation(s)
- Savio G Barreto
- Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Sector 38, Gurgaon, Haryana, India.
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Clemens DL, Schneider KJ, Arkfeld CK, Grode JR, Wells MA, Singh S. Alcoholic pancreatitis: New insights into the pathogenesis and treatment. World J Gastrointest Pathophysiol 2016; 7:48-58. [PMID: 26909228 PMCID: PMC4753189 DOI: 10.4291/wjgp.v7.i1.48] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/23/2015] [Accepted: 11/11/2015] [Indexed: 02/06/2023] Open
Abstract
Acute pancreatitis is a necro-inflammatory disease of the exocrine pancreas that is characterized by inappropriate activation of zymogens, infiltration of the pancreas by inflammatory cells, and destruction of the pancreatic exocrine cells. Acute pancreatitis can progress to a severe life-threatening disease. Currently there is no pharmacotherapy to prevent or treat acute pancreatitis. One of the more common factors associated with acute pancreatitis is alcohol abuse. Although commonly associated with pancreatitis alcohol alone is unable to cause pancreatitis. Instead, it appears that alcohol and its metabolic by-products predispose the pancreas to damage from agents that normally do not cause pancreatitis, or to more severe disease from agents that normally cause mild pancreatic damage. Over the last 10 to 20 years, a tremendous amount of work has defined a number of alcohol-mediated biochemical changes in pancreatic cells. Among these changes are: Sustained levels of intracellular calcium, activation of the mitochondrial permeability transition pore, endoplasmic reticulum stress, impairment in autophagy, alteration in the activity of transcriptional activators, and colocalization of lysosomal and pancreatic digestive enzymes. Elucidation of these changes has led to a deeper understanding of the mechanisms by which ethanol predisposes acinar cells to damage. This greater understanding has revealed a number of promising targets for therapeutic intervention. It is hoped that further investigation of these targets will lead to the development of pharmacotherapy that is effective in treating and preventing the progression of acute pancreatitis.
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Shafik NM, Abou-Fard GM. Ameliorative Effects of Curcumin on Fibrinogen-Like Protein-2 Gene Expression, Some Oxido-Inflammatory and Apoptotic Markers in a Rat Model of l-Arginine-Induced Acute Pancreatitis. J Biochem Mol Toxicol 2016; 30:302-8. [PMID: 26862043 DOI: 10.1002/jbt.21794] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Revised: 01/08/2016] [Accepted: 01/15/2016] [Indexed: 12/17/2022]
Abstract
The aim of the study was to investigate the ameliorative effects of curcumin on fibrinogen like protein-2 (fgl-2), some oxido-inflammatory and apoptotic markers in rat-induced acute pancreatitis (AP). Seventy-five albino rats were divided into control group, l-arginine (l-Arg)-induced AP group, curcumin pre-treated group before AP induction, curcumin post-treated group after AP induction, and curcumin injected group only. AP group showed severe necrotizing pancreatitis confirmed by histopathological changes and elevations in serum amylase and lipase activities, levels of epithelial neutrophil-activating peptide 78, tissue content of protein carbonyls, levels of tumor necrosis factor α, and caspase-3 as well as myeloperoxidase activity. Significant elevation in pancreatic fgl-2 mRNA expression was detected in AP group. Improvement of all parameters was detected with increase of caspase-3 in both curcumin-treated groups that confirmed curcumin ameliorative effects against AP through induction of apoptosis and inhibition of micro-thrombosis, inflammation, and oxidative stress.
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Affiliation(s)
- Noha M Shafik
- Department of Medical Biochemistry, Faculty of Medicine Tanta University, Tanta, Egypt.
| | - Ghada M Abou-Fard
- Department of Physiology, Faculty of Medicine Tanta University, Tanta, Egypt
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26
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Aluri HS, Kublin CL, Thotakura S, Armaos H, Samizadeh M, Hawley D, Thomas WM, Leavis P, Makarenkova HP, Zoukhri D. Role of Matrix Metalloproteinases 2 and 9 in Lacrimal Gland Disease in Animal Models of Sjögren's Syndrome. Invest Ophthalmol Vis Sci 2015; 56:5218-28. [PMID: 26244298 DOI: 10.1167/iovs.15-17003] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Chronic inflammation of the lacrimal gland results in changes in the composition of the extracellular matrix (ECM), which is believed to compromise tissue repair. We hypothesized that increased production/activity of matrix metalloproteinases (MMPs), especially MMP-2 and -9, in inflamed lacrimal glands modifies the ECM environment, therefore disrupting tissue repair. METHODS The lacrimal glands from female MRL/lpr and male NOD mice along with their respective control strains were harvested and divided into three pieces and processed for histology, immunohistochemistry, zymography, Western blotting, and RNA analyses. In another study, MRL/lpr mice were treated for 5 weeks with a selective MMP2/9 inhibitor peptide or a control peptide. At the end of treatment, the lacrimal glands were excised and the tissue was processed as described above. RESULTS There was a 2.5- and 2.7-fold increase in MMP2 gene expression levels in MRL/lpr and NOD mice, respectively. Matrix metalloproteinase 2 and 9 enzymatic activities and protein expression levels were significantly upregulated in the lacrimal glands of MRL/lpr and NOD mice compared to controls. Treatment with the MMP2/9 inhibitor resulted in decreased activity of MMP-2 and -9 both in vitro and in vivo. Importantly, MMP2/9 inhibitor treatment of MRL/lpr mice improved aqueous tear production and resulted in reduced number and size of lymphocytic foci in diseased lacrimal glands. CONCLUSIONS We conclude that MMP2/9 expression and activity are elevated in lacrimal glands of two murine models of Sjögren's syndrome, suggesting that manipulation of MMP2/9 activity might be a potential therapeutic target in chronically inflamed lacrimal glands.
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Affiliation(s)
- Hema S Aluri
- Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Claire L Kublin
- Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Suharika Thotakura
- Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Helene Armaos
- Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Mahta Samizadeh
- Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - Dillon Hawley
- Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States
| | - William M Thomas
- Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States
| | - Paul Leavis
- Department of Integrative Physiology and Pathobiology, Tufts University, Boston, Massachusetts, United States
| | - Helen P Makarenkova
- Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States
| | - Driss Zoukhri
- Department of Diagnosis and Health Promotion Tufts University School of Dental Medicine, Boston, Massachusetts, United States
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He X, Yu J, Guo W, Zuo T, Shi Q, Zhao K, Wang W. Effects of thymosin β4 on a rat model of severe acute pancreatitis. Exp Ther Med 2015; 10:2389-2395. [PMID: 26668646 DOI: 10.3892/etm.2015.2798] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Accepted: 08/10/2015] [Indexed: 12/16/2022] Open
Abstract
The aim of the present study was to investigate the effects of thymosin β4 on a rat model of severe acute pancreatitis (SAP) induced by sodium taurocholate (STC) and the underlying mechanism. SAP was induced by the retrograde infusion of 5% STC (1 ml/kg) into the bile-pancreatic duct. In certain rats, thymosin β4 (30 mg/kg) was administered intraperitoneally 30 min prior to the infusion of STC. The severity of pancreatitis was evaluated by the measurement of serum amylase, lipase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and myeloperoxidase (MPO) levels, and histological grading. Nuclear factor (NF)-κB activation was evaluated by immunohistochemistry and western blot analysis. Intercellular adhesion molecule (ICAM)-1 protein expression in the pancreas was studied using western blot analysis. Prophylactic administration of thymosin β4 was found to attenuate serum amylase and lipase activity and the serum concentrations of proinflammatory cytokines. In addition, it attenuated pathological pancreatic injury, pancreatic MPO activity, and the activation of NF-κB and ICAM-1 in the pancreas. These results suggest that thymosin β4 exerts a protective effect against STC-induced pancreatic injury.
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Affiliation(s)
- Xiaobo He
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Jia Yu
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Wenyi Guo
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Teng Zuo
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Qiao Shi
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Kailiang Zhao
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Weixing Wang
- Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
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Hegyi P, Rakonczay Z. The role of pancreatic ducts in the pathogenesis of acute pancreatitis. Pancreatology 2015; 15:S13-S17. [PMID: 25921231 DOI: 10.1016/j.pan.2015.03.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 03/09/2015] [Accepted: 03/17/2015] [Indexed: 12/11/2022]
Abstract
Pancreatic ducts secrete 2.5 l of alkaline, HCO3(-)-rich fluid daily which greatly contributes to the homeostasis of the pancreas. Ducts are also important in the pathophysiology of the pancreas; alteration of ductal function can lead to severe diseases such as cystic fibrosis and chronic pancreatitis. The role of pancreatic ducts in the development of acute pancreatitis has only been uncovered recently. Pancreatitis inducing agents like bile acids and ethanol dose-dependently affect pancreatic ductal secretion; low concentrations stimulate, whereas high concentrations inhibit secretion. The majority of the review will focus on the central role of cystic fibrosis transmembrane conductance regulator (CFTR), a critical protein in the regulation of ductal secretion, in the pathogenesis of acute pancreatitis which is highlighted by numerous investigations. Downregulation of CFTR expression results in increased severity of acute pancreatitis in mice. Furthermore, human genetic studies have demonstrated statistically significant association of CFTR mutations with acute recurrent pancreatitis. Overall, the data support the involvement of pancreatic ducts in the pathogenesis of acute pancreatitis.
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Affiliation(s)
- Peter Hegyi
- University of Szeged, First Department of Medicine, Szeged, Hungary; MTA-SZTE Lendület Translational Gastroenterology Research Group, Szeged, Hungary
| | - Zoltan Rakonczay
- University of Szeged, First Department of Medicine, Szeged, Hungary.
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29
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Abstract
Acute pancreatitis is an inflammatory process of the pancreatic gland that eventually may lead to a severe systemic inflammatory response. A key event in pancreatic damage is the intracellular activation of NF-κB and zymogens, involving also calcium, cathepsins, pH disorders, autophagy, and cell death, particularly necrosis. This review focuses on the new role of redox signaling in acute pancreatitis. Oxidative stress and redox status are involved in the onset of acute pancreatitis and also in the development of the systemic inflammatory response, being glutathione depletion, xanthine oxidase activation, and thiol oxidation in proteins critical features of the disease in the pancreas. On the other hand, the release of extracellular hemoglobin into the circulation from the ascitic fluid in severe necrotizing pancreatitis enhances lipid peroxidation in plasma and the inflammatory infiltrate into the lung and up-regulates the HIF-VEGF pathway, contributing to the systemic inflammatory response. Therefore, redox signaling and oxidative stress contribute to the local and systemic inflammatory response during acute pancreatitis.
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30
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Apte MV, Pirola RC, Wilson JS. Pancreatic Stellate Cells. STELLATE CELLS IN HEALTH AND DISEASE 2015:271-306. [DOI: 10.1016/b978-0-12-800134-9.00016-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Fang F, Pan J, Xu L, Su G, Li G, Wang J. Association between chemokine (C-C motif) ligand 2 gene -2518 A/G polymorphism and pancreatitis risk: a meta-analysis. Pancreatology 2014; 15:53-8. [PMID: 25499426 DOI: 10.1016/j.pan.2014.11.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 11/13/2014] [Accepted: 11/15/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Many studies have focused on the relationship between chemokine (C-C motif) ligand 2 gene (CCL2) -2518 A/G polymorphism and pancreatitis risk, but the results remain inconsistent. Thus, a meta-analysis was carried out to derive a more precise estimation of the association between CCL2 -2518 A/G polymorphism and pancreatitis risk. METHODS Relevant publications were searched in several widely used databases and six studies were included in the meta-analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between CCL2 -2518 A/G polymorphism and pancreatitis risk. RESULTS Significant associations between CCL2 -2518 A/G polymorphism and pancreatitis risk were observed in both overall meta-analysis (OR = 0.62, 95% CI = 0.43-0.89 for AA versus AG + GG; OR = 0.71, 95% CI = 0.51-0.98 for A allele versus G allele), and acute pancreatitis subgroup (OR = 0.56, 95% CI = 0.31-0.99 for AA versus AG + GG), especially severe acute pancreatitis subgroup when compared with controls (OR = 0.48, 95% CI = 0.24-0.97 for AG versus GG; OR = 0.35, 95% CI = 0.18-0.70 for AA + AG versus GG). However, no significant pancreatitis risk variation was detected for all genetic models in the severe acute pancreatitis versus mild acute pancreatitis subgroup and the subgroup analysis based on ethnicity. CONCLUSIONS The CCL2 -2518 A/G polymorphism probably associates with pancreatitis risk, especially severe acute pancreatitis risk when compared with controls, with the G allele acting as a risk factor.
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Affiliation(s)
- Fang Fang
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Jian Pan
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Lixiao Xu
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Guanghao Su
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Gang Li
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China
| | - Jian Wang
- Institute of Pediatric Research, Children's Hospital of Soochow University, 303 Jingde Road, Suzhou 215003, China.
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Montecucco F, Mach F, Lenglet S, Vonlaufen A, Gomes Quinderé AL, Pelli G, Burger F, Galan K, Dallegri F, Carbone F, Proudfoot AE, Vuilleumier N, Frossard JL. Treatment with Evasin-3 abrogates neutrophil-mediated inflammation in mouse acute pancreatitis. Eur J Clin Invest 2014; 44:940-950. [PMID: 25132144 DOI: 10.1111/eci.12327] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Accepted: 08/12/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Acute pancreatitis is characterized by inflammatory processes affecting not only the pancreas, but also the lung. Here, we investigated timing of leucocyte infiltration and chemokine expression within lung and pancreas during pancreatitis and whether treatments selectively inhibiting chemokines (using Evasins) could improve organ injury. MATERIAL AND METHODS C57Bl/6 mice were submitted in vivo to 10-h intraperitoneal injections of cerulein and followed for up to 168 h. Five minutes after the first cerulein injection, a single intraperitoneal injection of 10 μg Evasin-3, 1 μg Evasin-4 or an equal volume of vehicle (PBS) was performed. Leucocytes, reactive oxygen species (ROS), necrosis and chemokine/cytokine mRNA expression were assessed in different organs by immunohistology and real-time RT-PCR, respectively. RESULTS In the lung, neutrophil infiltration and macrophage infiltration peaked at 12 h and were accompanied by increased CXCL2 mRNA expression. CCL2, CXCL1 and TNF-alpha significantly increased after 24 h as compared to baseline. No increase in CCL3 and CCL5 was observed. In the pancreas, neutrophil infiltration peaked at 6 h, while macrophages increased only after 72 h. Treatment with Evasin-3 decreased neutrophil infiltration, ROS production and apoptosis in the lung and reduced neutrophils, macrophages apoptosis and necrosis in the pancreas. Evasin-4 only reduced macrophage content in the lung and did not provide any benefit at the pancreas level. CONCLUSION Chemokine production and leucocyte infiltration are timely regulated in lung and pancreas during pancreatitis. CXC chemokine inhibition with Evasin-3 improved neutrophil inflammation and injury, potentially interfering with damages in acute pancreatitis and related pulmonary complications.
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Affiliation(s)
- Fabrizio Montecucco
- Division of Cardiology, Foundation for Medical Researches, University of Geneva, Geneva, Switzerland; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa School of Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, Geneva, Switzerland
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Clemens DL, Wells MA, Schneider KJ, Singh S. Molecular mechanisms of alcohol associated pancreatitis. World J Gastrointest Pathophysiol 2014; 5:147-157. [PMID: 25133017 PMCID: PMC4133514 DOI: 10.4291/wjgp.v5.i3.147] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 04/26/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Alcohol abuse is commonly associated with the development of both acute and chronic pancreatitis. Despite this close association, the fact that only a small percentage of human beings who abuse alcohol develop pancreatitis indicates that alcohol abuse alone is not sufficient to initiate clinical pancreatitis. This contention is further supported by the fact that administration of ethanol to experimental animals does not cause pancreatitis. Because of these findings, it is widely believed that ethanol sensitizes the pancreas to injury and additional factors trigger the development of overt pancreatitis. How ethanol sensitizes the pancreas to pancreatitis is not entirely known. Numerous studies have demonstrated that ethanol and its metabolites have a number of deleterious effects on acinar cells. Important acinar cells properties that are affected by ethanol include: calcium signaling, secretion of zymogens, autophagy, cellular regeneration, the unfolded protein response, and mitochondrial membrane integrity. In addition to the actions of ethanol on acinar cells, it is apparent that ethanol also affects pancreatic stellate cells. Pancreatic stellate cells have a critical role in normal tissue repair and the pathologic fibrotic response. Given that ethanol and its metabolites affect so many pancreatic functions, and that all of these effects occur simultaneously, it is likely that none of these effects is “THE” effect. Instead, it is most likely that the cumulative effect of ethanol on the pancreas predisposes the organ to pancreatitis. The focus of this article is to highlight some of the important mechanisms by which ethanol alters pancreatic functions and may predispose the pancreas to disease.
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Difference in Early Activation of NF-κB and MCP-1 in Acinar-Cell-Rich versus Fibrotic Human Pancreas Exposed to Surgical Trauma and Hypoxia. Gastroenterol Res Pract 2014; 2014:460363. [PMID: 25147563 PMCID: PMC4131420 DOI: 10.1155/2014/460363] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 07/13/2014] [Accepted: 07/15/2014] [Indexed: 01/23/2023] Open
Abstract
Objectives. Previously we have shown that a pancreas with over 40% acinar cells is exposed to postoperative pancreatitis and other complications after pancreaticoduodenectomy (PD). Our aim was to analyze the expression of NF-κB and MCP-1 in the cut edge of human pancreas after PD in both acinar-cell-rich and fibrotic pancreata. Methods. Several pancreatic samples from six patients, three with acinar-cell-rich and three with fibrotic pancreata, were exposed to surgical trauma in PD, and thereafter to hypoxemia for 15 minutes, 2-2.5 hours, 4 hours, or 6 hours, to mimic postoperative conditions of the pancreatic remnant in a patient. Immunohistochemical analysis of inflammation markers (NF-κB, MCP-1) was performed. Results. In the acinar-cell-rich pancreata, intra-acinar NF-κB and MCP-1 expression increased from mild at 15 minutes to high during the first 4 hours, whereas in ductal cells MCP-1 staining was highly intense at both time points. Acinar cell NF-κB and MCP-1 expression and ductal cell MCP-1 expression were also observed in the fibrotic pancreata, but the activation remained low throughout the 6 hours. Conclusions. In acinar-cell-rich pancreas, an extensive inflammatory cascade begins almost immediately after surgical trauma. Fibrosis may limit the progression of inflammatory process in pancreas.
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Uchida M, Ito T, Nakamura T, Hijioka M, Igarashi H, Oono T, Kato M, Nakamura K, Suzuki K, Takayanagi R, Jensen RT. Pancreatic stellate cells and CX3CR1: occurrence in normal pancreas and acute and chronic pancreatitis and effect of their activation by a CX3CR1 agonist. Pancreas 2014; 43:708-719. [PMID: 24681877 PMCID: PMC4315317 DOI: 10.1097/mpa.0000000000000109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Numerous studies suggest important roles of the chemokine, fractalkine (CX3CL1), in acute/chronic pancreatitis; however, the possible mechanisms of the effects are unclear. Pancreatic stellate cells (PSCs) can play important roles in pancreatitis, secreting inflammatory cytokines/chemokines, as well as proliferation. Therefore, we investigated CX3CL1 receptor (CX3CR1) occurrence in normal pancreas and pancreatitis (acute/chronic) tissues and the effects of CX3CL1 on activated PSCs. METHODS CX3CR1 expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues was evaluated with immunohistochemical analysis. CX3CR1 expression and effects of CX3CL1 on activated PSCs were examined with real-time polymerase chain reaction, BrdU (5-bromo-2-deoxyuridine) assays, and Western blotting. RESULTS In normal pancreas, acinar cells expressed CX3CR1 within granule-like formations in the cytoplasm, whereas in acute/chronic pancreatitis, acinar, ductal, and activated PSCs expressed CX3CR1 on cell membranes. With activation of normal PSCs, CX3CR1 is increased. CX3CL1 activated multiple signaling cascades in PSCs. CX3CL1 did not induce inflammatory genes expression in activated PSCs, but induced proliferation. CONCLUSIONS CX3CR1s are expressed in normal pancreas. Expression is increased in acute/chronic pancreatitis, and the CX3CR1s are activated. CX3CL1 induces proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest that CX3CR1 activation of PSCs could be important in their effects in pancreatitis, especially to PSC proliferation in pancreatitis where CX3CL1 levels are elevated.
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Affiliation(s)
- Masahiko Uchida
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Taichi Nakamura
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
- Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, United States
| | - Masayuki Hijioka
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Hisato Igarashi
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Takamasa Oono
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Kazuhiko Nakamura
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Koichi Suzuki
- Department of Leprosy Research Center, National Institute of Infectious Diseases, Tokyo Japan
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Robert T. Jensen
- Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, United States
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Increased expression of the intercellular adhesion molecule-1 (ICAM-1) on peripheral blood neutrophils in acute pancreatitis. Adv Med Sci 2014; 59:102-7. [PMID: 24797984 DOI: 10.1016/j.advms.2014.01.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 09/13/2013] [Indexed: 02/06/2023]
Abstract
PURPOSE Considering the important role of neutrophils' activation in the pathogenesis of acute pancreatitis (AP), the aim of our study was to evaluate the expression of leukocytes' adhesion molecules in patients with AP. PATIENTS/METHODS Thirty-five patients (16 women and 19 men; age 32-77 years, median 56 years) with AP were prospectively included into our study. The absolute number of leukocytes was estimated by haematologic analyser. Surface neutrophils antigens (CD) were assayed by the direct fluorescence method for whole blood, using a flow cytometer. RESULTS At the day 1, significant increase of ICAM-1 expression was found in patients with severe AP (S-AP) (7280 mm(-3) vs 2850 mm(-3) in healthy control; p<0.05). In the days 2, 3 and 5 it sharply decreased and peaked again to 4860 mm(-3) at the day 10. In patients with mild AP (M-AP), not significant elevation of ICAM-1 quickly returned to normal level. In both forms of AP, neutrophil CD62L (L-selectin) expression reached the highest level at the day 1 (8800 mm(-3) and 9020 mm(-3), respectively in M-AP and S-AP, in comparison to 3400 mm(-3) in control; p<0.05). Expression of CD69 (neutrophils' marker of early activation) significantly increased in both M-AP and S-AP. CONCLUSIONS We have found an early and significant increase of peripheral blood neutrophil CD54/ICAM-1 expression, specific for S-AP but not for M-AP. It may provide a good marker predicting severe course of pancreatitis.
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Pancreatic acinar cells-derived cyclophilin A promotes pancreatic damage by activating NF-κB pathway in experimental pancreatitis. Biochem Biophys Res Commun 2014; 444:75-80. [DOI: 10.1016/j.bbrc.2014.01.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 01/08/2014] [Indexed: 01/07/2023]
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Nakamura T, Ito T, Uchida M, Hijioka M, Igarashi H, Oono T, Kato M, Nakamura K, Suzuki K, Jensen RT, Takayanagi R. PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist. J Transl Med 2014; 94:63-78. [PMID: 24217090 PMCID: PMC3879597 DOI: 10.1038/labinvest.2013.133] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 10/02/2013] [Accepted: 10/21/2013] [Indexed: 12/20/2022] Open
Abstract
There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term glucagon-like peptide-1 (GLP-1) analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells are well studied; however, there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can have an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute pancreatitis (AP)/chronic pancreatitis (CP), and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1 receptor (GLP-1R) expression/localization in normal pancreas and pancreatitis (AP/CP) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP-1R expression and effects of GLP-1 analog on activated PSCs was examined with real-time PCR, MTS assays and western blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in AP or CP, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the extracellular signal-regulated kinase pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in AP/CP. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.
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Affiliation(s)
- Taichi Nakamura
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
- Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, United States
| | - Tetsuhide Ito
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Masahiko Uchida
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Masayuki Hijioka
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Hisato Igarashi
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Takamasa Oono
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Kazuhiko Nakamura
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Koichi Suzuki
- Department of Leprosy Research Center, National Institute of Infectious Diseases, Tokyo Japan
| | - Robert T. Jensen
- Department of Cell Biology Section, NIDDK, National Institutes of Health, Bethesda, Maryland, United States
| | - Ryoichi Takayanagi
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
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García-Hernández V, Sarmiento N, Sánchez-Bernal C, Matellán L, Calvo JJ, Sánchez-Yagüe J. Modulation in the expression of SHP-1, SHP-2 and PTP1B due to the inhibition of MAPKs, cAMP and neutrophils early on in the development of cerulein-induced acute pancreatitis in rats. Biochim Biophys Acta Mol Basis Dis 2013; 1842:192-201. [PMID: 24225419 DOI: 10.1016/j.bbadis.2013.11.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 10/30/2013] [Accepted: 11/05/2013] [Indexed: 12/21/2022]
Abstract
The protein tyrosine phosphatases (PTPs) SHP-1, SHP-2 and PTP1B are overexpressed early on during the development of cerulein -induced acute pancreatitis (AP) in rats, and their levels can be modulated by some species of mitogen-activated protein kinases (MAPKs), the intracellular levels of cAMP and by general leukocyte infiltration, the latter at least for SHP-2 and PTP1B. In this study we show that cerulein treatment activates extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) but not p38 MAPK during the early phase of cerulein-induced AP (2h after the first injection of cerulein). Therefore, by using the MAPK inhibitors SP600125 (a specific JNK inhibitor) and PD98059 (a specific ERK inhibitor), we have unmasked the particular MAPK that underlies the modulation of the expression levels of these PTPs. JNK would act by preventing SHP-1 protein expression from increasing beyond a certain level. ERK 1/2 was the main MAPK involved in the increase in SHP-2 protein expression due to cerulein. JNK negatively modulated the SH2-domain containing PTPs. Both MAPKs played a role in the increase in PTP1B protein expression due to cerulein. Finally, by using the white blood cell inhibitors vinblastine sulfate, gadolinium chloride and FK506 (tacrolimus), we show that the macrophage activity or T-lymphocytes does not modulate the expression of any of the PTPs, although neutrophil infiltration was found to be a regulator of SHP-2 and PTP1B protein expression due to cerulein.
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Affiliation(s)
| | - Nancy Sarmiento
- Department of Biochemistry and Molecular Biology, University of Salamanca, Spain
| | | | - Laura Matellán
- Department of Biochemistry and Molecular Biology, University of Salamanca, Spain
| | - José J Calvo
- Department of Physiology and Pharmacology, University of Salamanca, Spain
| | - Jesús Sánchez-Yagüe
- Department of Biochemistry and Molecular Biology, University of Salamanca, Spain.
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Nunes QM, Mournetas V, Lane B, Sutton R, Fernig DG, Vasieva O. The heparin-binding protein interactome in pancreatic diseases. Pancreatology 2013; 13:598-604. [PMID: 24280576 DOI: 10.1016/j.pan.2013.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2013] [Revised: 07/23/2013] [Accepted: 08/14/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND The cellular microenvironment plays an important role in the regulation of homoeostasis and is a source of potential biomarkers and drug targets. In a genome-wide analysis the extracellular proteins that bind to heparin (HBPs) have been shown to form highly modular and interconnected extracellular protein regulatory networks. Using a systems biology approach, we have investigated the role of HBP networks in the normal pancreas and pancreatic digestive diseases. METHODS Lists of mRNAs encoding for HBPs associated with the normal pancreas (NP), acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) were obtained using public databases and publications. Networks of the putative protein interactomes derived from mRNA expression data of HBPs were built and analysed using cluster analysis, gene ontology term enrichment and canonical pathways analysis. RESULTS The extracellular heparin-binding putative protein interactomes in the pancreas were better connected than their non heparin-binding counterparts, having higher clustering coefficients in the normal pancreas (0.273), acute pancreatitis (0.457), chronic pancreatitis (0.329) and pancreatic ductal adenocarcinoma (0.269). 'Hepatic Fibrosis/Hepatic Stellate Cell Activation' appears to be a significant canonical pathway in pancreatic homoeostasis in health and disease with a large number of important HBPs. CONCLUSIONS Our analyses clearly demonstrate that HBPs form disease-specific and highly connected networks that can be explored for potential biomarkers and as collective drug targets via the modification of heparin binding properties.
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Affiliation(s)
- Q M Nunes
- NIHR Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, United Kingdom.
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Ni J, Hu G, Xiong J, Shen J, Shen J, Yang L, Tang M, Zhao Y, Ying G, Yu G, Hu Y, Xing M, Wan R, Wang X. Involvement of interleukin-17A in pancreatic damage in rat experimental acute necrotizing pancreatitis. Inflammation 2013; 36:53-65. [PMID: 22990529 DOI: 10.1007/s10753-012-9519-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Interleukin (IL)-17A is a proinflammatory cytokine, which has recently attracted much interest due to its pathogenic role in various inflammatory conditions such as ischemia/reperfusion injury, chronic inflammation, and autoimmune diseases, but the role of IL-17A in acute pancreatitis remains unclear. This study aimed to investigate the role of IL-17A in experimental acute necrotizing pancreatitis (ANP). We analyzed the expression of IL-17A during the pathogenesis of ANP in vivo induced by 3 % sodium taurocholate (NaTc), by microarray test, quantitative real-time PCR, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. The effects of IL-17A on pancreatic acinar cells and pancreatic stellate cells (PSCs) were further investigated in vitro using recombinant rat IL-17A (rIL-17A). Expression of IL-17A was significantly increased following experimental acute pancreatitis. In addition, rIL-17A induced rat pancreatic acinar cell necrosis and promoted expression of several target genes, including IL-6, IL-1β, CXCL1, CXCL2, and CXCL5, in acinar cells and PSCs. These findings suggest that IL-17A may be involved in pancreatic damage by regulating the expression of inflammatory cytokines and chemokines during experimental acute pancreatitis.
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Affiliation(s)
- Jianbo Ni
- Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, People's Republic of China
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Shen J, Gao J, Chen C, Lu H, Hu G, Shen J, Zhu S, Wu M, Wang X, Qian L, Yu Y, Han W, Wan R, Wang X. Antifibrotic role of chemokine CXCL9 in experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats. Cytokine 2013; 64:382-94. [PMID: 23819906 DOI: 10.1016/j.cyto.2013.05.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 05/09/2013] [Accepted: 05/17/2013] [Indexed: 02/07/2023]
Abstract
Chemokines have been shown to play an important role in the pathogenesis of pancreatitis, but the role of chemokine CXCL9 in pancreatitis is poorly understood. The aim of this study was to investigate whether CXCL9 was a modulating factor in chronic pancreatitis. Chronic pancreatitis was induced in Sprague-Dawley rats by intraductal infusion of trinitrobenzene sulfonic acid (TNBS) and CXCL9 expression was assessed by immunohistochemistry, Western blot analysis and enzyme linked immunosorbent assay (ELISA). Recombinant human CXCL9 protein (rCXCL9), neutralizing antibody and normal saline (NS) were administered to rats with chronic pancreatitis by subcutaneous injection. The severity of fibrosis was determined by measuring hydroxyproline in pancreatic tissues and histological grading. The effect of rCXCL9 on activated pancreatic stellate cells (PSCs) in vitro was examined and collagen 1α1, TGF-β1 and CXCR3 expression was assessed by Western blot analysis in isolated rat PSCs. Chronic pancreatic injury in rats was induced after TNBS treatment and CXCL9 protein was markedly upregulated during TNBS-induced chronic pancreatitis. Although parenchymal injury in the pancreas was not obviously affected after rCXCL9 and neutralizing antibody administration, rCXCL9 could attenuate fibrogenesis in TNBS-induced chronic pancreatitis in vivo and exerted antifibrotic effects in vitro, suppressing collagen production in activated PSCs. In conclusion, CXCL9 is involved in the modulation of pancreatic fibrogenesis in TNBS-induced chronic pancreatitis in rats, and may be a therapeutic target in pancreatic fibrosis.
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Affiliation(s)
- Jiaqing Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Jiangsu, China
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Luan ZG, Zhang J, Yin XH, Ma XC, Guo RX. Ethyl pyruvate significantly inhibits tumour necrosis factor-α, interleukin-1β and high mobility group box 1 releasing and attenuates sodium taurocholate-induced severe acute pancreatitis associated with acute lung injury. Clin Exp Immunol 2013; 172:417-26. [PMID: 23600830 DOI: 10.1111/cei.12062] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/02/2013] [Indexed: 12/16/2022] Open
Abstract
In this study, we examined the effect of ethyl pyruvate (EP) on pulmonary inflammation in rats with severe pancreatitis-associated acute lung injury (ALI). Severe acute pancreatitis (SAP) was induced in rats by the retrograde injection of 5% sodium taurocholate into the pancreatic duct. Rats were randomly divided into the following experimental groups: control group, SAP group and EP-treated group. The tissue specimens were harvested for morphological studies, Streptavidin-peroxidase immunohistochemistry examination. Pancreatic or lung tissue oedema was evaluated by tissue water content. Serum amylase and lung tissue malondialdehyde (MDA) and myeloperoxidase (MPO) were measured. Meanwhile, the nuclear factor-κB (NF-κB) activation, tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β) levels and HMGB1 protein expression levels in the lung were studied. In the present study, we demonstrated that treatment with EP after SAP was associated with a reduction in the severity of SAP and lung injury. Treatment with EP significantly decreased the expression of TNF-α, IL-1β, HMGB1 and ameliorated MDA concentration, MPO activity in the lung in SAP rats. Compared to SAP group, administration of EP prevented pancreatitis-induced increases in nuclear translocation of NF-κB in the lung. Similarly, treatment with EP significantly decreased the accumulation of neutrophils and markedly reduced the enhanced lung permeability. In conclusion, these results demonstrate that EP might play a therapeutic role in pulmonary inflammation in this SAP model.
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Affiliation(s)
- Z-G Luan
- Department of Intensive Care Unit, The First Hospital, China Medical University, Shenyang, China
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Gukovsky I, Li N, Todoric J, Gukovskaya A, Karin M. Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 2013; 144:1199-209.e4. [PMID: 23622129 PMCID: PMC3786712 DOI: 10.1053/j.gastro.2013.02.007] [Citation(s) in RCA: 250] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2012] [Revised: 02/05/2013] [Accepted: 02/13/2013] [Indexed: 12/11/2022]
Abstract
Inflammation and autophagy are cellular defense mechanisms. When these processes are deregulated (deficient or overactivated) they produce pathologic effects, such as oxidative stress, metabolic impairments, and cell death. Unresolved inflammation and disrupted regulation of autophagy are common features of pancreatitis and pancreatic cancer. Furthermore, obesity, a risk factor for pancreatitis and pancreatic cancer, promotes inflammation and inhibits or deregulates autophagy, creating an environment that facilitates the induction and progression of pancreatic diseases. However, little is known about how inflammation, autophagy, and obesity interact to promote exocrine pancreatic disorders. We review the roles of inflammation and autophagy, and their deregulation by obesity, in pancreatic diseases. We discuss the connections among disordered pathways and important areas for future research.
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Affiliation(s)
- Ilya Gukovsky
- Veterans Affairs Greater Los Angeles Healthcare System, California, USA
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Herreros-Villanueva M, Hijona E, Bañales JM, Cosme A, Bujanda L. Alcohol consumption on pancreatic diseases. World J Gastroenterol 2013; 19:638-647. [PMID: 23429423 PMCID: PMC3574589 DOI: 10.3748/wjg.v19.i5.638] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Revised: 08/14/2012] [Accepted: 08/16/2012] [Indexed: 02/06/2023] Open
Abstract
Although the association between alcohol and pancreatic diseases has been recognized for a long time, the impact of alcohol consumption on pancreatitis and pancreatic cancer (PC) remains poorly defined. Nowadays there is not consensus about the epidemiology and the beverage type, dose and duration of alcohol consumption causing these diseases. The objective of this study was to review the epidemiology described in the literature for pancreatic diseases as a consequence of alcoholic behavior trying to understand the association between dose, type and frequency of alcohol consumption and risk of pancreatitis and PC. The majority of the studies conclude that high alcohol intake was associated with a higher risk of pancreatitis (around 2.5%-3% between heavy drinkers and 1.3% between non drinkers). About 70% of pancreatitis are due to chronic heavy alcohol consumption. Although this incidence rate differs between countries, it is clear that the risk of developing pancreatitis increases with increasing doses of alcohol and the average of alcohol consumption vary since 80 to 150 g/d for 10-15 years. With regard to PC, the role of alcohol consumption remains less clear, and low to moderate alcohol consumption do not appear to be associated with PC risk, and only chronic heavy drinking increase the risk compared with lightly drinkers. In a population of 10%-15% of heavy drinkers, 2%-5% of all PC cases could be attributed to alcohol consumption. However, as only a minority (less than 10% for pancreatitis and 5% for PC) of heavily drinkers develops these pancreatic diseases, there are other predisposing factors besides alcohol involved. Genetic variability and environmental exposures such as smoking and diet modify the risk and should be considered for further investigations.
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Christen S, Coppieters K, Rose K, Holdener M, Bayer M, Pfeilschifter JM, Hintermann E, von Herrath MG, Aurrand-Lions M, Imhof BA, Christen U. Blockade but not overexpression of the junctional adhesion molecule C influences virus-induced type 1 diabetes in mice. PLoS One 2013; 8:e54675. [PMID: 23372751 PMCID: PMC3556033 DOI: 10.1371/journal.pone.0054675] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 12/13/2012] [Indexed: 01/13/2023] Open
Abstract
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing beta-cells in the pancreas. Recruitment of inflammatory cells is prerequisite to beta-cell-injury. The junctional adhesion molecule (JAM) family proteins JAM-B and JAM–C are involved in polarized leukocyte transendothelial migration and are expressed by vascular endothelial cells of peripheral tissue and high endothelial venules in lympoid organs. Blocking of JAM-C efficiently attenuated cerulean-induced pancreatitis, rheumatoid arthritis or inflammation induced by ischemia and reperfusion in mice. In order to investigate the influence of JAM-C on trafficking and transmigration of antigen-specific, autoaggressive T-cells, we used transgenic mice that express a protein of the lymphocytic choriomeningitis virus (LCMV) as a target autoantigen in the β-cells of the islets of Langerhans under the rat insulin promoter (RIP). Such RIP-LCMV mice turn diabetic after infection with LCMV. We found that upon LCMV-infection JAM-C protein was upregulated around the islets in RIP-LCMV mice. JAM-C expression correlated with islet infiltration and functional beta-cell impairment. Blockade with a neutralizing anti-JAM-C antibody reduced the T1D incidence. However, JAM-C overexpression on endothelial cells did not accelerate diabetes in the RIP-LCMV model. In summary, our data suggest that JAM-C might be involved in the final steps of trafficking and transmigration of antigen-specific autoaggressive T-cells to the islets of Langerhans.
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Affiliation(s)
- Selina Christen
- Pharmazentrum Frankfurt/ZAFES, Goethe University Hospital, Frankfurt am Main, Germany.
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Differentiating Branch Duct and Mixed IPMN in Endoscopically Collected Pancreatic Cyst Fluid via Cytokine Analysis. Gastroenterol Res Pract 2012; 2012:247309. [PMID: 23326260 PMCID: PMC3543798 DOI: 10.1155/2012/247309] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 10/31/2012] [Accepted: 11/14/2012] [Indexed: 01/13/2023] Open
Abstract
Background. Differentiating branch duct from mixed intraductal papillary mucinous neoplasm (BD-IPMN) is problematic, but clinically important as mixed IPMNs are managed surgically, while some BD-IPMN may be followed. Inflammatory mediator proteins (IMPs) have been implicated in acute and chronic inflammatory and malignant pancreatic diseases. Aim. To compare IMP profile of pancreatic cyst fluid collected endoscopically from BD-IPMN and mixed IPMN. Methods. Pancreatic cyst fluid from ten patients (5 BD-IPMN and 5 mixed IPMN) was collected by endoscopic ultrasound-guided fine needle aspiration or endoscopic retrograde cholangiopancreatography. Concentrations of 89 IMPs in these samples were determined using a multiplexed bead-based microarray protein assay and compared between BD-IPMN and mixed IPMN. Results. Eighty-six of 89 IMPs were detected in at least one of the 10 samples. Fourteen IMPs were detected only in mixed IPMN, while none were only in BD-IPMN. Of these, TGF-β1 was most prevalent, present in 3 of 5 mixed IPMNs. Seventy-two IMPs were detected in both BD-IPMN and mixed IPMNs. Of these, only G-CSF (P < 0.05) was present in higher concentrations in mixed IPMNs. Conclusion. TGF-β1 and G-CSF detected in endoscopically collected pancreatic cyst fluid are potential diagnostic biomarkers capable of distinguishing mixed IPMN from BD-IPMN.
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Serum proinflammatory cytokine levels and white blood cell differential count in patients with different degrees of severity of acute alcoholic pancreatitis. POLISH JOURNAL OF SURGERY 2012; 84:230-7. [PMID: 22763297 DOI: 10.2478/v10035-012-0038-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
UNLABELLED Several studies suggest that cytokines and neutrophils play an important role in the pathogenesis of acute pancreatitis (AP). The AIM OF THE STUDY was to assess the systemic release of proinflammatory cytokines and WBC (white blood cells) count with differential in patients with acute alcoholic pancreatitis (AAP) and to characterize the differences between patients with mild and severe forms of the disease. MATERIAL AND METHODS Thirty-five patients with the mild form of acute alcoholic pancreatitis (MAAP) were compared to 11 patients with severe acute alcoholic pancreatitis (SAAP). Serum levels of IL-6, IL-8, IL-12p40 and WBC differential count were measured every second day during the first week after admission. RESULTS During the course of the study, the average level of IL-6 was significantly (p<0.05) higher in patients with SAAP than in patients with the mild form of the disease (MAAP). Serum levels of IL-8 and IL-12p40 on admission were higher in patients with SAAP than in patients with MAAP but the difference was not statistically significant. Of all the types of WBCs, neutrophils were significantly (p<0.05) elevated the entire time in SAAP patients when compared to patients with MAAP on 5th and 7th day from admission to hospital. CONCLUSIONS Patients with SAAP had significantly higher proinflammatory cytokine IL-6 levels and neutrophil counts than patients with MAAP. The results suggest that proliferation and overstimulation of this subset of leukocytes might contribute to the development of the systemic inflammatory response in patients with SAAP.
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Inhibition of poly(ADP-ribose) polymerase attenuates acute kidney injury in sodium taurocholate-induced acute pancreatitis in rats. Pancreas 2012; 41:1299-305. [PMID: 22750969 DOI: 10.1097/mpa.0b013e318252dbc3] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVES The aim of our present study was to investigate the efficacy of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in the development of acute kidney injury in an experimental model of severe acute pancreatitis induced by retrograde infusion of sodium taurocholate into the bile-pancreatic duct. METHODS Severity of pancreatitis was evaluated by serum amylase, lipase, tumor necrosis factor α, interleukin-1β, interleukin-6, and histological grading. The following markers of renal dysfunction and injury were measured: serum creatinine level, urea nitrogen level, myeloperoxidase activity, and histology. Activation of PARP, intercellular adhesion molecule-1, and P-selectin protein in the kidney was studied using Western blot analysis. RESULTS 3-Aminobenzamide attenuated the following: (1) serum amylase, lipase, and renal dysfunction; (2) serum concentrations of proinflammatory cytokines; (3) pancreatic and renal pathological injury; (4) renal myeloperoxidase activity; and (5) activation of PARP, intercellular adhesion molecule-1, and P-selectin in the kidney. CONCLUSIONS Our results suggest that PARP activation may contribute to kidney injury and that PARP inhibitors may be beneficial in renal disorders associated with severe acute pancreatitis.
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Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front Physiol 2012; 3:344. [PMID: 22973234 PMCID: PMC3428781 DOI: 10.3389/fphys.2012.00344] [Citation(s) in RCA: 242] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Accepted: 08/09/2012] [Indexed: 12/12/2022] Open
Abstract
While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as 20 years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas-chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumor growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.
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Affiliation(s)
- Minoti V. Apte
- Pancreatic Research Group, Faculty of Medicine, South Western Sydney Clinical School, University of New South WalesSydney, NSW, Australia
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