|
1
|
Prahm AP, Nissen NI, Werge MP, Hadi A, Willumsen N, Karsdal MA, Gluud LL, Olesen SS, Karstensen JG, Novovic S. Markers of Collagen Formation and Degradation in Serum and Pancreatic Fluid Collections in Patients With Acute and Chronic Pancreatitis. Pancreas 2025; 54:e136-e143. [PMID: 39928891 DOI: 10.1097/mpa.0000000000002410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2025]
Abstract
OBJECTIVES Current knowledge on the fibro-inflammatory process underlying chronic pancreatitis originates from animal studies or human studies based on circulating biomarkers. To provide new insight into the underlying fibro-inflammatory processes, we simultaneously assessed fibrosis biomarkers in pancreatic fluid collections and the systemic circulation. MATERIALS AND METHODS This prospective observational cross-sectional study included patients with acute and chronic pancreatitis undergoing drainage of pancreatic fluid collections, as well as 20 healthy controls (only serum levels). PRO-C3, PRO-C11 and PRO-C19 (markers of collagen formation), and C3M and C4M (markers of collagen degradation) were evaluated for both compartments (serum and fluid collection). RESULTS Forty-three patients were included: 26 with walled-off necrosis and 17 with pseudocyst. Serum levels of all 5 fibrosis biomarkers were elevated in patients as compared to controls (all P < 0.001). PRO-C3 levels were significantly higher in pancreatic fluid vs serum (280.6 vs 20.8 ng/mL, P < 0.001). In contrast, levels of C3M (20.5 vs 13.1 ng/mL, P = 0.003), PRO-C19 (64.9 vs 14.3 nM, P < 0.001), and C4M (55.6 vs 20.4 ng/mL, P < 0.001) were significantly higher in serum vs pancreatic fluid. CONCLUSIONS The high serum levels in patients suggest increased overall fibrotic activity in pancreatitis patients as compared to healthy controls. PRO-C3 elicited higher levels in the pancreatic fluid, indicating localized fibrotic activity.
Collapse
Affiliation(s)
- August Pilegaard Prahm
- From the Pancreatitis Centre East (PACE), Gastro unit, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | | | - Mikkel Parsberg Werge
- From the Pancreatitis Centre East (PACE), Gastro unit, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | - Amer Hadi
- From the Pancreatitis Centre East (PACE), Gastro unit, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Denmark
| | | | | | | | | | | | | |
Collapse
|
|
2
|
Mihoc T, Latcu SC, Secasan CC, Dema V, Cumpanas AA, Selaru M, Pirvu CA, Valceanu AP, Zara F, Dumitru CS, Novacescu D, Pantea S. Pancreatic Morphology, Immunology, and the Pathogenesis of Acute Pancreatitis. Biomedicines 2024; 12:2627. [PMID: 39595191 PMCID: PMC11591934 DOI: 10.3390/biomedicines12112627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/28/2024] Open
Abstract
Acute pancreatitis is a complex inflammatory disorder with significant morbidity and mortality. This review aims to integrate the current knowledge of pancreatic morphology and immunology with the pathogenesis of acute pancreatitis, providing a comprehensive understanding of this critical condition. We conducted an extensive literature review, synthesizing data from recent studies and authoritative sources on pancreatic anatomy, histology, immunology, and the pathophysiology of acute pancreatitis. We also incorporated epidemiological data, clinical features, diagnostic criteria, and prognostic factors. The pancreas exhibits a complex morphology with intricate interactions between its exocrine and endocrine components. Its unique immunological landscape plays a crucial role in maintaining homeostasis and orchestrating responses to pathological conditions. In acute pancreatitis, the disruption of intracellular calcium signaling leads to premature enzyme activation, triggering a cascade of events including mitochondrial dysfunction, ATP depletion, and the release of proinflammatory mediators. This process can escalate from localized inflammation to systemic complications. The interplay between pancreatic morphology, immune responses, and pathophysiological mechanisms contributes to the varied clinical presentations and outcomes observed in acute pancreatitis. Understanding the intricate relationships between pancreatic morphology, immunology, and the pathogenesis of acute pancreatitis is crucial for developing more effective diagnostic and therapeutic strategies. This integrated approach provides new insights into the complex nature of acute pancreatitis and may guide future research directions in pancreatic disorders.
Collapse
Affiliation(s)
- Tudorel Mihoc
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (T.M.); (V.D.)
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Silviu Constantin Latcu
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (T.M.); (V.D.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Cosmin-Ciprian Secasan
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Vlad Dema
- Doctoral School, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (T.M.); (V.D.)
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Alin Adrian Cumpanas
- Department XV, Discipline of Urology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (C.-C.S.); (A.A.C.)
| | - Mircea Selaru
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Catalin Alexandru Pirvu
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Andrei Paul Valceanu
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| | - Flavia Zara
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (C.-S.D.); (D.N.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Cristina-Stefania Dumitru
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (C.-S.D.); (D.N.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Dorin Novacescu
- Department II of Microscopic Morphology, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (F.Z.); (C.-S.D.); (D.N.)
- Angiogenesis Research Center, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania
| | - Stelian Pantea
- Department X, General Surgery II, Discipline of Surgical Emergencies, Victor Babes University of Medicine and Pharmacy Timisoara, E. Murgu Square, No. 2, 300041 Timisoara, Romania; (M.S.); (C.A.P.); (A.P.V.); (S.P.)
| |
Collapse
|
|
3
|
Wang H, Qi L, Han H, Li X, Han M, Xing L, Li L, Jiang H. Nanomedicine regulating PSC-mediated intercellular crosstalk: Mechanisms and therapeutic strategies. Acta Pharm Sin B 2024; 14:4756-4775. [PMID: 39664424 PMCID: PMC11628839 DOI: 10.1016/j.apsb.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 05/15/2024] [Accepted: 06/04/2024] [Indexed: 12/13/2024] Open
Abstract
Pancreatic fibrosis (PF) is primarily distinguished by the stimulation of pancreatic stellate cells (PSCs) and excessive extracellular matrix deposition, which is the main barrier impeding drug delivery and distribution. Recently, nanomedicine, with efficient, targeted, and controllable drug release characteristics, has demonstrated enormous advantages in the regression of pancreas fibrotic diseases. Notably, paracrine signals from parenchymal and immune cells such as pancreatic acinar cells, islet cells, pancreatic cancer cells, and immune cells can directly or indirectly modulate PSC differentiation and activation. The intercellular crosstalk between PSCs and these cells has been a critical event involved in fibrogenesis. However, the connections between PSCs and other pancreatic cells during the progression of diseases have yet to be discussed. Herein, we summarize intercellular crosstalk in the activation of PSCs and its contribution to the development of common pancreatic diseases, including pancreatitis, pancreatic cancer, and diabetes. Then, we also examine the latest treatment strategies of nanomedicine and potential targets for PSCs crosstalk in fibrosis, thereby offering innovative insights for the design of antifibrotic nanomedicine. Ultimately, the enhanced understanding of PF will facilitate the development of more precise intervention strategies and foster individually tailored therapeutic approaches for pancreatic diseases.
Collapse
Affiliation(s)
- Hui Wang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Han Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Xuena Li
- College of Pharmacy, Yanbian University, Yanji 133000, China
| | - Mengmeng Han
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
| | - Lei Xing
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
- Institute of Glucose and Lipid Metabolism, Southeast University, Nanjing 210009, China
- Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
| | - Hulin Jiang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
- College of Pharmacy, Yanbian University, Yanji 133000, China
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing 210009, China
| |
Collapse
|
|
4
|
Tsomidis I, Voumvouraki A, Kouroumalis E. The Pathogenesis of Pancreatitis and the Role of Autophagy. GASTROENTEROLOGY INSIGHTS 2024; 15:303-341. [DOI: 10.3390/gastroent15020022] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The pathogenesis of acute and chronic pancreatitis has recently evolved as new findings demonstrate a complex mechanism operating through various pathways. In this review, the current evidence indicating that several mechanisms act in concert to induce and perpetuate pancreatitis were presented. As autophagy is now considered a fundamental mechanism in the pathophysiology of both acute and chronic pancreatitis, the fundamentals of the autophagy pathway were discussed to allow for a better understanding of the pathophysiological mechanisms of pancreatitis. The various aspects of pathogenesis, including trypsinogen activation, ER stress and mitochondrial dysfunction, the implications of inflammation, and macrophage involvement in innate immunity, as well as the significance of pancreatic stellate cells in the development of fibrosis, were also analyzed. Recent findings on exosomes and the miRNA regulatory role were also presented. Finally, the role of autophagy in the protection and aggravation of pancreatitis and possible therapeutic implications were reviewed.
Collapse
Affiliation(s)
- Ioannis Tsomidis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| | - Elias Kouroumalis
- Laboratory of Gastroenterology and Hepatology, University of Crete Medical School, 71500 Heraklion, Crete, Greece
| |
Collapse
|
|
5
|
Kong F, Pan Y, Wu D. Activation and Regulation of Pancreatic Stellate Cells in Chronic Pancreatic Fibrosis: A Potential Therapeutic Approach for Chronic Pancreatitis. Biomedicines 2024; 12:108. [PMID: 38255213 PMCID: PMC10813475 DOI: 10.3390/biomedicines12010108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 12/16/2023] [Accepted: 12/28/2023] [Indexed: 01/24/2024] Open
Abstract
In the complex progression of fibrosis in chronic pancreatitis, pancreatic stellate cells (PSCs) emerge as central figures. These cells, initially in a dormant state characterized by the storage of vitamin A lipid droplets within the chronic pancreatitis microenvironment, undergo a profound transformation into an activated state, typified by the secretion of an abundant extracellular matrix, including α-smooth muscle actin (α-SMA). This review delves into the myriad factors that trigger PSC activation within the context of chronic pancreatitis. These factors encompass alcohol, cigarette smoke, hyperglycemia, mechanical stress, acinar cell injury, and inflammatory cells, with a focus on elucidating their underlying mechanisms. Additionally, we explore the regulatory factors that play significant roles during PSC activation, such as TGF-β, CTGF, IL-10, PDGF, among others. The investigation into these regulatory factors and pathways involved in PSC activation holds promise in identifying potential therapeutic targets for ameliorating fibrosis in chronic pancreatitis. We provide a summary of recent research findings pertaining to the modulation of PSC activation, covering essential genes and innovative regulatory mediators designed to counteract PSC activation. We anticipate that this research will stimulate further insights into PSC activation and the mechanisms of pancreatic fibrosis, ultimately leading to the discovery of groundbreaking therapies targeting cellular and molecular responses within these processes.
Collapse
Affiliation(s)
- Fanyi Kong
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (F.K.); (Y.P.)
| | - Yingyu Pan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (F.K.); (Y.P.)
| | - Dong Wu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (F.K.); (Y.P.)
- Clinical Epidemiology Unit, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| |
Collapse
|
|
6
|
Lewis SA, Cinco IR, Doratt BM, Blanton MB, Hoagland C, Newman N, Davies M, Grant KA, Messaoudi I. Chronic alcohol consumption dysregulates innate immune response to SARS-CoV-2 in the lung. EBioMedicine 2023; 97:104812. [PMID: 37793211 PMCID: PMC10562860 DOI: 10.1016/j.ebiom.2023.104812] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 09/13/2023] [Accepted: 09/14/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Alcohol consumption is widespread with over half of the individuals over 18 years of age in the U.S. reporting alcohol use in the last 30 days. Moreover, 9 million Americans engaged in binge or chronic heavy drinking (CHD) in 2019. CHD negatively impacts pathogen clearance and tissue repair, including in the respiratory tract, thereby increasing susceptibility to infection. Although, it has been hypothesized that chronic alcohol consumption negatively impacts COVID-19 outcomes; the interplay between chronic alcohol use and SARS-CoV-2 infection outcomes has yet to be elucidated. METHODS In this study we employed luminex, scRNA sequencing, and flow cytometry to investigate the impact of chronic alcohol consumption on SARS-CoV-2 anti-viral responses in bronchoalveolar lavage cell samples from humans with alcohol use disorder and rhesus macaques that engaged in chronic drinking. FINDINGS Our data show that in both humans (n = 6) and macaques (n = 11), the induction of key antiviral cytokines and growth factors was decreased with chronic ethanol consumption. Moreover, in macaques fewer differentially expressed genes mapped to Gene Ontology terms associated with antiviral immunity following 6 month of ethanol consumption while TLR signaling pathways were upregulated. INTERPRETATION These data are indicative of aberrant inflammation and reduced antiviral responses in the lung with chronic alcohol drinking. FUNDING This study was supported by NIH 1R01AA028735-04 (Messaoudi), U01AA013510-20 (Grant), R24AA019431-14 (Grant), R24AA019661 (Burnham), P-51OD011092 (ONPRC core grant support). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Collapse
Affiliation(s)
- Sloan A Lewis
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, USA
| | - Isaac R Cinco
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, USA
| | - Brianna M Doratt
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, USA
| | - Madison B Blanton
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, USA; Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, USA
| | - Cherise Hoagland
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, USA
| | - Natali Newman
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, USA
| | - Michael Davies
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, USA
| | - Kathleen A Grant
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, USA
| | - Ilhem Messaoudi
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky, USA.
| |
Collapse
|
|
7
|
Kattner N. Immune cell infiltration in the pancreas of type 1, type 2 and type 3c diabetes. Ther Adv Endocrinol Metab 2023; 14:20420188231185958. [PMID: 37529508 PMCID: PMC10387691 DOI: 10.1177/20420188231185958] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 06/16/2023] [Indexed: 08/03/2023] Open
Abstract
The different types of diabetes differ in disease pathogenesis but share the impairment or loss of β-cell function leading to chronic hyperglycaemia. While immune cells are present throughout the whole pancreas in normality, their number and activation is increased in diabetes. Different patterns and composition of inflammation could be observed in type 1, type 2 and type 3c diabetes. Immune cells, pancreatic stellate cells and fibrosis were present in the islet microenvironment and could add to β-cell dysfunction and therefore development and progression of diabetes. First studies investigating the use of anti-inflammatory drugs demonstrate their ability to rescue remaining β-cell function and their potential benefit in diabetes treatment. This article provides an overview of immune cell infiltrates in different types of diabetes, highlights the knowledge of their impact on β-cell function and introduces the potential of immunomodulatory strategies.
Collapse
Affiliation(s)
- Nicole Kattner
- Translational and Clinical Research Institute, Newcastle University, Medical School, Framlington Place, Newcastle upon Tyne, UK
| |
Collapse
|
|
8
|
An J, Jiang T, Qi L, Xie K. Acinar cells and the development of pancreatic fibrosis. Cytokine Growth Factor Rev 2023; 71-72:40-53. [PMID: 37291030 DOI: 10.1016/j.cytogfr.2023.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/10/2023]
Abstract
Pancreatic fibrosis is caused by excessive deposition of extracellular matrixes of collagen and fibronectin in the pancreatic tissue as a result of repeated injury often seen in patients with chronic pancreatic diseases. The most common causative conditions include inborn errors of metabolism, chemical toxicity and autoimmune disorders. Its pathophysiology is highly complex, including acinar cell injury, acinar stress response, duct dysfunction, pancreatic stellate cell activation, and persistent inflammatory response. However, the specific mechanism remains to be fully clarified. Although the current therapeutic strategies targeting pancreatic stellate cells show good efficacy in cell culture and animal models, they are not satisfactory in the clinic. Without effective intervention, pancreatic fibrosis can promote the transformation from pancreatitis to pancreatic cancer, one of the most lethal malignancies. In the normal pancreas, the acinar component accounts for 82% of the exocrine tissue. Abnormal acinar cells may activate pancreatic stellate cells directly as cellular source of fibrosis or indirectly via releasing various substances and initiate pancreatic fibrosis. A comprehensive understanding of the role of acinar cells in pancreatic fibrosis is critical for designing effective intervention strategies. In this review, we focus on the role of and mechanisms underlying pancreatic acinar injury in pancreatic fibrosis and their potential clinical significance.
Collapse
Affiliation(s)
- Jianhong An
- SCUT-QMPH Joint Laboratory for Pancreatic Cancer Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong 511518, China; Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
| | - Tingting Jiang
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China
| | - Ling Qi
- SCUT-QMPH Joint Laboratory for Pancreatic Cancer Research, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong 511518, China.
| | - Keping Xie
- Center for Pancreatic Cancer Research, The South China University of Technology School of Medicine, Guangzhou, Guangdong 510006, China.
| |
Collapse
|
|
9
|
Lewis SA, Cinco IR, Doratt BM, Blanton MB, Hoagland C, Davies M, Grant KA, Messaoudi I. Chronic alcohol consumption dysregulates innate immune response to SARS-CoV-2 in the lung. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.02.539139. [PMID: 37205543 PMCID: PMC10187161 DOI: 10.1101/2023.05.02.539139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Alcohol consumption is widespread with over half of the individuals over 18 years of age in the U.S. reporting alcohol use in the last 30 days. Moreover, 9 million Americans engaged in binge or chronic heavy drinking (CHD) in 2019. CHD negatively impacts pathogen clearance and tissue repair, including in the respiratory tract, thereby increasing susceptibility to infection. Although, it has been hypothesized that chronic alcohol consumption negatively impacts COVID-19 outcomes; the interplay between chronic alcohol use and SARS-CoV-2 infection outcomes has yet to be elucidated. Therefore, in this study we investigated the impact of chronic alcohol consumption on SARS-CoV-2 anti-viral responses in bronchoalveolar lavage cell samples from humans with alcohol use disorder and rhesus macaques that engaged in chronic drinking. Our data show that in both humans and macaques, the induction of key antiviral cytokines and growth factors was decreased with chronic ethanol consumption. Moreover, in macaques fewer differentially expressed genes mapped to Gene Ontology terms associated with antiviral immunity following 6 month of ethanol consumption while TLR signaling pathways were upregulated. These data are indicative of aberrant inflammation and reduced antiviral responses in the lung with chronic alcohol drinking.
Collapse
Affiliation(s)
- Sloan A. Lewis
- Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine
| | - Isaac R. Cinco
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky
| | - Brianna M. Doratt
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky
| | - Madison B. Blanton
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky
- Pharmaceutical Sciences, College of Pharmacy, University of Kentucky
| | - Cherise Hoagland
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University
| | - Michael Davies
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University
| | - Kathleen A. Grant
- Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University
| | - Ilhem Messaoudi
- Microbiology, Immunology and Molecular Genetics, College of Medicine, University of Kentucky
| |
Collapse
|
|
10
|
Macrophage and Neutrophil Interactions in the Pancreatic Tumor Microenvironment Drive the Pathogenesis of Pancreatic Cancer. Cancers (Basel) 2021; 14:cancers14010194. [PMID: 35008355 PMCID: PMC8750413 DOI: 10.3390/cancers14010194] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/27/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The survival rates for patients with pancreatic adenocarcinoma are very low. This dismal prognosis is due in part to late detection and early development of metastases, and successful treatments for pancreatic adenocarcinoma are also lacking. One potential method of treatment is immunotherapy, which has been successfully implemented in several cancers. Despite success in other cancer types, there has been little progress in pancreatic adenocarcinoma. To understand these shortcomings, we explore the roles of macrophages and neutrophils, two prominent immune cell types in the pancreatic tumor environment. In this review, we discuss how macrophages and neutrophils lead to the harsh environment that is unique to pancreatic adenocarcinoma. We further explore how these immune cells can impact standard of care therapies and decrease their effectiveness. Macrophages and neutrophils could ultimately be targeted to improve outcomes for patients with pancreatic adenocarcinoma. Abstract Despite modest improvements in survival in recent years, pancreatic adenocarcinoma remains a deadly disease with a 5-year survival rate of only 9%. These poor outcomes are driven by failure of early detection, treatment resistance, and propensity for early metastatic spread. Uncovering innovative therapeutic modalities to target the resistance mechanisms that make pancreatic cancer largely incurable are urgently needed. In this review, we discuss the immune composition of pancreatic tumors, including the counterintuitive fact that there is a significant inflammatory immune infiltrate in pancreatic cancer yet anti-tumor mechanisms are subverted and immune behaviors are suppressed. Here, we emphasize how immune cell interactions generate tumor progression and treatment resistance. We narrow in on tumor macrophage (TAM) spatial arrangement, polarity/function, recruitment, and origin to introduce a concept where interactions with tumor neutrophils (TAN) perpetuate the microenvironment. The sequelae of macrophage and neutrophil activities contributes to tumor remodeling, fibrosis, hypoxia, and progression. We also discuss immune mechanisms driving resistance to standard of care modalities. Finally, we describe a cadre of treatment targets, including those intended to overcome TAM and TAN recruitment and function, to circumvent barriers presented by immune infiltration in pancreatic adenocarcinoma.
Collapse
|
|
11
|
Zheng M, Li H, Sun L, Brigstock DR, Gao R. Interleukin-6 participates in human pancreatic stellate cell activation and collagen I production via TGF-β1/Smad pathway. Cytokine 2021; 143:155536. [PMID: 33893003 DOI: 10.1016/j.cyto.2021.155536] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/24/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic stellate cells (PSCs) play a key role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor-β1 (TGF-β1) is a major regulator of PSC activation and extracellular matrix production. Interleukin-6 (IL-6) has shown to participate in TGF-β1 production and rat PSC activation. This study aimed to investigate whether IL-6 promotes human PSC activation and collagen 1(Col1) production through the TGF-β1/Smad pathway. Our results showed that the expression of IL-6 and IL-6R in activated PSCs and macrophages (Mφs) were enhanced in the pancreas of ACP compared to healthy controls and that the mRNA expression of IL-6, IL-6R, TGF-β1, α-SMA or Col1a1 were significantly increased in the pancreas of ACP, showing positive correlations between elevated IL-6 levels and either TGF-β1 or α-SMA or Col1a1 levels and between elevated TGF-β1 levels and α-SMA or Col1a1 levels. In in vitro studies, we identified that IL-6R expression or IL-6 and TGF-β1 secretions were significantly increased in, respectively, Mφs and PSCs by ethanol (EtOH) or lipopolysaccharide (LPS) stimulation while EtOH- or LPS-induced α-SMA or Col1a1 mRNA and protein production in PSCs were partially blocked by IL-6 antibody. IL-6-induced TGF-β1 production in PSCs was antagonized by si-IL-6R RNA or by an inhibitor of STAT3. Additionally, IL-6-promoted α-SMA or Col1a1 protein production was blocked by TGF-β1 antibody and IL-6-induced phosphorylation of Smad2/3 and transcription of α-SMA and Col1a1 mRNA were antagonized by si-TGF-β1 RNA. Our findings indicate that IL-6 contributes to PSC activation and Col1 production through up-regulation of TGF-β1/Smad2/3 pathway.
Collapse
Affiliation(s)
- Meifang Zheng
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - Hongyan Li
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - Li Sun
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China
| | - David R Brigstock
- The Research Institute at Nationwide Children's Hospital, Columbus, OH United States
| | - Runping Gao
- Department of Hepatic Biliary Pancreatic Medicine, First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
|
12
|
Sagami R, Yamao K, Nakahodo J, Minami R, Tsurusaki M, Murakami K, Amano Y. Pre-Operative Imaging and Pathological Diagnosis of Localized High-Grade Pancreatic Intra-Epithelial Neoplasia without Invasive Carcinoma. Cancers (Basel) 2021; 13:cancers13050945. [PMID: 33668239 PMCID: PMC7956417 DOI: 10.3390/cancers13050945] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/08/2021] [Accepted: 02/19/2021] [Indexed: 12/11/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions, such as pancreatic intra-epithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). The prognosis of high-grade precancerous lesions, including high-grade PanIN and high-grade IPMN, without invasive carcinoma is good, despite the overall poor prognosis of PDAC. High-grade PanIN, as a lesion preceding invasive PDAC, is therefore a primary target for intervention. However, detection of localized high-grade PanIN is difficult when using standard radiological approaches. Therefore, most studies of high-grade PanIN have been conducted using specimens that harbor invasive PDAC. Recently, imaging characteristics of high-grade PanIN have been revealed. Obstruction of the pancreatic duct due to high-grade PanIN may induce a loss of acinar cells replaced by fibrosis and lobular parenchymal atrophy. These changes and additional inflammation around the branch pancreatic ducts (BPDs) result in main pancreatic duct (MPD) stenosis, dilation, retention cysts (BPD dilation), focal pancreatic parenchymal atrophy, and/or hypoechoic changes around the MPD. These indirect imaging findings have become important clues for localized, high-grade PanIN detection. To obtain pre-operative histopathological confirmation of suspected cases, serial pancreatic-juice aspiration cytologic examination is effective. In this review, we outline current knowledge on imaging characteristics of high-grade PanIN.
Collapse
Affiliation(s)
- Ryota Sagami
- Department of Gastroenterology, Oita San-ai Medical Center, 1213 Oaza Ichi, Oita, Oita 870-1151, Japan
- Pancreatic Cancer Research for Secure Salvage Young Investigators (PASSYON), Osaka-Sayama, Osaka 589-8511, Japan; (K.Y.); (J.N.); (R.M.)
- Correspondence: ; Tel.: +81-97-541-1311; Fax: +81-97-541-5218
| | - Kentaro Yamao
- Pancreatic Cancer Research for Secure Salvage Young Investigators (PASSYON), Osaka-Sayama, Osaka 589-8511, Japan; (K.Y.); (J.N.); (R.M.)
- Department of Gastroenterology and Hepatology, Kindai University, Osaka-Sayama, Osaka 589-8511, Japan
| | - Jun Nakahodo
- Pancreatic Cancer Research for Secure Salvage Young Investigators (PASSYON), Osaka-Sayama, Osaka 589-8511, Japan; (K.Y.); (J.N.); (R.M.)
- Department of Gastroenterology Tokyo Metropolitan Cancer and Infectious Disease Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8677, Japan
| | - Ryuki Minami
- Pancreatic Cancer Research for Secure Salvage Young Investigators (PASSYON), Osaka-Sayama, Osaka 589-8511, Japan; (K.Y.); (J.N.); (R.M.)
- Department of Gastroenterology, Tenri Hospital, 200 Mishimacho, Tenri, Nara 632-0015, Japan
| | - Masakatsu Tsurusaki
- Department of Diagnostic Radiology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka 589-8511, Japan;
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasamacho, Yufu, Oita 879-5593, Japan;
| | - Yuji Amano
- Department of Endoscopy, Urawa Kyosai Hospital, 3-15-31 Harayama, Midoriku, Saitama 336-0931, Japan;
| |
Collapse
|
|
13
|
Sun S, Zhou N, Feng Y, Lv Y, He J, Liu S, Chen W, Kong W, Zhou Z. Evaluation of Chronic Pancreatitis With T 1 ρ MRI: A Preliminary Study. J Magn Reson Imaging 2021; 53:577-584. [PMID: 32770605 DOI: 10.1002/jmri.27302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Chronic pancreatitis (CP) can result in persistent damage to the endocrine and exocrine tissues of the pancreas. There is an unmet need for quantitative methods to evaluate CP noninvasively. PURPOSE To investigate the utility of T1 ρ magnetic resonance imaging (MRI) for the assessment of CP. STUDY TYPE Prospective. POPULATION Twenty patients with CP and 24 healthy volunteers. FIELD STRENGTH/SEQUENCE 3T MRI including T1 ρ sequence (spin lock time = 0, 1, 10, 20, 40, 60 msec). ASSESSMENT Pancreatic T1 ρ values and anterior-posterior (AP) diameters in the head, body, and tail were measured in all participants. Regions of interest with circle (ROIcircle ) and free-hand (ROIFH ) were drawn for T1 ρ value measurements. STATISTICAL TESTS Mann-Whitney U-test; Wilcoxon Signed Ranks test; receiver operating characteristic (ROC) curve; and Bland-Altman analysis. RESULTS The T1 ρ values of pancreatic tail and the mean T1 ρ values for ROIcircle and the T1 ρ values of pancreatic tail for ROIFH in patients with CP were significantly higher than those in healthy volunteers (all P < 0.05). Pancreatic head AP diameter significantly increased, while pancreatic tail AP diameter significantly decreased in patients with CP compared with healthy volunteers (both P < 0.05). The areas under the ROC curves (AUCs) of pancreatic tail T1 ρ values with ROIcircle and tail AP diameter in diagnosing CP were 0.744 and 0.798, respectively. A combination of pancreatic tail T1 ρ values with ROIcircle and tail AP diameter achieved good performance for diagnosing CP (AUC = 0.838). DATA CONCLUSION T1 ρ MRI might be a potential technique for the noninvasive evaluation of CP. Level of Evidence 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:577-584.
Collapse
Affiliation(s)
- Shuangshuang Sun
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Nan Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yongjing Feng
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ying Lv
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jian He
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Song Liu
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | | | - Wentao Kong
- Department of Ultrasound, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhengyang Zhou
- Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| |
Collapse
|
|
14
|
Goyal S, Sakhuja P. Autoimmune pancreatitis: Current perspectives. INDIAN J PATHOL MICR 2021; 64:S149-S159. [PMID: 34135159 DOI: 10.4103/ijpm.ijpm_59_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Over the last two decades, our knowledge and understanding regarding the pathogenesis and biology of autoimmune pancreatitis (AIP) have improved tremendously. Type 1 AIP or IgG4-related pancreatitis (IgG4-RP) is now believed to be the prototype of the multisystemic IgG4-related disease. In view of clinical features like obstructive jaundice and mass-forming lesions in the pancreas in elderly men, type 1 AIP often mimics pancreatic cancer. IgG4-related sclerosing cholangitis concomitantly involving the extrahepatic and intrahepatic biliary tree is the most common extrapancreatic involvement seen in up to 80% of these patients, which needs to distinguish from cholangiocarcinoma. Histology is characterised by lymphoplasmacytic inflammation, abundant IgG4 positive plasma cell infiltration, storiform fibrosis and obliterative phlebitis. Apart from histology, high serum IgG4 levels, pancreatic parenchymal and duct imaging findings and other organ involvement aid in diagnosis especially in cases where definitive histology is not evident. Also, these parameters lay the foundation of various diagnostic criteria proposed over last few years. On the contrary, histology alone is the mainstay for establishing diagnosis of idiopathic duct-centric pancreatitis (IDCP) as it lacks any specific serological marker or imaging. Since both types of AIP respond dramatically to corticosteroid treatment, a biopsy is crucial to establish the preoperative diagnosis and to exclude malignancy so as to avoid unnecessary surgery. This review discusses the morphologic spectrum, treatment and prognosis of IgG4-RP and IDCP with an emphasis on approach to diagnosis with relevant histologic features, differential diagnoses and the challenges faced during biopsy interpretation.
Collapse
Affiliation(s)
- Surbhi Goyal
- Department of Pathology, GIPMER, New Delhi, India
| | - Puja Sakhuja
- Department of Pathology, GIPMER, New Delhi, India
| |
Collapse
|
|
15
|
Pancreatic Islet Changes in Human Whole Organ Pancreas Explants: What Can Be Learned From Explanted Samples? Transplant Direct 2020; 6:e613. [PMID: 33134489 PMCID: PMC7575169 DOI: 10.1097/txd.0000000000001059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/24/2020] [Accepted: 07/14/2020] [Indexed: 01/09/2023] Open
Abstract
Background. Whole pancreas transplantation (Tx) is a successful treatment for type 1 diabetes resulting in independence from antidiabetic therapies. Transplant-related factors contributing to pancreatic islet failure are largely unknown; both recurring insulitis and pancreatitis have been implicated. The aim was to determine if cellular changes in islets and exocrine tissue are evident early in Tx, which could contribute to eventual graft failure using well-preserved tissue of grafts explanted from largely normoglycemic recipients. Methods. Histological specimens of explants (n = 31), Tx duration 1 day–8 years (median 29 d), cold ischemia time 7.2–17.3 hours (median 11.1 h), donor age 13–54 years (median 38 y) were examined; sections were labeled for inflammation, islet amyloidosis, and tissue fibrosis, and morphometry performed on immunolabeled insulin and glucagon positive islet cells. Data were related to clinical details of donor, recipient, and features of Tx. Results. Islet inflammation consistent with recurrent insulitis was not seen in any sample. Insulin-labeled islet cell proportion decreased with donor age (P < 0.05) and cold ischemia (P < 0.01) in explants from 26 normoglycemic patients; glucagon-labeled area proportion increased with cold ischemia (P < 0.05). Clinical pancreatitis was the explant reason in 12 of 28 normoglycemic cases. Exocrine fibrotic area/pancreas was variable (0.7%–55%) and unrelated to clinical/pathological features. Islet amyloid was present in 3 normoglycemic cases (donor ages 58, 42, and 31 y; Tx duration 8 y, 31 and 33 d, respectively). In 1 patient receiving antidiabetic therapy, the insulin-labeled area was reduced but with no evidence of islet inflammation. Conclusions. Explant histological changes after short-term Tx are similar to those seen in type 2 diabetes and occur in the absence of immunologic rejection without causing hyperglycemia. This suggests that factors associated with Tx affect islet stability; persistent deterioration of islet integrity and exocrine tissue fibrosis could impact on sustainability of islet function.
Collapse
|
|
16
|
Luchini C, Fassan M, Doglioni C, Capelli P, Ingravallo G, Renzulli G, Pecori S, Paolino G, Florena AM, Scarpa A, Zamboni G. Inflammatory and tumor-like lesions of the pancreas. Pathologica 2020; 112:197-209. [PMID: 33179622 PMCID: PMC7931580 DOI: 10.32074/1591-951x-168] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 07/07/2020] [Indexed: 12/12/2022] Open
Abstract
Inflammatory/tumor-like lesions of the pancreas represent a heterogeneous group of diseases that can variably involve the pancreatic gland determining different signs and symptoms. In the category of inflammatory/tumor-like lesions of the pancreas, the most important entities are represented by chronic pancreatitis, which includes alcoholic, obstructive and hereditary pancreatitis, paraduodenal (groove) pancreatitis, autoimmune pancreatitis, lymphoepithelial cyst, pancreatic hamartoma and intrapancreatic accessory spleen. An in-depth knowledge of such diseases is essential, since they can cause severe morbidity and may represent a potential life-threatening risk for patients. Furthermore, in some cases the differential diagnosis with malignant tumors may be challenging. Herein we provide a general overview of all these categories, with the specific aim of highlighting their most important clinic-pathological hallmarks to be used in routine diagnostic activities and clinical practice.
Collapse
Affiliation(s)
- Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
| | - Claudio Doglioni
- Vita e Salute University, Milan, Italy
- Pathology Unit, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Giuseppe Ingravallo
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppina Renzulli
- Department of Emergency and Organ Transplantation, Section of Pathological Anatomy, University of Bari Aldo Moro, Bari, Italy
| | - Sara Pecori
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Gaetano Paolino
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Ada M. Florena
- Department of Sciences for Promotion of Health and Mother and Child Care, Anatomic Pathology, University of Palermo, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Giuseppe Zamboni
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
- IRCSS Sacro Cuore Don Calabria Hospital, Negrar, Italy
| |
Collapse
|
|
17
|
Żorniak M, Sirtl S, Mayerle J, Beyer G. What Do We Currently Know about the Pathophysiology of Alcoholic Pancreatitis: A Brief Review. Visc Med 2020; 36:182-190. [PMID: 32775348 PMCID: PMC7383280 DOI: 10.1159/000508173] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/21/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Alcoholic pancreatitis is a serious medical concern worldwide and remains to be one of the common causes of pancreatic disease. SUMMARY While alcohol consumption causes direct damage to pancreatic tissue, only a small percentage of active drinkers will develop pancreatitis. An explanation of this phenomenon is probably that alcohol increases pancreatic vulnerability to damage; however, the simultaneous presence of additional risk factors and pancreatic costressors is required to increase the risk of pancreatitis and its complications caused by alcohol misuse. Recently, a number of important genetic as well as environmental factors influencing the risk of alcoholic pancreatitis have been described. KEY MESSAGES In brief, this review reports established factors for the development of alcoholic pancreatitis and summarizes recent progress made in basic and clinical research.
Collapse
Affiliation(s)
- Michał Żorniak
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
- Department of Gastroenterology, Medical University of Silesia, Katowice, Poland
| | - Simon Sirtl
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
| | - Julia Mayerle
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
| | - Georg Beyer
- Medical Department II, University Hospital, LMU Munich, Munich, Germany
| |
Collapse
|
|
18
|
Bansod S, Aslam Saifi M, Khurana A, Godugu C. Nimbolide abrogates cerulein-induced chronic pancreatitis by modulating β-catenin/Smad in a sirtuin-dependent way. Pharmacol Res 2020; 156:104756. [PMID: 32194177 DOI: 10.1016/j.phrs.2020.104756] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 12/28/2019] [Accepted: 03/13/2020] [Indexed: 12/18/2022]
Abstract
Chronic pancreatitis (CP) is one of the leading causes of mortality worldwide with no clinically approved therapeutic interventions. The present study was designed to investigate the protective effect of nimbolide (NB), an active constituent of neem tree (Azadirachta indica), by targeting β-catenin/Smad/SIRT1 in cerulein-induced CP model. The effects of NB was investigated on cerulein (50 μg/kg/hr*6 exposures /day, 3 days a week for 3 weeks) induced CP in mice. Amylase and lipase activity were measured and histopathological evaluation was performed. Collagen deposition in the pancreatic tissue was estimated by hydroxyproline assay, and collagen specific staining picrosirius red and Masson's trichrome. Cerulein-induced CP was significantly controlled by NB treatment, as shown by the downregulation of β-catenin/Smad signaling in a SIRT1 dependent manner. NB treatment significantly decreased α-SMA, MMP-2, collagen1a, fibronectin, TGF-β1, p-Smad-2/3 expression and extracellular matrix (ECM) deposition in pancreatic tissue. However, the protective effects of NB on cerulein-induced CP were undermined by nicotinamide (NMD) or splitomicin, sirtuin 1 (SIRT1) inhibitors treatment. NB treatment modulated protein expression by activating SIRT1 and decreasing the expression of β-catenin/Smad proteins in CP mice. However, the expression of SIRT1 in pancreatic tissue was elevated by NB treatment and it was decreased by NMD or splitomicin treatment. In summary, our results strongly suggest that NB exerted promising protective effects in cerulein-induced CP model by inhibiting β-catenin/Smad in a sirtuin-dependent manner, which could be attributed to its anti-inflammatory and antifibrotic effects. Our study suggests that NB could be an effective therapeutic intervention for the treatment of CP.
Collapse
Affiliation(s)
- Sapana Bansod
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Mohd Aslam Saifi
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Amit Khurana
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India
| | - Chandraiah Godugu
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad, Telangana, 500037, India.
| |
Collapse
|
|
19
|
Pezzilli R, Caputo F, Testino G, Patussi V, Greco G, Macciò L, Rossin MR, Mioni D, Balbinot P, Gandin C, Zanesini F, Frulloni L, Aricò S, Bottaro LC, Pellicano R, Scafato E. Alcohol-related chronic exocrine pancreatic insufficiency: diagnosis and therapeutic management. A proposal for treatment by the Italian Association for the Study of the Pancreas (AISP) and the Italian Society of Alcohology (SIA). Minerva Med 2019; 110:425-438. [PMID: 30938130 DOI: 10.23736/s0026-4806.19.06043-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Current estimates of the prevalence of chronic pancreatitis, one of the most common causes of exocrine pancreatic insufficiency, are in the range of 3-10 per 100,000 people in many parts of the world. Alcohol consumption is a very important risk factor for exocrine pancreatic insufficiency and is involved in nearly half of all cases. The main hypothesis regarding the role of chronic alcohol consumption in pancreatitis is that there must be additional environmental or genetic risk factors involved for ongoing damage to occur. Treatment of patients with alcohol-related exocrine pancreatic insufficiency is complex, as the patient has two concomitant pathologies, alcohol-use disorder (AUD) and exocrine pancreatic insufficiency/chronic pancreatitis. Alcohol abstinence is the starting point for treatment, although even this along with the most advanced therapies allow only a slowdown in progression rather than restoration of function. This position paper of the Italian Association for the Study of the Pancreas and the Italian Society of Alcohology provides an overview of the pathogenesis of alcohol-related pancreatitis and discuss diagnostic issues. Treatment options for both exocrine pancreatic insufficiency/chronic pancreatitis (with a focus on pancreatic enzyme replacement therapy) and AUD (acamprosate, disulfiram, oral naltrexone, long-acting injectable naltrexone, sodium oxybate, nalmefene, baclofen, and psychosocial interventions) are also reviewed.
Collapse
Affiliation(s)
- Raffaele Pezzilli
- Pancreas Unit, Department of Gastroenterology, Polyclinic of Sant'Orsola, Bologna, Italy -
- Italian Association for the Study of the Pancreas, Rome, Italy -
| | - Fabio Caputo
- Department of Internal Medicine, SS. Annunziata Hospital, Cento, Ferrara, Italy
- G. Fontana Center for the Study and Multidisciplinary Treatment of Alcohol Addiction, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Gianni Testino
- Regional Alcohol Center of Liguria Region, ASL3, San Martino Hospital, Genoa, Italy
| | | | - Giovanni Greco
- Department of Mental Health and Pathological Dependency, AUSL Romagna, SerT Ravenna, Ravenna, Italy
| | | | | | - Davide Mioni
- Casa di Cura Parco dei Tigli, Villa Di Teolo, Padua, Italy
| | - Patrizia Balbinot
- Regional Alcohol Center of Liguria Region, ASL3, San Martino Hospital, Genoa, Italy
| | - Claudia Gandin
- National Observatory on Alcohol, National Institute of Health, Rome, Italy
| | | | - Luca Frulloni
- Department of Medicine, Pancreas Institute, University of Verona, Verona, Italy
| | - Sarino Aricò
- Unit of Gastroenterology, Mauriziano Hospital, Turin, Italy
| | | | | | - Emanuele Scafato
- National Observatory on Alcohol, National Institute of Health, Rome, Italy
| |
Collapse
|
|
20
|
Whittle MC, Hingorani SR. Fibroblasts in Pancreatic Ductal Adenocarcinoma: Biological Mechanisms and Therapeutic Targets. Gastroenterology 2019; 156:2085-2096. [PMID: 30721663 PMCID: PMC6486863 DOI: 10.1053/j.gastro.2018.12.044] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 12/05/2018] [Accepted: 12/18/2018] [Indexed: 12/13/2022]
Abstract
The desmoplastic reaction of pancreas cancer may begin as a wound healing response to the nascent neoplasm, but it soon creates an insidious shelter that can sustain the growing tumor and rebuff therapy. Among the many cell types subverted by transformed epithelial cells, fibroblasts are recruited and activated to lay a foundation of extracellular matrix proteins and glycosaminoglycans that alter tumor biophysics and signaling. Their near-universal presence in pancreas cancer and ostensible support of disease progression make fibroblasts attractive therapeutic targets. More recently, however, it has also become apparent that diverse subpopulations of fibroblasts with distinct phenotypes and secretomes inhabit the stroma, and that targeted depletion of particular fibroblast subsets could either provide substantial therapeutic benefit or accelerate disease progression. An improved characterization of these fibroblast subtypes, along with their potential relationships to tumor subtypes and mutational repertoires, is needed in order to make anti-fibroblast therapies clinically viable.
Collapse
Affiliation(s)
- Martin C. Whittle
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109,Correspondence: Martin C. Whittle, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M5-C800, Seattle, WA 98109-1024, , Sunil R. Hingorani, MD, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M5-C800, Seattle, WA 98109-1024,
| | - Sunil R. Hingorani
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109,Division of Medical Oncology, University of Washington School of Medicine, Seattle, WA, 98195,Correspondence: Martin C. Whittle, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M5-C800, Seattle, WA 98109-1024, , Sunil R. Hingorani, MD, PhD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, M5-C800, Seattle, WA 98109-1024,
| |
Collapse
|
|
21
|
Malla RR, Kumari S, Amajala KC, Deepak KGK, Gugalavath S, Rokkam P. Methods and Models in Exploring Pancreatic Functions. EXPLORING PANCREATIC METABOLISM AND MALIGNANCY 2019:253-268. [DOI: 10.1007/978-981-32-9393-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
22
|
Adamska A, Elaskalani O, Emmanouilidi A, Kim M, Abdol Razak NB, Metharom P, Falasca M. Molecular and cellular mechanisms of chemoresistance in pancreatic cancer. Adv Biol Regul 2018; 68:77-87. [PMID: 29221990 DOI: 10.1016/j.jbior.2017.11.007] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 11/21/2017] [Indexed: 02/07/2023]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most chemoresistant cancers, and current therapies targeting cancer-associated molecular pathways have not given satisfactory results, owing in part to rapid upregulation of alternative compensatory pathways. Most of the available treatments are palliative, focussing on improving the quality of life. At present, available options are surgery, embolization, radiation, chemotherapy, immunotherapy and use of other more targeted drugs. In this review, we describe the cellular and molecular effects of current chemotherapy drugs such as gemcitabine, FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, irinotecan, and leucovorin) and ABRAXANE (nab-Paclitaxel), which have shown a survival benefit, although modest, for pancreatic cancer patients. Nevertheless, gemcitabine remains the standard first-line option for advanced-stage pancreatic cancer patients and, as resistance to the drug has attracted an increasing scientific interest, we deliberate on the main intracellular processes and proteins vital in acquired chemoresistance to gemcitabine. Lastly, our review examines various microenvironmental factors capable of instigating PDAC to develop resistance to chemotherapeutic drugs.
Collapse
Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6102, Australia
| | - Omar Elaskalani
- Platelet Research Laboratory, Curtin Health Innovation and Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6102, Australia
| | - Aikaterini Emmanouilidi
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6102, Australia
| | - Minkyoung Kim
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6102, Australia
| | - Norbaini Binti Abdol Razak
- Platelet Research Laboratory, Curtin Health Innovation and Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6102, Australia
| | - Pat Metharom
- Platelet Research Laboratory, Curtin Health Innovation and Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6102, Australia
| | - Marco Falasca
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, Western Australia 6102, Australia.
| |
Collapse
|
|
23
|
Quantitative MR Evaluation of Chronic Pancreatitis: Extracellular Volume Fraction and MR Relaxometry. AJR Am J Roentgenol 2018; 210:533-542. [PMID: 29336598 DOI: 10.2214/ajr.17.18606] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE The purpose of this study was to determine if extracellular volume fraction and T1 mapping can be used to diagnose chronic pancreatitis (CP). MATERIALS AND METHODS This HIPAA-compliant study analyzed 143 consecutive patients with and without CP who underwent MR imaging between May 2016 and February 2017. Patients were selected for the study according to inclusion and exclusion criteria that considered history and clinical and laboratory findings. Eligible patients (n = 119) were grouped as normal (n = 60) or with mild (n = 22), moderate (n = 27), or severe (n = 10) CP on the basis of MRCP findings using the Cambridge classification as the reference standard. T1 maps were acquired in unenhanced and late contrast-enhanced phases using a 3D dual flip-angle gradient-echo sequence. All patients were imaged on the same 3-T scanner using the same imaging parameters, contrast agent, and dosage. RESULTS Mean extracellular volume fractions and T1 relaxation times were significantly different within the study groups (one-way ANOVA, p < 0.001). Using the AUC curve analysis, extracellular volume fraction of > 0.27 showed 92% sensitivity (54/59) and 77% specificity (46/60) for the diagnosis of CP (AUC = 0.90). A T1 relaxation time of > 950 ms revealed 64% sensitivity (38/59) and 88% specificity (53/60) (AUC = 0.80). Combining extracellular volume fraction and T1 mapping yielded sensitivity of 85% (50/59) and specificity of 92% (55/60) (AUC = 0.94). CONCLUSION Extracellular volume fraction and T1 mapping may provide quantitative metrics for determining the presence and severity of acinar cell loss and aid in the diagnosis of CP.
Collapse
|
|
24
|
Li H, Xiu M, Wang S, Brigstock DR, Sun L, Qu L, Gao R. Role of Gut-Derived Endotoxin on Type I Collagen Production in the Rat Pancreas After Chronic Alcohol Exposure. Alcohol Clin Exp Res 2017; 42:306-314. [PMID: 29121396 DOI: 10.1111/acer.13550] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2017] [Accepted: 11/02/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Hongyan Li
- Department of Hepatic, Biliary Pancreatic Medicine; First Hospital of Jilin University; Changchun China
| | - Ming Xiu
- Department of Hepatic, Biliary Pancreatic Medicine; First Hospital of Jilin University; Changchun China
| | - Shuhua Wang
- Department of Surgical Gastroenterolog; First Hospital of Jilin University; Changchun China
| | | | - Li Sun
- Department of Hepatic, Biliary Pancreatic Medicine; First Hospital of Jilin University; Changchun China
| | - Limei Qu
- Department of Hepatic, Biliary Pancreatic Medicine; First Hospital of Jilin University; Changchun China
| | - Runping Gao
- Department of Hepatic, Biliary Pancreatic Medicine; First Hospital of Jilin University; Changchun China
| |
Collapse
|
|
25
|
Detlefsen S, Klöppel G. IgG4-related disease: with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis. Virchows Arch 2017; 472:545-556. [PMID: 29196804 DOI: 10.1007/s00428-017-2275-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Revised: 11/16/2017] [Accepted: 11/19/2017] [Indexed: 12/19/2022]
Abstract
In 2011, chronic fibroinflammatory processes occurring simultaneously or metachronously in various organs and associated with elevated IgG4 serum levels and/or tissue infiltration with IgG4-positive plasma cells have been recognized as manifestations of a systemic disorder called IgG4-related disease (IgG4-RD). The histologic key findings are lymphoplasmacytic infiltration rich in IgG4-positive plasma cells combined with storiform fibrosis and obliterative phlebitis. Among the organs mainly affected by IgG4-RD are the pancreas and the extrahepatic bile ducts. The pancreatic and biliary alterations have been described under the terms autoimmune pancreatitis (AIP) and sclerosing cholangitis, respectively. These diseases are currently more precisely called IgG4-related pancreatitis (or type 1 AIP to distinguish it from type 2 AIP that is unrelated to IgG4-RD) and IgG4-related sclerosing cholangitis (IgG4-related SC). Clinically and grossly, both diseases commonly imitate pancreatic and biliary adenocarcinoma, tumors that are well known for their dismal prognosis. As IgG4-RD responds to steroid treatment, making a resection of a suspected tumor unnecessary, a biopsy is often required to establish the preoperative diagnosis. This review discusses the morphologic spectrum of IgG4-related pancreatitis and IgG4-related SC and focuses on the biopsy relevant histologic features for the diagnosis and differential diagnosis of these diseases.
Collapse
Affiliation(s)
- Sönke Detlefsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark.
| | - Günter Klöppel
- Department of Pathology, Consultation Center of Pancreatic and Endocrine Tumors, Technical University Munich, Ismaninger Str. 22, 81675, Munich, Germany
| |
Collapse
|
|
26
|
Duan LF, Xu XF, Zhu LJ, Liu F, Zhang XQ, Wu N, Fan JW, Xin JQ, Zhang H. Dachaihu decoction ameliorates pancreatic fibrosis by inhibiting macrophage infiltration in chronic pancreatitis. World J Gastroenterol 2017; 23:7242-7252. [PMID: 29142471 PMCID: PMC5677205 DOI: 10.3748/wjg.v23.i40.7242] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 09/22/2017] [Accepted: 09/29/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the role of macrophages in chronic pancreatitis (CP) and the effect of Dachaihu decoction (DCHD) on pancreatic fibrosis in mice. METHODS KunMing mice were randomly divided into a control group, CP group, and DCHD group. In the CP and DCHD groups, mice were intraperitoneally injected with 20% L-arginine (3 g/kg twice 1 d/wk for 6 wk). Mice in the DCHD group were administered DCHD intragastrically at a dose of 14 g/kg/d 1 wk after CP induction. At 2 wk, 4 wk and 6 wk post-modeling, the morphology of the pancreas was observed using hematoxylin and eosin, and Masson staining. Interleukin-6 (IL-6) serum levels were assayed using an enzyme-linked immunosorbent assay. Double immunofluorescence staining was performed to observe the co-expression of F4/80 and IL-6 in the pancreas. Inflammatory factors including monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α) and IL-6 were determined using real time-polymerase chain reaction. Western blot analysis was used to detect fibronectin levels in the pancreas. RESULTS Compared with the control group, mice with 20% L-arginine-induced CP had obvious macrophage infiltration and a higher level of fibrosis. IL-6 serum concentrations were significantly increased. Double immunofluorescence staining showed that IL-6 and F4/80 were co-expressed in the pancreas. With the administration of DCHD, the infiltration of macrophages and degree of fibrosis in the pancreas were significantly attenuated; IL-6, MCP-1 and MIP-1α mRNA, and fibronectin levels were reduced. CONCLUSION The dominant role of macrophages in the development of CP was mainly related to IL-6 production. DCHD was effective in ameliorating pancreatic fibrosis by inhibiting macrophage infiltration and inflammatory factor secretion in the pancreas.
Collapse
Affiliation(s)
- Li-Fang Duan
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Xiao-Fan Xu
- Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Lin-Jia Zhu
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Fang Liu
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Xiao-Qin Zhang
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Nan Wu
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Jian-Wei Fan
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Jia-Qi Xin
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| | - Hong Zhang
- Department of Pathophysiology, Shaanxi University of Chinese Medicine, Xianyang 712046, Shaanxi Province, China
| |
Collapse
|
|
27
|
Nielsen MFB, Mortensen MB, Detlefsen S. Identification of markers for quiescent pancreatic stellate cells in the normal human pancreas. Histochem Cell Biol 2017; 148:359-380. [PMID: 28540429 DOI: 10.1007/s00418-017-1581-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/13/2017] [Indexed: 12/16/2022]
Abstract
Pancreatic stellate cells (PSCs) play a central role as source of fibrogenic cells in pancreatic cancer and chronic pancreatitis. In contrast to quiescent hepatic stellate cells (qHSCs), a specific marker for quiescent PSCs (qPSCs) that can be used in formalin-fixed and paraffin embedded (FFPE) normal human pancreatic tissue has not been identified. The aim of this study was to identify a marker enabling the identification of qPSCs in normal human FFPE pancreatic tissue. Immunohistochemical (IHC), double-IHC, immunofluorescence (IF) and double-IF analyses were carried out using a tissue microarray consisting of cores with normal human pancreatic tissue. Cores with normal human liver served as control. Antibodies directed against adipophilin, α-SMA, CD146, CRBP-1, cytoglobin, desmin, GFAP, nestin, S100A4 and vinculin were examined, with special emphasis on their expression in periacinar cells in the normal human pancreas and perisinusoidal cells in the normal human liver. The immunolabelling capacity was evaluated according to a semiquantitative scoring system. Double-IF of the markers of interest together with markers for other periacinar cells was performed. Moreover, the utility of histochemical stains for the identification of human qPSCs was examined, and their ultrastructure was revisited by electron microscopy. Adipophilin, CRBP-1, cytoglobin and vinculin were expressed in qHSCs in the liver, whereas cytoglobin and adipophilin were expressed in qPSCs in the pancreas. Adipophilin immunohistochemistry was highly dependent on the preanalytical time interval (PATI) from removal of the tissue to formalin fixation. Cytoglobin, S100A4 and vinculin were expressed in periacinar fibroblasts (FBs). The other examined markers were negative in human qPSCs. Our data indicate that cytoglobin and adipophilin are markers of qPSCs in the normal human pancreas. However, the use of adipophilin as a qPSC marker may be limited due to its high dependence on optimal PATI. Cytoglobin, on the other hand, is a sensitive marker for qPSCs but is expressed in FBs as well.
Collapse
Affiliation(s)
- Michael Friberg Bruun Nielsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark.,Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark
| | - Michael Bau Mortensen
- Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark.,Department of Surgery, HPB Section, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark
| | - Sönke Detlefsen
- Department of Pathology, Odense University Hospital, J.B. Winsløws Vej 15, 5000, Odense C, Denmark. .,Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 19, 5000, Odense C, Denmark.
| |
Collapse
|
|
28
|
Abstract
Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas, leading to its fibrotic destruction. There are currently no drugs that can stop or slow the progression of the disease. The etiology of the disease is multifactorial, whereas recurrent attacks of acute pancreatitis are thought to precede the development of CP. A better understanding of the pathology of CP is needed to facilitate improved diagnosis and treatment strategies for this disease. The present paper develops a mathematical model of CP based on a dynamic network that includes macrophages, pancreatic stellate cells, and prominent cytokines that are present at high levels in the CP microenvironment. The model is represented by a system of partial differential equations. The model is used to explore in silico potential drugs that could slow the progression of the disease, for example infliximab (anti-TNF-[Formula: see text]) and tocilizumab or siltuximab (anti-IL-6/IL-6R).
Collapse
|
|
29
|
Ferdek PE, Jakubowska MA. Biology of pancreatic stellate cells-more than just pancreatic cancer. Pflugers Arch 2017; 469:1039-1050. [PMID: 28382480 PMCID: PMC5554282 DOI: 10.1007/s00424-017-1968-0] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 03/13/2017] [Accepted: 03/16/2017] [Indexed: 01/18/2023]
Abstract
Pancreatic stellate cells, normally quiescent, are capable of remarkable transition into their activated myofibroblast-like phenotype. It is now commonly accepted that these cells play a pivotal role in the desmoplastic reaction present in severe pancreatic disorders. In recent years, enormous scientific effort has been devoted to understanding their roles in pancreatic cancer, which continues to remain one of the most deadly diseases. Therefore, it is not surprising that considerably less attention has been given to studying physiological functions of pancreatic stellate cells. Here, we review recent advances not only in the field of pancreatic stellate cell pathophysiology but also emphasise their roles in physiological processes.
Collapse
Affiliation(s)
- Pawel E Ferdek
- Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, CF10 3AX, UK.
| | - Monika A Jakubowska
- Medical Research Council Group, Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, CF10 3AX, UK
| |
Collapse
|
|
30
|
Poulsen JL, Olesen SS, Drewes AM, Ye B, Li WQ, Aghdassi AA, Sendler M, Mayerle J, Lerch MM. The Pathogenesis of Chronic Pancreatitis. CHRONIC PANCREATITIS 2017:29-62. [DOI: 10.1007/978-981-10-4515-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
31
|
Abstract
Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is multifactorial and involves complex interaction of environmental, genetic, and/or other risk factors. The pathology is dependent on the underlying pathogenesis of the disease. This review describes the clinical, gross, and microscopic findings of the main subtypes of chronic pancreatitis: alcoholic chronic pancreatitis, obstructive chronic pancreatitis, paraduodenal ("groove") pancreatitis, pancreatic divisum, autoimmune pancreatitis, and genetic factors associated with chronic pancreatitis. As pancreatic ductal adenocarcinoma may be confused with chronic pancreatitis, the main distinguishing features between these 2 diseases are discussed.
Collapse
|
|
32
|
Kozak A, Talar-Wojnarowska R, Kaczka A, Borkowska A, Czupryniak L, Małecka-Panas E, Gąsiorowska A. Utility of different serum fibrosis markers in diagnosing patients with chronic pancreatitis and pancreatic adenocarcinoma. World J Gastrointest Oncol 2016; 8:635-641. [PMID: 27574557 PMCID: PMC4980655 DOI: 10.4251/wjgo.v8.i8.635] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/21/2016] [Accepted: 06/16/2016] [Indexed: 02/05/2023] Open
Abstract
AIM: To estimate the levels of serum cytokines in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) patients in order to evaluate their usefulness as possible biomarkers.
METHODS: The study included 167 Caucasian patients: 74 with PDAC (28 men and 42 women, aged 30-88 years), 78 with CP (50 men and 21 women, aged 20-79 years) and 15 age-matched healthy controls hospitalized in the Department of Digestive Tract Diseases, Medical University of Lodz, Poland between 2006 and 2013. Serum MCP-1, transforming growth factor (TGF)-β1, HA and s-Fr were measured in patients with CP (n = 78), PDAC (n = 74) and healthy controls (n = 15) using ELISA (Corgenix United Kingdom Ltd R and D Systems). The severity of CP was assessed according to the Cambridge classification.
RESULTS: Both patients with CP and PDAC had a significantly higher mean TGF-β1 serum level (1066 ± 582 and 888 ± 356 vs 264 ± 93, P < 0.0001), mean s-Fr (2.42 ± 1.385 and 2.41 ± 1.275 vs 0.6 ± 0.370, P < 0.0001) and mean HA (199 ± 254 and 270 ± 358 vs 40 ± 26, P < 0.0001) compared to controls. There was no difference in mean MCP-1 between all the groups. There were no significant differences in any cytokine levels between the PC and PDAC groups. No significant differences between serum cytokines depending on age, gender or smoking status were found in CP patients. Mean s-Fr concentration was significantly higher in CP, lasting longer than 5 years compared to those with a shorter disease clinical course (2.639 ± 1.125 vs 1.870 ± 0.970, P < 0.03). There was no correlation between tumor size, localization or TNM classification and serum TGF-β1, MCP-1, s-Fr and HA levels in patients with PDAC. No significant differences between cytokines depending on diabetes presence in CP were found. Nevertheless, mean serum TGF-β1 concentration in PDAC patients was higher in those with diabetes compared to the remaining group (986 vs 839, P = 0.043).
CONCLUSION: Serum TGF-β1, s-Fr and HA may be considered additional diagnostic markers of CP and PDAC. TGF-β1 may be useful to predict endocrine insufficiency in PDAC.
Collapse
|
|
33
|
Nielsen MFB, Mortensen MB, Detlefsen S. Key players in pancreatic cancer-stroma interaction: Cancer-associated fibroblasts, endothelial and inflammatory cells. World J Gastroenterol 2016; 22:2678-2700. [PMID: 26973408 PMCID: PMC4777992 DOI: 10.3748/wjg.v22.i9.2678] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Revised: 12/19/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts (CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and non-cellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a context-dependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.
Collapse
|
|
34
|
Atsawarungruangkit A, Pongprasobchai S. Current understanding of the neuropathophysiology of pain in chronic pancreatitis. World J Gastrointest Pathophysiol 2015; 6:193-202. [PMID: 26600977 PMCID: PMC4644883 DOI: 10.4291/wjgp.v6.i4.193] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 07/22/2015] [Accepted: 09/16/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas. The main symptom of patients with CP is chronic and severe abdominal pain. However, the pathophysiology of pain in CP remains obscure. Traditionally, researchers believed that the pain was caused by anatomical changes in pancreatic structure. However, treatment outcomes based on such beliefs are considered unsatisfactory. The emerging explanations of pain in CP are trending toward neurobiological theories. This article aims to review current evidence regarding the neuropathophysiology of pain in CP and its potential implications for the development of new treatments for pain in CP.
Collapse
|
|
35
|
Xiao W, Jiang W, Shen J, Yin G, Fan Y, Wu D, Qiu L, Yu G, Xing M, Hu G, Wang X, Wan R. Retinoic Acid Ameliorates Pancreatic Fibrosis and Inhibits the Activation of Pancreatic Stellate Cells in Mice with Experimental Chronic Pancreatitis via Suppressing the Wnt/β-Catenin Signaling Pathway. PLoS One 2015; 10:e0141462. [PMID: 26556479 PMCID: PMC4640570 DOI: 10.1371/journal.pone.0141462] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 10/08/2015] [Indexed: 01/11/2023] Open
Abstract
Pancreatic fibrosis, a prominent feature of chronic pancreatitis (CP), induces persistent and permanent damage in the pancreas. Pancreatic stellate cells (PSCs) provide a major source of extracellular matrix (ECM) deposition during pancreatic injury, and persistent activation of PSCs plays a vital role in the progression of pancreatic fibrosis. Retinoic acid (RA), a retinoid, has a broad range of biological functions, including regulation of cell differentiation and proliferation, attenuating progressive fibrosis of multiple organs. In the present study, we investigated the effects of RA on fibrosis in experimental CP and cultured PSCs. CP was induced in mice by repetitive cerulein injection in vivo, and mouse PSCs were isolated and activated in vitro. Suppression of pancreatic fibrosis upon administration of RA was confirmed based on reduction of histological damage, α-smooth muscle actin (α-SMA) expression and mRNA levels of β-catenin, platelet-derived growth factor (PDGF)-Rβ transforming growth factor (TGF)-βRII and collagen 1α1 in vivo. Wnt 2 and β-catenin protein levels were markedly down-regulated, while Axin 2 expression level was up-regulated in the presence of RA, both in vivo and in vitro. Nuclear translation of β-catenin was significantly decreased following RA treatment, compared with cerulein-induced CP in mice and activated PSCs. Furthermore, RA induced significant PSC apoptosis, inhibited proliferation, suppressed TCF/LEF-dependent transcriptional activity and ECM production of PSC via down-regulation of TGFβRII, PDGFRβ and collagen 1α1 in vitro. These results indicate a critical role of the Wnt/β-catenin signaling pathway in RA-induced effects on CP and PSC regulation and support the potential of RA as a suppressor of pancreatic fibrosis in mice.
Collapse
MESH Headings
- Actins/biosynthesis
- Actins/genetics
- Active Transport, Cell Nucleus/drug effects
- Animals
- Apoptosis/drug effects
- Axin Protein/biosynthesis
- Axin Protein/genetics
- Cells, Cultured
- Ceruletide/toxicity
- Collagen Type I/biosynthesis
- Collagen Type I/genetics
- Disease Progression
- Drug Evaluation, Preclinical
- Fibrosis/prevention & control
- Gene Expression Regulation/drug effects
- Lipase/blood
- Male
- Mice
- Mice, Inbred BALB C
- Organ Size/drug effects
- Pancreas/drug effects
- Pancreas/pathology
- Pancreatic Stellate Cells/drug effects
- Pancreatic Stellate Cells/metabolism
- Pancreatic alpha-Amylases/blood
- Pancreatitis, Chronic/chemically induced
- Pancreatitis, Chronic/drug therapy
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Proteoglycans/biosynthesis
- Proteoglycans/genetics
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- Random Allocation
- Receptor, Platelet-Derived Growth Factor beta/biosynthesis
- Receptor, Platelet-Derived Growth Factor beta/genetics
- Receptors, Transforming Growth Factor beta/biosynthesis
- Receptors, Transforming Growth Factor beta/genetics
- Tretinoin/pharmacology
- Tretinoin/therapeutic use
- Wnt Signaling Pathway/drug effects
Collapse
Affiliation(s)
- Wenqin Xiao
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Weiliang Jiang
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jie Shen
- Department of Gastroenterology, Shanghai Changzheng Hospital, Shanghai Second Military Medical University, Shanghai, China
| | - Guojian Yin
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuting Fan
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Deqing Wu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lei Qiu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ge Yu
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Miao Xing
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Guoyong Hu
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xingpeng Wang
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rong Wan
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Gastroenterology, Shanghai First People’s Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- * E-mail:
| |
Collapse
|
|
36
|
Sendler M, Beyer G, Mahajan UM, Kauschke V, Maertin S, Schurmann C, Homuth G, Völker U, Völzke H, Halangk W, Wartmann T, Weiss FU, Hegyi P, Lerch MM, Mayerle J. Complement Component 5 Mediates Development of Fibrosis, via Activation of Stellate Cells, in 2 Mouse Models of Chronic Pancreatitis. Gastroenterology 2015; 149:765-76.e10. [PMID: 26001927 PMCID: PMC4560830 DOI: 10.1053/j.gastro.2015.05.012] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Revised: 05/09/2015] [Accepted: 05/12/2015] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS Little is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients. METHODS Chronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling. RESULTS During the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood. CONCLUSIONS In mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis.
Collapse
MESH Headings
- Aniline Compounds/pharmacology
- Animals
- Case-Control Studies
- Ceruletide
- Complement C5/deficiency
- Complement C5/genetics
- Complement C5/metabolism
- Disease Models, Animal
- Fibrosis
- Genetic Predisposition to Disease
- Ligation
- Mice, Inbred C57BL
- Mice, Knockout
- Pancreatic Ducts/surgery
- Pancreatic Stellate Cells/drug effects
- Pancreatic Stellate Cells/immunology
- Pancreatic Stellate Cells/metabolism
- Pancreatic Stellate Cells/pathology
- Pancreatitis, Chronic/chemically induced
- Pancreatitis, Chronic/drug therapy
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/immunology
- Pancreatitis, Chronic/metabolism
- Pancreatitis, Chronic/pathology
- Phenotype
- Polymorphism, Single Nucleotide
- Receptor, Anaphylatoxin C5a/antagonists & inhibitors
- Receptor, Anaphylatoxin C5a/metabolism
- Tetrahydronaphthalenes/pharmacology
- Time Factors
Collapse
Affiliation(s)
- Matthias Sendler
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Georg Beyer
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Ujjwal M Mahajan
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Vivien Kauschke
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Sandrina Maertin
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Claudia Schurmann
- Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Georg Homuth
- Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Uwe Völker
- Interfaculty Institutes for Genetics and Functional Genomics, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Henry Völzke
- Institute for Community Medicine, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Walter Halangk
- Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Thomas Wartmann
- Department of Surgery, Division of Experimental Surgery, Otto-von-Guericke University, Magdeburg, Germany
| | - Frank-Ulrich Weiss
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Peter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary; MTA-SZTE Lendulet Translational Gastroenterology Research Group, Szeged, Hungary
| | - Markus M Lerch
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany
| | - Julia Mayerle
- Department of Medicine A, University Medicine, Ernst-Moritz-Arndt University, Greifswald, Germany.
| |
Collapse
|
|
37
|
Abstract
PURPOSE OF REVIEW This report reviews recent animal model and human studies associated with inflammatory responses in acute and chronic pancreatitis. RECENT FINDINGS Animal model and limited human acute and chronic pancreatitis studies unravel the dynamic nature of the inflammatory processes and the ability of the immune cells to sense danger and environmental signals. In acute pancreatitis, such molecules include pathogen-associated molecular pattern recognition receptors such as toll-like receptors, and the more recently appreciated damage-associated molecular pattern molecules or 'alarmin' high mobility group box 1 and IL-33. In chronic pancreatitis, a recent understanding of a critical role for macrophage-pancreatic stellate cell interaction offers a potential targetable pathway that can alter fibrogenesis. Microbiome research in pancreatitis is a new field gaining interest but will require further investigation. SUMMARY Immune cell contribution to the pathogenesis of acute and chronic pancreatitis is gaining more appreciation and further understanding in immune signaling presents potential therapeutic targets that can alter disease progression.
Collapse
|
|
38
|
Xue J, Sharma V, Hsieh MH, Chawla A, Murali R, Pandol SJ, Habtezion A. Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis. Nat Commun 2015; 6:7158. [PMID: 25981357 PMCID: PMC4632846 DOI: 10.1038/ncomms8158] [Citation(s) in RCA: 278] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 04/10/2015] [Indexed: 12/17/2022] Open
Abstract
Chronic pancreatitis (CP) is a progressive and irreversible inflammatory and fibrotic disease with no cure. Unlike acute pancreatitis (AP), we find that alternatively activated macrophages (AAMs) are dominant in mouse and human CP. AAMs are dependent on interleukin (IL)-4 and IL-13 signalling, and we show that mice lacking IL-4Rα, myeloid-specific IL-4Rα and IL-4/IL-13 were less susceptible to pancreatic fibrosis. Furthermore, we demonstrate that mouse and human pancreatic stellate cells (PSCs) are a source of IL-4/IL-13. Notably, we show that pharmacologic inhibition of IL-4/IL-13 in human ex vivo studies as well as in established mouse CP decreases pancreatic AAMs and fibrosis. We identify a critical role for macrophages in pancreatic fibrosis and in turn PSCs as important inducers of macrophage-alternative activation. Our study challenges and identifies pathways involved in crosstalk between macrophages and PSCs that can be targeted to reverse or halt pancreatic fibrosis progression.
Collapse
Affiliation(s)
- Jing Xue
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Vishal Sharma
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Michael H Hsieh
- Department of Urology, Stanford University School of Medicine, Stanford University, Stanford, California 94305, USA
| | - Ajay Chawla
- Department of Physiology and Medicine, Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA
| | - Ramachandran Murali
- Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
| | - Stephen J Pandol
- Research division of immunology, Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
| |
Collapse
|
|
39
|
González-Reimers E, Santolaria-Fernández F, Martín-González MC, Fernández-Rodríguez CM, Quintero-Platt G. Alcoholism: A systemic proinflammatory condition. World J Gastroenterol 2014; 20:14660-14671. [PMID: 25356029 PMCID: PMC4209532 DOI: 10.3748/wjg.v20.i40.14660] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Excessive ethanol consumption affects virtually any organ, both by indirect and direct mechanisms. Considerable research in the last two decades has widened the knowledge about the paramount importance of proinflammatory cytokines and oxidative damage in the pathogenesis of many of the systemic manifestations of alcoholism. These cytokines derive primarily from activated Kupffer cells exposed to Gram-negative intestinal bacteria, which reach the liver in supra-physiological amounts due to ethanol-mediated increased gut permeability. Reactive oxygen species (ROS) that enhance the inflammatory response are generated both by activation of Kupffer cells and by the direct metabolic effects of ethanol. The effects of this increased cytokine secretion and ROS generation lie far beyond liver damage. In addition to the classic consequences of endotoxemia associated with liver cirrhosis that were described several decades ago, important research in the last ten years has shown that cytokines may also induce damage in remote organs such as brain, bone, muscle, heart, lung, gonads, peripheral nerve, and pancreas. These effects are even seen in alcoholics without significant liver disease. Therefore, alcoholism can be viewed as an inflammatory condition, a concept which opens the possibility of using new therapeutic weapons to treat some of the complications of this devastating and frequent disease. In this review we examine some of the most outstanding consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver.
Collapse
|
|
40
|
Lennon AM, Wolfgang CL, Canto MI, Klein AP, Herman JM, Goggins M, Fishman EK, Kamel I, Weiss MJ, Diaz LA, Papadopoulos N, Kinzler KW, Vogelstein B, Hruban RH. The early detection of pancreatic cancer: what will it take to diagnose and treat curable pancreatic neoplasia? Cancer Res 2014; 74:3381-9. [PMID: 24924775 DOI: 10.1158/0008-5472.can-14-0734] [Citation(s) in RCA: 167] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult. Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window of opportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new, potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges of screening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular genetics into these efforts.
Collapse
Affiliation(s)
| | | | | | - Alison P Klein
- Pathology; Oncology; Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland
| | | | - Michael Goggins
- Authors' Affiliations: Departments of Medicine; Pathology; Oncology
| | - Elliot K Fishman
- Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine; and
| | - Ihab Kamel
- Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine; and
| | | | | | | | | | | | | |
Collapse
|
|
41
|
Effect of antioxidant supplementation on surrogate markers of fibrosis in chronic pancreatitis: a randomized, placebo-controlled trial. Pancreas 2013; 42:589-95. [PMID: 23531998 DOI: 10.1097/mpa.0b013e31826dc2d7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES This study aimed to determine the effect of antioxidant (AO) supplementation on surrogate markers of fibrosis in patients with chronic pancreatitis (CP). METHODS In a randomized, placebo (PL)-controlled trial, patients with CP were randomized to groups that were given PL or AO for 3 months. Outcome measures were change in serum levels of transforming growth factor β1 and platelet-derived growth factor AA (PDGF-AA) (primary outcome) as well as blood markers of oxidative stress (thiobarbituric acid-reactive substances) and AO status (ferric-reducing ability of plasma) (secondary outcome). Pain relief and analgesic requirement was also recorded. RESULTS Patients (n = 61; mean [SD] age, 35.2 [10.0]; male patients, 43) were assigned to AO (n = 31) and PL (n = 30) groups. The median (range) percent reduction from baseline to 3 months in levels of PDGF-AA (17.1% [-25.3% to 88.7%] vs 2.8% [-243.1% to 30.2%]; P = 0.001), transforming growth factor β1 (P = 0.573), and thiobarbituric acid-reactive substances (P = 0.207) as well as percent increment from baseline to 3 months in ferric-reducing ability of plasma (P = 0.003) were higher in the AO group compared with the PL group. Proportion of patients who had both reduced PDGF-AA and reduced pain was greater in AO as compared with PL group (17/31 vs 9/30, P = 0.05) CONCLUSIONS Reduction in markers of fibrosis (PDGF-AA) translated into clinical outcome (reduction in pain and analgesic requirements) in those supplemented with AOs in CP (trial registration, CTRI/2011/05/001747).
Collapse
|
|
42
|
Imaoka M, Jindo T, Takasaki W. The Process and Development Mechanism of Age-related Fibrosis in the Pancreatic Islets of Sprague-Dawley Rats: Immunohistochemical Detection of Myofibroblasts and Suppression Effect by Estrogen Treatment. J Toxicol Pathol 2013; 26:1-10. [PMID: 23723562 PMCID: PMC3620208 DOI: 10.1293/tox.26.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 09/21/2012] [Indexed: 12/17/2022] Open
Abstract
The mechanism of spontaneous islet fibrosis in Sprague-Dawley rats was investigated. Using sections of the pancreas in naive males aged 26 to 102 weeks old and 26-week-old males injected with β-estradiol 3-benzoate (EB), the incidence of lesions and histological scores of fibrosis were examined in conjunction with immunohistochemistry for α-smooth muscle actin (α-SMA), platelet-derived growth factor receptor-α (PDGFRα) and estrogen receptor-α (ERα). The incidence of islet fibrosis increased in 78-week-old animals compared to the 26-week-old animals, and the incidence of atrophy in the fibrotic islet increased in animals over 52 weeks old. α-SMA and PDGFRα were positively stained mainly in fibrotic/inflammatory islets, and the histological score of α-SMA in the fibrotic islet decreased age-dependently. Notably, α-SMA and PDGFRα were co-expressed in inflammatory islets with a high score at all ages. The positive index of ERα in the EB-treated group increased when compared with that of the naive group. However, it was independent of the existence of fibrosis. In contrast, the score of α-SMA and PDGFRα decreased in the EB-treated group. In conclusion, it was clarified that a part of age-related fibrosis in islets became atrophy with age, and α-SMA-positive myofibroblasts were considered to contribute to the development of fibrosis. Strong PDGFRα stainability in fibrotic/inflammatory islets may imply that myofibroblasts were stimulated by PDGF to produce an extracellular matrix. Although estradiol has been known to suppress fibrosis/inflammation in the islet, nuclear-located ER-dependent signaling was considered not to be involved in the suppression mechanism. EB possibly affected the inhibition of the appearance of myofibroblasts.
Collapse
Affiliation(s)
- Masako Imaoka
- Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan
| | | | | |
Collapse
|
|
43
|
Adrych K, Stojek M, Smoczynski M, Sledzinski T, Sylwia SW, Swierczynski J. Increased serum chemerin concentration in patients with chronic pancreatitis. Dig Liver Dis 2012; 44:393-7. [PMID: 21798828 DOI: 10.1016/j.dld.2011.06.020] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2010] [Revised: 06/03/2011] [Accepted: 06/24/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND Chemerin is a potent chemoattractant for chemokine-like receptor 1 expressing cells and is involved in inflammatory and immune processes that play an important role in chronic pancreatitis. AIM To test the hypothesis that serum chemerin concentration may be affected in chronic pancreatitis patients and that chemerin can influence the course of chronic pancreatitis by increasing profibrotic cytokine production. METHODS Serum concentrations of chemerin and the major cytokines involved in pancreatic fibrosis such as platelet-derived growth factor BB and transforming growth factor β-1 were determined by ELISA in samples from 40 nondiabetic and 28 diabetic male patients with chronic pancreatitis of alcoholic origin and 40 age-matched healthy controls. RESULTS Serum concentrations of chemerin were increased both in nondiabetic and diabetic chronic pancreatitis patients compared to controls. Moreover, in chronic pancreatitis patients a positive correlation was found between serum chemerin and platelet-derived growth factor BB as well as transforming growth factor β-1 concentrations. CONCLUSIONS The results indicate for the first time that: (a) chronic pancreatitis in humans is associated with an increased serum chemerin concentration and (b) serum chemerin concentration correlates with serum concentrations of the major profibrotic cytokines. Elevated level of chemerin, by stimulating macrophage infiltration of the pancreas, might lead to overproduction of platelet-derived growth factor BB and transforming growth factor β-1 and, consequently, to pancreatic fibrosis.
Collapse
Affiliation(s)
- Krystian Adrych
- Department of Gastroenterology and Hepatology, Medical University of Gdansk, Gdansk, Poland
| | | | | | | | | | | |
Collapse
|
|
44
|
Bhatia V, Kim SOK, Aronson JF, Chao C, Hellmich MR, Falzon M. Role of parathyroid hormone-related protein in the pro-inflammatory and pro-fibrogenic response associated with acute pancreatitis. ACTA ACUST UNITED AC 2012; 175:49-60. [PMID: 22280800 DOI: 10.1016/j.regpep.2012.01.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Revised: 12/19/2011] [Accepted: 01/10/2012] [Indexed: 12/14/2022]
Abstract
Pancreatitis is a common and potentially lethal necro-inflammatory disease with both acute and chronic manifestations. Current evidence suggests that the accumulated damage incurred during repeated bouts of acute pancreatitis (AP) can lead to chronic disease, which is associated with an increased risk of pancreatic cancer. While parathyroid hormone-related protein (PTHrP) exerts multiple effects in normal physiology and disease states, its function in pancreatitis has not been previously addressed. Here we show that PTHrP levels are transiently elevated in a mouse model of cerulein-induced AP. Treatment with alcohol, a risk factor for both AP and chronic pancreatitis (CP), also increases PTHrP levels. These effects of cerulein and ethanol are evident in isolated primary acinar and stellate cells, as well as in the immortalized acinar and stellate cell lines AR42J and irPSCc3, respectively. Ethanol sensitizes acinar and stellate cells to the PTHrP-modulating effects of cerulein. Treatment of acinar cells with PTHrP (1-36) increases expression of the inflammatory mediators interleukin-6 (IL-6) and intracellular adhesion protein (ICAM-1), suggesting a potential autocrine loop. PTHrP also increases apoptosis in AR42J cells. Stellate cells mediate the fibrogenic response associated with pancreatitis; PTHrP (1-36) increases procollagen I and fibronectin mRNA levels in both primary and immortalized stellate cells. The effects of cerulein and ethanol on levels of IL-6 and procollagen I are suppressed by the PTH1R antagonist, PTHrP (7-34). Together these studies identify PTHrP as a potential mediator of the inflammatory and fibrogenic responses associated with alcoholic pancreatitis.
Collapse
Affiliation(s)
- Vandanajay Bhatia
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | | | | | | | | | | |
Collapse
|
|
45
|
Adrych K, Smoczynski M, Stojek M, Sledzinski T, Korczynska J, Goyke E, Swierczynski J. Coordinated increase in serum platelet-derived growth factor-BB and transforming growth factor-β1 in patients with chronic pancreatitis. Pancreatology 2011; 11:434-40. [PMID: 21921666 DOI: 10.1159/000330294] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2010] [Accepted: 06/22/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND In vitro studies suggest that platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1 (TGF-β1) play an important role in pancreatic fibrosis. The aim of this study was to evaluate serum PDGF-BB and TGF-β1 concentrations in patients with chronic pancreatitis (CP). METHODS Forty male patients with a history of alcoholic CP and 35 age-matched healthy subjects were examined. Serum concentrations of PDGF-BB, TGF-β1, laminin and hyaluronic acid were determined by ELISA assay. Additionally, we determined serum concentrations of PDGF-BB and TGF-β1 in patients with functional dyspepsia, ulcerative colitis and Crohn's disease. RESULTS Patients with advanced CP had significantly higher serum PDGF-BB and TGF-β1 concentrations compared to control subjects. A strong positive correlation between serum PDGF-BB and TGF-β1 concentrations was found in patients with CP. Serum laminin and hyaluronic acid were also elevated in patients with CP. No increase in serum PDGF-BB and TGF-β1 concentrations was found in patients with functional dyspepsia, ulcerative colitis or Crohn's disease. CONCLUSION The obtained results indicate for the first time that serum levels of PDGF-BB are elevated in patients with CP. However, ROC curve analysis suggests that PDGF-BB is not superior to laminin as a potential marker of advanced CP.
Collapse
Affiliation(s)
- Krystian Adrych
- Department of Gastroenterology and Hepatology, Medical University of Gdansk, Gdansk, Poland
| | | | | | | | | | | | | |
Collapse
|
|
46
|
Cytokine profiling of pancreatic fluid using the ePFT collection method in tandem with a multiplexed microarray assay. J Immunol Methods 2011; 369:98-107. [PMID: 21569776 DOI: 10.1016/j.jim.2011.04.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 04/18/2011] [Accepted: 04/25/2011] [Indexed: 02/08/2023]
Abstract
Cytokines are secreted immunomodulating proteins involved in pancreatic stellate cell activation and propagation of fibrosis in chronic pancreatitis. We aim to show that cytokines can be identified from pancreatic fluid by (1) collecting pancreatic fluid with the ePFT method, (2) processing the fluid for cytokine-targeted microarray analysis, and (3) comparing cytokine profiles in pancreatic fluid of chronic pancreatitis (CP) patients and of chronic abdominal pain (CAP) controls. We endoscopically collected pancreatic fluid from patients with CP and those with CAP using the ePFT method. This fluid was subjected directly to a multiplexed cytokine protein microarray assay. Six patients (3 CP, 3 CAP) underwent a secretin-stimulated ePFT. The mean peak bicarbonate concentrations [meq/L] of the CP and CAP patients were 43 and 97, respectively. Statistically significant decreases in the cytokine concentrations of EGF, IP-10, eotaxin, IL-3, MIP-1a, IL-15, PDGF-AB/BB, and IL-1a were observed in the CP specimens (p<0.05). We have successfully identified differences in the abundance of cytokines in ePFT-collected pancreatic fluid with a multiplexed microarray assay comparing CP and CAP controls. Further targeted investigation of cytokines in ePFT-collected fluid will broaden our knowledge of pancreatic immune response and pathogenesis in chronic pancreatitis.
Collapse
|
|
47
|
Detlefsen S, Bräsen JH, Zamboni G, Capelli P, Klöppel G. Deposition of complement C3c, immunoglobulin (Ig)G4 and IgG at the basement membrane of pancreatic ducts and acini in autoimmune pancreatitis. Histopathology 2011; 57:825-35. [PMID: 21166697 DOI: 10.1111/j.1365-2559.2010.03717.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIMS Autoimmune pancreatitis (AIP) is a type of pancreatitis whose immunopathogenesis is still unknown. It has been reported that renal biopsy specimens from patients diagnosed with both AIP and tubulointerstitial nephritis reveal deposits containing complement C3, immunoglobulin (Ig)G and IgG4 at the tubular basement membranes (BMs). The aim was to investigate the deposition of complement and immunoglobulins in pancreatic tissue from AIP patients compared to non-AIP patients. METHODS Double immunofluorescence microscopy for C3c, IgG4 and IgG together with CK7, trypsin, collagen IV, CD31 and CD79a, as well as immunofluorescence microscopy for C1q, IgA and IgM, were performed on frozen pancreatic tissue from AIP and alcoholic chronic pancreatitis (ACP) patients. RESULTS In AIP patients, complement C3c, IgG4 and IgG were deposited at the collagen IV-positive BMs of pancreatic and bile ducts and of acini. In a minority of the ACP patients, weak C3c-positive BM deposits were detected, but no IgG4- or IgG-positive BM deposits were present. CONCLUSION The deposition of C3c, IgG4 and IgG at the BM of small- and medium-sized ducts and acini of the pancreas is characteristic of AIP. This suggests that immune complex-mediated destruction of ducts and acini play a role in the pathogenesis of AIP.
Collapse
Affiliation(s)
- Sönke Detlefsen
- Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
| | | | | | | | | |
Collapse
|
|
48
|
Autoimmune pancreatitis: the clinicopathological characteristics of the subtype with granulocytic epithelial lesions. J Gastroenterol 2010; 45:787-93. [PMID: 20549251 DOI: 10.1007/s00535-010-0265-x] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Accepted: 05/17/2010] [Indexed: 02/04/2023]
Abstract
Autoimmune pancreatitis (AIP) has been established as a distinct form of chronic pancreatitis that is distinguishable from other types such as alcoholic, hereditary or obstructive chronic pancreatitis. AIP seems to be a global disease, since it has been reported in many different countries, especially from Japan, USA and Europe (Germany, Italy, United Kingdom). Typical histopathological findings in the pancreas in AIP include a periductal lymphoplasmacytic infiltration with fibrosis, causing narrowing of the involved ducts. The typical clinical features include presentation with obstructive jaundice/pancreatic mass and a dramatic response to steroids. However, while the reports from Japan describe uniform changes called lymphoplasmacytic sclerosing pancreatitis (LPSP) in the pancreas from AIP patients, the reports from Europe and USA distinguish two histopathologic patterns in AIP patients: one with the characteristics of LPSP and another with slightly different histological features, called idiopathic duct centric pancreatitis (IDCP) or AIP with granulocytic epithelial lesions (GELs). This article reviews the evidence that GEL-positive AIP or IDCP is a second type of AIP, distinct from LPSP, in regard to pancreatic pathology, immunology and epidemiology.
Collapse
|
|
49
|
Overexpression of Smad6 exacerbates pancreatic fibrosis in murine caerulein-induced chronic pancreatic injuries. Pancreas 2010; 39:385-91. [PMID: 19823096 DOI: 10.1097/mpa.0b013e3181bb9603] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES We examined the effect of the overexpression of Smad6 on pancreatic fibrosis after chronic pancreatic injury. METHODS Chronic pancreatic injury was induced in transgenic mice overexpressing Smad6 (Tg mice) in acini and wild-type (Wt) mice by 3 episodes of acute pancreatitis per week for 1 to 4 consecutive weeks. Acute pancreatitis was elicited by 6 intraperitoneal injections of caerulein (Cn) at 50 microg/kg of body weight at hourly intervals. Pancreatic fibrosis was evaluated by histological examination and hydroxyproline content before and 1, 2, 3, and 4 weeks of repetitive episodes of Cn-induced acute pancreatitis. We further determined transforming growth factor beta1 (TGF-beta1) messenger RNA expression and trypsin activity in the pancreas. RESULTS After repetitive episodes of acute pancreatitis, pancreatic fibrosis in Tg mice was significantly severer than that in Wt mice at all time points (weeks 1-4). The expression of TGF-beta1 messenger RNA and the activity of trypsin in the pancreas in the Tg mice were significantly high compared with those in the Wt mice at all corresponding time points after repetitive episodes of acute pancreatitis. CONCLUSIONS These results demonstrated that overexpression of Smad6 in acini enhanced the development of pancreatic fibrosis after chronic pancreatic injury.
Collapse
|
|
50
|
Abstract
BACKGROUND Autoimmune pancreatitis (AIP) is a relatively newly recognized type of pancreatitis that is characterized by diffuse or focal swelling of the pancreas due to lymphoplasmacytic infiltration and fibrosis of the pancreatic parenchyma. MATERIAL AND METHODS A PubMed literature search was performed using the keywords "autoimmune pancreatitis". Sometimes, bibliographies were cross-referenced and related article searches were performed once an article of interest was identified. RESULTS Pathologically, AIP shows narrowing of the pancreatic ducts and the intrapancreatic portion of the common bile duct. Obstructive jaundice is a common symptom at presentation, and pancreatic cancer represents an important clinical differential diagnosis. In late stages of the disease, the normal pancreatic parenchyma is often replaced by large amounts of fibrosis. Histologically, there seem to be two subtypes of the disease-one showing infiltration with IgG4-positive plasma cells but lacking granulocytic epithelial lesions (GELs), the other showing GELs but lacking strong IgG4 positivity. AIP is in at least some instances the pancreatic manifestation of a clinicopathological entity of IgG4-related systemic sclerosing disease. On the basis of pancreatic imaging, together with serological measurement of IgG4 and evaluation of other organ involvement, many AIP patients can be identified. The remaining patients require further diagnostic work-up. In these patients, pancreatic core needle biopsy and, as AIP responds to steroid treatment, also a trial with steroids, can help to differentiate AIP from pancreatic cancer. OUTLOOK AND DISCUSSION: This review presents the pathological, radiologic and laboratory findings of AIP. Moreover, the treatment and pathogenesis are discussed.
Collapse
Affiliation(s)
- Sönke Detlefsen
- Department of Pathology, Odense University Hospital, Odense, Denmark.
| | | |
Collapse
|