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Schaub JR, Chen JY, Turner SM. Integrins in biliary injury and fibrosis. Curr Opin Gastroenterol 2024; 40:85-91. [PMID: 38190346 DOI: 10.1097/mog.0000000000000995] [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: 01/10/2024]
Abstract
PURPOSE OF REVIEW Current treatment options for cholangiopathies are severely limited and there is thus a critical need to identify and develop therapies. This review discusses the role of integrins in biliary injury and fibrosis and their potential as therapeutic targets. RECENT FINDINGS There are a diverse set of roles that integrins play in biliary injury and fibrosis. Some integrins activate TGF-β signaling or are involved in sensing of the extracellular matrix, making them attractive targets for biliary fibrosis. In recent work, autoantibodies to α v β 6 were identified in patients with PSC, supporting the relevance of this integrin in the disease. In addition, a role for α 2 β 1 in cyst formation was identified in a mouse model of polycystic liver disease. Leukocyte integrins (e.g. α E β 7 and α 4 β 7 ) contribute to lymphocyte trafficking, making them potential targets for biliary inflammation; however, this has not yet translated to the clinic. SUMMARY While all members of the same family of proteins, integrins have diverse roles in the pathogenesis of biliary disease. Targeting one or multiple of these integrins may slow or halt the progression of biliary injury and fibrosis by simultaneously impacting different pathologic cells and processes.
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Affiliation(s)
| | - Jennifer Y Chen
- Department of Medicine
- The Liver Center, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
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2
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Luo P, Liu L, Hou W, Xu K, Xu P. Gene Set Enrichment Analysis Detected Immune Cell-Related Pathways Associated with Primary Sclerosing Cholangitis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:2371347. [PMID: 36060137 PMCID: PMC9439919 DOI: 10.1155/2022/2371347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022]
Abstract
Aim To explore various immune cell-related causal pathways for primary sclerosing cholangitis (PSC). Methods Immune cell-related pathway association study was conducted via integrative analysis of PSC GWAS summary and five immune cell-related eQTL datasets. The GWAS summary data of PSC was driven from 4,796 PSC cases and 19,955 healthy controls. The eQTL datasets of CD4+ T cells, CD8+ T cells, B cells, natural killer cells (NK), monocytes, and peripheral blood cells (PB) were collected from recently eQTL study. The PSC GWAS summary dataset was first aligned with eQTL datasets of six blood cells to obtain the GWAS summary data at overlapped eQTL loci, separately. For each type of cell, the obtained PSC GWAS summary dataset of eQTLs was subjected to pathway enrichment analysis. 853 biological pathways from Kyoto Encyclopedia of Genes and Genomes, BioCarta, and Reactome pathway databases were analyzed. Results We identified 36 pathways for B cells, 33 pathways for CD4+ T cells, 28 pathways for CD8+ T cells, 33 pathways for monocytes (MN), 35 pathways for NK cells, and 33 for PB cells (all empirical P values <5.0 × 10-5). Comparing the pathway analysis results detected 25 pathways shared by five immune cells, such as KEGG_CELL_ADHESION_MOLECULES_CAMS (P value <5.0 × 10-5) and REACTOME_MHC_CLASS_II_ANTIGEN_ PRESENTATION (P value <5.0 × 10-5). Several cell-specific pathways were also identified, including BIOCARTA_INFLAM_PATHWAY (P value <5 × 10-5) for B cell. Conclusion Our study holds potential to identify novel candidate causal pathways and provides clues for revealing the complex genetic mechanism of PSC.
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Affiliation(s)
- Pan Luo
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shanxi 710054, China
| | - Lin Liu
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shanxi 710054, China
| | - Weikun Hou
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shanxi 710054, China
| | - Ke Xu
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shanxi 710054, China
| | - Peng Xu
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shanxi 710054, China
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3
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Gao RY, Shearn CT, Orlicky DJ, Battista KD, Alexeev EE, Cartwright IM, Lanis JM, Kostelecky RE, Ju C, Colgan SP, Fennimore BP. Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis. Mucosal Immunol 2021; 14:479-490. [PMID: 33004979 PMCID: PMC7954872 DOI: 10.1038/s41385-020-00347-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone. Multidrug resistance protein 2 knockout (Mdr2-/-) mice develop spontaneous cholestatic liver injury and fibrosis mirroring human PSC. As a novel model of PSC-IBD, we treated Mdr2-/- mice with dextran sulfate sodium (DSS) to chemically induce colitis (Mdr2-/-/DSS). Mdr2-/- mice demonstrate alterations in fecal bile acid composition and enhanced colitis susceptibility with increased colonic adhesion molecule expression, particularly mucosal addressin-cell adhesion molecule 1 (MAdCAM-1). In vitro, ursodeoxycholic acid (UDCA) co-treatment resulted in a dose dependent attenuation of TNF-α-induced endothelial MAdCAM-1 expression. In the combined Mdr2-/-/DSS model, UDCA supplementation attenuated colitis severity and downregulated intestinal MAdCAM-1 expression. These findings suggest a potential mechanistic role for alterations in bile acid signaling in modulating MAdCAM-1 expression and colitis susceptibility in cholestasis-associated colitis. Together, our findings provide a novel model and new insight into the pathogenesis and potential treatment of PSC-IBD.
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Affiliation(s)
- Rachel Y Gao
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Colin T Shearn
- Department of Pediatrics Division of Pediatric Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - David J Orlicky
- Department of Pathology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kayla D Battista
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Erica E Alexeev
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ian M Cartwright
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Jordi M Lanis
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Rachael E Kostelecky
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Cynthia Ju
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Sean P Colgan
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Blair P Fennimore
- Department of Medicine and the Mucosal Inflammation Program, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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4
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Abstract
The human liver is an organ with a diverse array of immunologic functions. Its unique anatomic position that leads to it receiving all the mesenteric venous blood, combined with its unique micro anatomy, allows it to serve as a sentinel for the body's immune system. Hepatocytes, biliary epithelial cells, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells express key molecules that recruit and activate innate and adaptive immunity. Additionally, a diverse array of lymphoid and myeloid immune cells resides within and traffics to the liver in specific circumstances. Derangement of these trafficking mechanisms underlies the pathophysiology of autoimmune liver diseases, nonalcoholic steatohepatitis, and liver transplantation. Here, we review these pathways and interactions along with potential targets that have been identified to be exploited for therapeutic purposes.
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5
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The Many Roles of Cell Adhesion Molecules in Hepatic Fibrosis. Cells 2019; 8:cells8121503. [PMID: 31771248 PMCID: PMC6952767 DOI: 10.3390/cells8121503] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/17/2019] [Accepted: 11/18/2019] [Indexed: 01/09/2023] Open
Abstract
Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell–cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.
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6
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Denk G, Omary AJ, Reiter FP, Hohenester S, Wimmer R, Holdenrieder S, Rust C. Soluble intracellular adhesion molecule, M30 and M65 as serum markers of disease activity and prognosis in cholestatic liver diseases. Hepatol Res 2014; 44:1286-98. [PMID: 24451045 DOI: 10.1111/hepr.12304] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 01/12/2014] [Accepted: 01/16/2014] [Indexed: 12/12/2022]
Abstract
AIM Hepatic apoptosis is involved in the pathogenesis of immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). The aim of our study was to quantify distinct markers of apoptosis in sera of patients with AIH, PBC and PSC, and to evaluate correlation with markers of disease activity and prognosis. METHODS Sera of patients with AIH, PBC and PSC, and of healthy controls were collected and distinct cell death markers were quantified using a bead-based multiplex enzyme linked immunosorbent assay (soluble intracellular adhesion molecule [sICAM], macrophage migration inhibitory factor [MIF], soluble Fas [sFas], plasminogen activator inhibitor 1 [PAI-1]) or single enzyme-linked immunosorbent assays (DNAse, M30, M65). RESULTS In comparison with healthy controls, the apoptotic markers sFas, sICAM (only in PSC patients), M30 and the cell death marker M65 were substantially elevated in sera of patients with immune-mediated liver diseases, whereas DNAse activity was reduced. Interestingly, patients with advanced PSC presented with higher levels of sICAM, M30 and M65 than patients with mild PSC. Regression analysis revealed correlations between serum levels of sICAM, M30 and M65 with the Mayo Risk Score for PSC, and of M65 with the Mayo Risk Score for PBC. CONCLUSION Concentrations of the serum markers of apoptosis sFas and M30 and of the marker of total cell death M65 are elevated in patients with immune-mediated liver diseases, whereas activity of DNAse is reduced. In patients with PSC, sICAM, M30 and M65 may serve as indicators for disease activity and prognosis.
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Affiliation(s)
- Gerald Denk
- Department of Medicine II - Grosshadern, University of Munich, Munich, Germany
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7
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Ali AH, Carey EJ, Lindor KD. An overview of current and future therapeutic strategies for the treatment of primary sclerosing cholangitis. Expert Opin Orphan Drugs 2014. [DOI: 10.1517/21678707.2014.908701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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8
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Fickert P, Pollheimer MJ, Beuers U, Lackner C, Hirschfield G, Housset C, Keitel V, Schramm C, Marschall HU, Karlsen TH, Melum E, Kaser A, Eksteen B, Strazzabosco M, Manns M, Trauner M. Characterization of animal models for primary sclerosing cholangitis (PSC). J Hepatol 2014; 60:1290-303. [PMID: 24560657 PMCID: PMC4517670 DOI: 10.1016/j.jhep.2014.02.006] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 02/01/2014] [Accepted: 02/08/2014] [Indexed: 01/17/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholangiopathy characterized by biliary fibrosis, development of cholestasis and end stage liver disease, high risk of malignancy, and frequent need for liver transplantation. The poor understanding of its pathogenesis is also reflected in the lack of effective medical treatment. Well-characterized animal models are utterly needed to develop novel pathogenetic concepts and study new treatment strategies. Currently there is no consensus on how to evaluate and characterize potential PSC models, which makes direct comparison of experimental results and effective exchange of study material between research groups difficult. The International Primary Sclerosing Cholangitis Study Group (IPSCSG) has therefore summarized these key issues in a position paper proposing standard requirements for the study of animal models of PSC.
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Affiliation(s)
- Peter Fickert
- Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University of Graz, Austria.
| | - Marion J. Pollheimer
- Research Unit for Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria,Institute of Pathology, Medical University of Graz, Austria
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, The Netherlands
| | | | - Gideon Hirschfield
- Centre for Liver Research, Institute of Biomedical Research, School of Immunity and Infection, University of Birmingham, UK
| | - Chantal Housset
- UPMC Univ Paris 06 & INSERM, UMR-S 938, Centre de Recherche Saint-Antoine, F-75012 Paris, France
| | - Verena Keitel
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Düsseldorf Germany
| | | | - Hanns-Ulrich Marschall
- Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, The Sahlgrenska Academy, Sweden
| | - Tom H. Karlsen
- Division of Gastroenterology and Hepatology, Department of Medicine, Rikshospitalet, Oslo, Norway,Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Espen Melum
- Division of Gastroenterology and Hepatology, Department of Medicine, Rikshospitalet, Oslo, Norway,Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway,Research Institute of Internal Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Arthur Kaser
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooek's Hospital, UK
| | - Bertus Eksteen
- Centre for Liver Research, MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, and The Queen Elizabeth Hospital, University Hospitals Birmingham NHS Trust, Birmingham, UK
| | - Mario Strazzabosco
- Section of Gastroenterology, University of Milan-Bicocca, Milan, Italy,Liver Center, Yale University School of Medicine, United States
| | - Michael Manns
- Division of Gastroenterology, Hepatology and Endocrinology, Medical University Hannover, Germany
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
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9
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Pollheimer MJ, Fickert P, Stieger B. Chronic cholestatic liver diseases: clues from histopathology for pathogenesis. Mol Aspects Med 2013; 37:35-56. [PMID: 24141039 DOI: 10.1016/j.mam.2013.10.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Revised: 10/04/2013] [Accepted: 10/07/2013] [Indexed: 02/06/2023]
Abstract
Chronic cholestatic liver diseases include fibrosing cholangiopathies such as primary biliary cirrhosis or primary sclerosing cholangitis. These and related cholangiopathies clearly display pathologies associated with (auto)immunologic processes. As the cholangiocyte's apical membrane is exposed to the toxic actions of the bile fluid, the interaction of bile with cholangiocytes and the biliary tree in general must be considered to completely understand the pathogenesis of cholangiopathies. While the molecular processes involved in the hepatocellular formation of bile are well understood in both normal and pathophysiologic conditions, those in the bile ducts of normal liver and in livers with cholangiopathies lag behind. This survey highlights key mechanisms known to date that are important for the formation of bile by hepatocytes and its modification by the biliary tree. It also delineates the clinical pathophysiologic findings for cholangiopathies and puts them in perspective with current experimental models to reveal the pathogenesis of cholangiopathies and develop novel therapeutic approaches.
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Affiliation(s)
- Marion J Pollheimer
- Division of Gastroenterology and Hepatology, Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University of Graz, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University of Graz, Austria; Institute of Pathology, Medical University of Graz, Austria.
| | - Bruno Stieger
- Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
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10
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Possible Association Between Toxoplasma Gondii Infection and Schizophrenia. INFECTIOUS DISEASES IN CLINICAL PRACTICE 2012. [DOI: 10.1097/ipc.0b013e31826991aa] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Abstract
Cholestasis develops either from a defect in bile synthesis, impairment in bile secretion, or obstruction to bile flow, and is characterized by an elevated serum alkaline phosphatase and gamma-glutamyltransferase disproportionate to elevation of aminotransferase enzymes. Key elements to the diagnostic workup include visualization of the biliary tree by cholangiography and evaluation of liver histology. The hope is that recent advances in understanding the genetic factors and immune mechanisms involved in the pathogenesis of cholestasis will lead to newer therapeutic interventions in the treatment of these diseases.
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Affiliation(s)
- Asma Siddique
- Department of Gastroenterology, Center for Liver Disease, Digestive Disease Institute, Seattle, WA 98111, USA
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12
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Nguyen DL, LaRusso NF, Lazaridis KN. Primary sclerosing cholangitis. BLUMGART'S SURGERY OF THE LIVER, PANCREAS AND BILIARY TRACT 2012:603-614.e3. [DOI: 10.1016/b978-1-4377-1454-8.00041-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Hu G, Gong AY, Liu J, Zhou R, Deng C, Chen XM. miR-221 suppresses ICAM-1 translation and regulates interferon-gamma-induced ICAM-1 expression in human cholangiocytes. Am J Physiol Gastrointest Liver Physiol 2010; 298:G542-50. [PMID: 20110463 PMCID: PMC2853302 DOI: 10.1152/ajpgi.00490.2009] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Aberrant cholangiocyte reactions in response to inflammatory stimuli are important pathogenic factors for the persistent biliary inflammation in patients with cholangiopathies. Overexpression of intercellular cell adhesion molecule-1 (ICAM-1) in cholangiocytes is a common pathological feature in inflammatory cholangiopathies and can promote cholangiocyte interactions with effector lymphocytes in the portal region. In this study, we tested the involvement of miRNA-mediated posttranscriptional regulation in IFN-gamma-induced ICAM-1 expression in cholangiocytes. Using both immortalized and nonimmortalized human cholangiocyte cell lines, we found that IFN-gamma activated ICAM-1 transcription and increased ICAM-1 protein expression. Inhibition of ICAM-1 transcription could only partially block IFN-gamma-induced ICAM-1 expression at the protein level. In silico target prediction analysis revealed complementarity of miR-221 to the 3'-untranslated region of ICAM-1 mRNA. Targeting of ICAM-1 3'-untranslated region by miR-221 resulted in translational repression in cholangiocytes but not ICAM-1 mRNA degradation. Functional inhibition of miR-221 with anti-miR-221 induced ICAM-1 protein expression. Moreover, IFN-gamma stimulation decreased miR-221 expression in cholangiocytes in a signal transducer and activator of transcription 1-dependent manner. Transfection of miR-221 precursor abolished IFN-gamma-stimulated ICAM-1 protein expression. In addition, miR-221-mediated expression of ICAM-1 on cholangiocytes showed a significant influence on the adherence of cocultured T cells. These findings indicate that both transcriptional and miRNA-mediated posttranscriptional mechanisms are involved in IFN-gamma-induced ICAM-1 expression in human cholangiocytes, suggesting an important role for miRNAs in the regulation of cholangiocyte inflammatory responses.
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Affiliation(s)
- Guoku Hu
- Departments of 1Medical Microbiology and Immunology and
| | - Ai-Yu Gong
- Departments of 1Medical Microbiology and Immunology and
| | - Jun Liu
- Departments of 1Medical Microbiology and Immunology and
| | - Rui Zhou
- Departments of 1Medical Microbiology and Immunology and
| | - Caishu Deng
- 2Pathology, Creighton University Medical Center, Omaha, Nebraska
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Borchers AT, Shimoda S, Bowlus C, Keen CL, Gershwin ME. Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis. Semin Immunopathol 2009; 31:309-22. [PMID: 19533132 PMCID: PMC2758172 DOI: 10.1007/s00281-009-0167-2] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2009] [Accepted: 05/27/2009] [Indexed: 02/07/2023]
Abstract
The mechanisms operating in lymphocyte recruitment and homing to liver are reviewed. A literature review was performed on primary biliary cirrhosis (PBC), progressive sclerosing cholangitis (PSC), and homing mechanisms; a total of 130 papers were selected for discussion. Available data suggest that in addition to a specific role for CCL25 in PSC, the CC chemokines CCL21 and CCL28 and the CXC chemokines CXCL9 and CXCL10 are involved in the recruitment of T lymphocytes into the portal tract in PBC and PSC. Once entering the liver, lymphocytes localize to bile duct and retain by the combinatorial or sequential action of CXCL12, CXCL16, CX3CL1, and CCL28 and possibly CXCL9 and CXCL10. The relative importance of these chemokines in the recruitment or the retention of lymphocytes around the bile ducts remains unclear. The available data remain limited but underscore the importance of recruitment and homing.
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Affiliation(s)
- Andrea T Borchers
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA
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15
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Li HY, Lin MS, Wei JN, Hung CS, Chiang FT, Lin CH, Hsu HC, Su CY, Wu MY, Smith DJ, Vainio J, Chen MF, Chuang LM. Change of serum vascular adhesion protein-1 after glucose loading correlates to carotid intima-medial thickness in non-diabetic subjects. Clin Chim Acta 2009; 403:97-101. [PMID: 19361461 DOI: 10.1016/j.cca.2009.01.027] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2008] [Revised: 12/11/2008] [Accepted: 01/27/2009] [Indexed: 11/16/2022]
Abstract
BACKGROUND We investigated if serum vascular adhesion protein-1 (SSAO/VAP-1) changed acutely following oral glucose loading and whether such changes are correlated with surrogate markers of atherosclerosis. METHODS A total of 115 non-diabetics subjects were enrolled for an oral glucose tolerance test (OGTT). Carotid intima-medial thickness (IMT) was measured by ultrasonography. Serum SSAO/VAP-1 was analyzed by time-resolved immunofluorometric assay. Serum thiobarbituric acid reactive substances (TBARS) and advanced glycated end products (AGEs) were measured by fluorometric assays. RESULTS Serum SSAO/VAP-1 increased significantly at 30 min after oral glucose loading and lasted to 2 h (p=0.0005 and p<0.0001, for 30 min and 2 h respectively). The area under curve of serum SSAO/VAP-1 during OGTT (AUC-VAP-1) correlated significantly with carotid IMT, independent of age, gender, low-density lipoprotein cholesterol, systolic blood pressure, hemoglobin A1c, serum TBARS, AGEs, and high-sensitivity C-reactive protein. Subjects with a positive AUC-VAP-1 had significantly higher serum TBARS and AGEs than subjects with a negative AUC-VAP-1 adjusted for age and gender. CONCLUSIONS Serum SSAO/VAP-1 changed acutely following oral glucose loading in non-diabetic subjects. Change of serum SSAO/VAP-1 correlated independently to serum TBARS, AGEs, and carotid IMT. Our findings suggest that acute change of serum SSAO/VAP-1 is a novel marker for hyperglycemia-induced atherosclerosis.
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Affiliation(s)
- Hung-Yuan Li
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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16
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Maurer KJ, Carey MC, Fox JG. Roles of infection, inflammation, and the immune system in cholesterol gallstone formation. Gastroenterology 2009; 136:425-40. [PMID: 19109959 PMCID: PMC2774219 DOI: 10.1053/j.gastro.2008.12.031] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Revised: 12/05/2008] [Accepted: 12/08/2008] [Indexed: 12/12/2022]
Abstract
Cholesterol gallstone formation is a complex process mediated by genetic and environmental factors. Until recently, the role of the immune system in the pathogenesis of cholesterol gallstones was not considered a valid topic of research interest. This review collates and interprets an extensive body of basic literature, some of which is not customarily considered to be related to cholelithogenesis, describing the multiple facets of the immune system that appear to be involved in cholesterol cholelithogenesis. A thorough understanding of the immune interactions with biliary lipids and cholecystocytes should modify current views of the pathogenesis of cholesterol gallstones, promote further research on the pathways involved, and lead to novel diagnostic tools, treatments, and preventive measures.
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Affiliation(s)
- Kirk J. Maurer
- Division of Gastroenterology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston,Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Martin C. Carey
- Division of Gastroenterology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
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17
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease. Associations with inflammatory bowel disease (IBD) especially ulcerative colitis (UC), and with particular autoimmune diseases, as well as the genetic associations further suggest PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease. PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.
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Abstract
Cholangiocytes, the epithelial cells lining bile ducts, provide the first line of defense against lumenal microbes in the biliary system. Recent advances in biliary immunity indicate that cholangiocytes express a variety of pathogen-recognition receptors and can activate a set of intracellular signaling cascades to initiate a profound antimicrobial defense, including release of proinflammatory cytokines and chemokines, production of antimicrobial peptides and maintenance of biliary epithelial integrity. Cholangiocytes also interact with other cell types in the liver (for example, lymphocytes and Kupffer cells) through expression and release of adhesion molecules and immune mediators. Subsequently, through an intricate feedback mechanism involving both epithelial and other liver cells, a set of intracellular signaling pathways are activated to regulate the functional state of cholangiocyte responses during microbial infection. Thus, cholangiocytes are actively involved in mucosal immunity of the biliary system and represent a fine-tuned, integral component of liver immunity.
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Dufour J. Biliary Epithelial Cells. TEXTBOOK OF HEPATOLOGY 2007:52-57. [DOI: 10.1002/9780470691861.ch1g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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SMALL A, LARUSSO N, LAZARIDIS K. Primary Sclerosing Cholangitis. SURGERY OF THE LIVER, BILIARY TRACT AND PANCREAS 2007:613-627. [DOI: 10.1016/b978-1-4160-3256-4.50052-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Elferink RO. "Return to sender, address unknown...." Are variant addressins involved in PSC? J Hepatol 2006; 45:633-5. [PMID: 16982108 DOI: 10.1016/j.jhep.2006.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
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Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol 2006. [PMID: 15879616 DOI: 10.1385/criai: 28: 2: 093] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology;however, lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for PSC. Associations with inflammatory bowel disease--especially ulcerative colitis--and with other auto-immune diseases, together with genetic associations, further suggest that PSC may be an immune-mediated disease. The immunogenetics of PSC have been the subject of active research, and several human leukocyte antigen (HLA)- and non-HLA-associated genes have been implicated in the development of the disease. Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and, therefore, evoking an abnormal immune response.
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Affiliation(s)
- Joy Worthington
- Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, UK
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Vejchapipat P, Jirapanakorn N, Thawornsuk N, Theamboonlers A, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. There is no association between K469E ICAM-1 gene polymorphism and biliary atresia. World J Gastroenterol 2005; 11:4886-90. [PMID: 16097065 PMCID: PMC4398743 DOI: 10.3748/wjg.v11.i31.4886] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine whether there was an association between inter-cellular adhesion molecule-1 (ICAM-1) gene polymorphism and biliary atresia (BA), and to investigate the relationship between serum soluble ICAM-1 (sICAM-1) and clinical outcome in BA patients after surgical treatment.
METHODS: Eighty-three BA patients and 115 normal controls were genotyped. K469E ICAM-1 polymorphism was analyzed using PCR assay. Serum sICAM-1 was determined using ELISA method from 72 BA patients. In order to evaluate the association between these variables and their clinical outcome, the patients were categorized into two groups: patients without jaundice and those with persistent jaundice.
RESULTS: There were no significant differences between BA patients and controls in terms of gender, K469E ICAM-1 genotypes, and alleles. The proportion of patients having serum sICAM-1 ≥3 500 ng/mL in persistent jaundice group was significantly higher than that in the other group. In addition, there was no association between K469E ICAM-1 polymorphism and the status of jaundice in BA patients after Kasai operation.
CONCLUSION: ICAM-1 possibly plays an important and active role in the disease progression. However, the process is not associated with genetic variation of K469E ICAM-1 polymorphism.
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Affiliation(s)
- Paisarn Vejchapipat
- Pediatric Surgery Unit, Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Yokomori H, Oda M, Ogi M, Wakabayashi G, Kawachi S, Yoshimura K, Nagai T, Kitajima M, Nomura M, Hibi T. Expression of adhesion molecules on mature cholangiocytes in canal of Hering and bile ductules in wedge biopsy samples of primary biliary cirrhosis. World J Gastroenterol 2005; 11:4382-9. [PMID: 16038038 PMCID: PMC4434666 DOI: 10.3748/wjg.v11.i28.4382] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the expression of intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) expression on canals of Hering (CoH) and bile ductules associated with the autoimmune process of bile duct destruction in primary biliary cirrhosis (PBC).
METHODS: Ten wedged liver biopsies of PBC (five cases each of stages 2 and 3) were studied. The liver specimens were processed for transmission electron microscopy. Immunohistochemistry was performed using anti-ICAM-1 and anti-LFA-1 mouse mAbs. In situ hybridization was done to examine the messenger RNA expression of ICAM-1 in formalin-fixed, paraffin-embedded sections using peptide nucleic acid probes and the catalyzed signal amplification (CSA) technique. Immunogold-silver staining for electron microscopy was performed using anti-ICAM and anti-LFA-1 mouse mAbs. The immunogold particles on epithelial cells of bile ductules and cholangiocytes of CoH cells were counted and analyzed semi-quantitatively. Western blotting was performed to confirm ICAM-1 protein expression.
RESULTS: In liver tissues of PBC patients, immunohi-stochemistry showed aberrant ICAM-1 expression on the plasma membrane of epithelial cells lining bile ductules, and also on mature cholangiocytes but not on hepatocytes in CoH. LFA-1-positive lymphocytes were closely associated with epithelial cells in bile ductules. ICAM-1 expression at protein level was confirmed by Western blot. In situhybridization demonstrated ICAM-1 mRNA expression in bile ductules and LFA-1 mRNA in lymphocytes infiltrating the bile ductules. By immunoelectron microscopy, ICAM-1 was demonstrated on the basal surface of epithelial cells in bile ductules and on the luminal surfaces of cholangiocytes in damaged CoH. Cells with intermediate morphology resembling progenitor cells in CoH were not labeled with ICAM-1 and LFA-1.
CONCLUSION: De novo expression of ICAM-1 both on mature cholangiocytes in CoH and epithelial cells in bile ductules in PBC implies that lymphocyte-induced destruction through adhesion by ICAM-1 and binding of LFA-1-expressing activated lymphocytes takes place not only in bile ductules but also in the CoH.
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Affiliation(s)
- Hiroaki Yokomori
- Kitasato Institute Medical Center Hospital, 121-1 Arai, Kitamotoshi, Saitama 364-8501, Japan.
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Yang X, Cullen SN, Li JH, Chapman RW, Jewell DP. Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1. J Hepatol 2004; 40:375-9. [PMID: 15123348 DOI: 10.1016/j.jhep.2003.11.009] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2003] [Revised: 11/11/2003] [Accepted: 11/11/2003] [Indexed: 01/06/2023]
Abstract
BACKGROUND/AIMS Intercellular adhesion molecule-1 (ICAM-1, CD54) gene polymorphisms have been implicated in the susceptibility to a range of inflammatory diseases, including inflammatory bowel disease (IBD). Primary sclerosing cholangitis (PSC) is an immune-mediated chronic cholestatic liver disease associated with IBD. ICAM-1 is expressed on proliferating bile ducts and interlobular bile ducts in late stage PSC and serum levels of soluble intercellular adhesion molecules are increased in PSC. The aim of this study was to analyse ICAM-1 gene polymorphisms in PSC patients. METHODS In this study, 104 patients with PSC and 213 healthy controls were recruited from Oxfordshire Caucasians. PCR with sequence-specific primers (PCR-SSP) was used to detect both ICAM-1 biallelic polymorphisms G241R and K469E. The results were controlled for the HLA haplotypes associated with PSC. RESULTS The E/E frequency of K469E in PSC was 12% (12/104), significantly lower than that in controls (24%, 51/213;P = 0.009; Pc = 0.02; OR, 0.41). The occurrence of the haplotype G241-E469/G241-E469 in PSC was 4% (4/104), significantly lower than the control group (13%, 28/213; P = 0.01; Pc = 0.04; OR, 0.26). There was no difference between PSC and control groups in the frequencies of the genotype R241G or in allele frequencies of K469E. CONCLUSIONS The E469E homozygote status for ICAM-1 is associated with protection against PSC.
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Affiliation(s)
- Xuesong Yang
- Gastroenterology Unit, Gibson Laboratories, Nuffield Department of Medicine, University of Oxford, 2nd Floor, Radcliffe Infirmary, Oxford OX2 6HE, UK
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Ala A, Dhillon AP, Hodgson HJ. Role of cell adhesion molecules in leukocyte recruitment in the liver and gut. Int J Exp Pathol 2003; 84:1-16. [PMID: 12694483 PMCID: PMC2517541 DOI: 10.1046/j.1365-2613.2003.00235.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2002] [Accepted: 09/27/2002] [Indexed: 12/30/2022] Open
Abstract
This article reviews the evidence that adhesion molecules are critical in leukocyte recirculation and pathogenesis of diseases affecting the closely related tissues of the liver and gut, which offer novel opportunities for treatment.
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Affiliation(s)
- A Ala
- Centre for Hepatology, Department of Medicine, Royal Free & University College School of Medicine, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
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Granot E, Shouval D, Ashur Y. Cell adhesion molecules and hyaluronic acid as markers of inflammation, fibrosis and response to antiviral therapy in chronic hepatitis C patients. Mediators Inflamm 2001; 10:253-8. [PMID: 11759109 PMCID: PMC1781718 DOI: 10.1080/09629350120093722] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE Cell adhesion molecules (intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1)) and hyaluronic acid, markers of inflammation and fibrosis were monitored in hepatitis C patients to determine whether changes in plasma levels, during antiviral treatment, can predict long-term response to therapy. METHODS In 55 patients with chronic hepatitis C virus (HCV), 33 treated with interferon (IFN) and 22 treated with IFN + ribavirin, sera was collected prior to treatment, at 3 + 6 months of therapy and 6 months post-treatment. Levels of ICAM-1, VCAM-1 and hyaluronic acid were correlated with alanine aminotransferase levels, HCV-RNA-polymerase chain reaction status and histological fibrosis scoring. RESULTS A decrease in ICAM-1 levels at 3 and 6 months of therapy, compared with pretreatment levels, was observed in responders to IFN + ribavirin therapy but this decrease in ICAM-1 levels was not evident following cessation of treatment. Hyaluronic acid levels, in both treatment groups, did not differ significantly between responders and non-responders. Hyaluronic acid levels did correlate, significantly, with degree of fibrosis whereas VCAM-1 levels were marginally increased only in patients with moderate (grade III) fibrosis. CONCLUSIONS Monitoring of VCAM-1 and hyaluronic acid, during antiviral therapy, does not differentiate between responders and non-responders. A decrease in ICAM-1 levels during IFN + ribavirin treatment is associated with response to therapy, and its efficacy in predicting long-term response should be further substantiated.
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Affiliation(s)
- E Granot
- Pediatric Gastroenterology Unit, Pediatrics Department, Hebrew University-Hadassah Medical School, PO. Box 12000, Jerusalem 91120, Israel.
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Battista S, Bar F, Mengozzi G, Pollet C, Torchio M, Cavalli G, Rosina F, David E, Cutrin JC, Cavalieri B, Poli G, Molino G. Evidence of an increased nitric oxide production in primary biliary cirrhosis. Am J Gastroenterol 2001; 96:869-75. [PMID: 11280567 DOI: 10.1111/j.1572-0241.2001.03470.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Although possible implications of nitric oxide in the pathophysiology of liver cirrhosis have been extensively studied, until now few articles have addressed the assessment of nitric oxide production in primary biliary cirrhosis. This study was directed to evaluate circulating nitrosyl-hemoglobin levels as well as neutrophil elastase and soluble adhesion molecule concentrations in this condition, by assuming these parameters as possible markers of either inflammatory response or neutrophil activation. METHODS Laboratory investigations were performed in 30 patients with primary biliary cirrhosis, in 13 patients with postviral and/or alcoholic cirrhosis, and in a group of eight subjects with chronic hepatitis. RESULTS Although no difference was detected with respect to chronic hepatitis subjects, higher levels of nitrosyl-hemoglobin adducts were found in primary biliary cirrhosis patients than in postviral or alcoholic cirrhotics and in normal subjects (3.55+/-1.75 arbitrary units vs 1.95+/-0.57 and 0.84+/-0.34, p = 0.0004 and p < 0.0001, respectively). Similarly, more elevated concentrations of neutrophil elastase (213.7+/-192.0 microg/L vs 51.1+/-34.3 and 38.0+/-11.5, p < 0.0001 and p < 0.0001, respectively) as well as of soluble forms of intercellular adhesion molecule 1 and endothelial-leukocyte adhesion molecule 1 were shown in primary biliary cirrhosis patients than in subjects with cirrhosis of other etiologies and in controls. CONCLUSIONS Highly enhanced nitric oxide production in primary biliary cirrhosis could be related to the development of strong inflammation and at least partially to neutrophil activation, thus suggesting a putative role of these cellular mediators in the development of liver damage owing to their ability to synthesize and release a wide variety of important factors, including elastase and nitric oxide.
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Affiliation(s)
- S Battista
- Department of Pathology, San Giovanni Battista Hospital of Turin, Italy
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Kurkijärvi R, Yegutkin GG, Gunson BK, Jalkanen S, Salmi M, Adams DH. Circulating soluble vascular adhesion protein 1 accounts for the increased serum monoamine oxidase activity in chronic liver disease. Gastroenterology 2000; 119:1096-103. [PMID: 11040196 DOI: 10.1053/gast.2000.18163] [Citation(s) in RCA: 87] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS Vascular adhesion protein 1 (VAP-1) is an endothelial glycoprotein that supports adhesion of lymphocytes to hepatic endothelium and has sequence homology with semicarbazide-sensitive amine oxidases (SSAOs). We investigated whether soluble VAP-1 (sVAP-1) displays SSAO activity and thereby accounts for increased monoamine oxidase activity in the serum of patients with liver diseases. METHODS sVAP-1 concentration and SSAO activity were measured in peripheral, hepatic, and portal blood and in bile from patients with liver disease and in peripheral blood of control subjects, using enzyme-linked immunosorbent assay and enzymatic assays. RESULTS sVAP-1 concentration (mean [+/-SE], 143. 67 [34.97-92.67] ng/mL) and SSAO activity (18.8 [12.0-24.6] nmol. mL(-1). h(-1)) were significantly increased in chronic liver diseases compared with healthy controls (87.1 [53.5-127] ng/mL [P<0.001] and 10.7 [6.5-12.7] nmol. mL(-1) x h(-1) [P<0.05]) but not in massive necrosis caused by paracetamol poisoning (109 [80.3-140] ng/mL and 8.9 [5.7-12.3] nmol. mL(-1) x h(-1)). sVAP-1 correlated with serum transaminase and bilirubin but not with creatinine. In 5 paired samples, sVAP-1 concentration was higher in hepatic (median, 113 [range, 53-122]) than in portal vein (102 [42-109]; 2P<0.05), and was not detected in bile. There was a highly significant correlation between serum sVAP-1 and SSAO activity in normal subjects, patients with acute liver failure, and those with chronic liver disease (r = 0.895; P<0.001). When serum was depleted of sVAP-1 by immunoaffinity chromatography, SSAO activity was eliminated. CONCLUSIONS sVAP-1 levels are increased in chronic liver disease, and sVAP-1 is likely derived from the liver. Serum sVAP-1 displays SSAO activity and accounts for most of the monoamine oxidase activity in human serum.
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Affiliation(s)
- R Kurkijärvi
- MediCity Research Laboratories, University of Turku and National Public Health Institute Department in Turku, Turku, Finland
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Affiliation(s)
- S A Mitchell
- Department of Gastroenterology, Oxford Radcliffe Hospital, UK
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Hillan KJ, Hagler KE, MacSween RN, Ryan AM, Renz ME, Chiu HH, Ferrier RK, Bird GL, Dhillon AP, Ferrell LD, Fong S. Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease. LIVER 1999; 19:509-18. [PMID: 10661685 DOI: 10.1111/j.1478-3231.1999.tb00084.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
AIMS/BACKGROUND The integrin alpha4beta7 and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) are involved in normal recirculation of lymphocytes between the blood and the tissues of the gastrointestinal tract. In this study we have examined the expression of MAdCAM-1 in human liver. METHODS MAdCAM-1 expression was determined in archival human liver tissues by immunohistochemistry. RESULTS While MAdCAM-1 was not detected in normal fetal or adult human liver, expression was observed in association with portal tract inflammation in a variety of liver diseases. Detailed analysis of liver biopsies from patients with hepatitis C showed a positive correlation between the portal/periportal component of the histological activity index (HAI) grade and the presence or absence of MAdCAM-1 expression. CONCLUSION MAdCAM-1 expression may be important in the recruitment of lymphocytes to the liver during inflammation.
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Affiliation(s)
- K J Hillan
- Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA
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Assy N, Jacob G, Spira G, Edoute Y. Diagnostic approach to patients with cholestatic jaundice. World J Gastroenterol 1999; 5:252-262. [PMID: 11819442 PMCID: PMC4688481 DOI: 10.3748/wjg.v5.i3.252] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/1999] [Revised: 05/12/1999] [Accepted: 05/28/1999] [Indexed: 02/06/2023] Open
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Howell CD, Li J, Chen W. Role of intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 during nonsuppurative destructive cholangitis in a mouse graft-versus-host disease model. Hepatology 1999; 29:766-76. [PMID: 10051478 DOI: 10.1002/hep.510290350] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Intercellular adhesion molecule-1 (ICAM-1) is expressed abnormally on the bile duct epithelium during the course of primary biliary cirrhosis (PBC), but the importance of ICAM-1 and its lymphocyte function-associated antigen-1 (LFA-1) receptor during the course of nonsuppurative destructive cholangitis (NSDC) has not been defined. To address this question, we defined the relationship between ICAM-1 on the intrahepatic bile duct epithelium and the evolution of NSDC lesions in a mouse graft-versus-host disease (GVHD) model. We also determined the effects of anti-ICAM-1 and anti-LFA-1 treatments on NSDC, intrahepatic lymphokine production, and the homing of lymphocytes to the livers of GVHD mice. ICAM-1 was initially detected on the bile duct epithelium and portal vein endothelium on day 7 of GVHD. There was a significant positive correlation between the intensity of ICAM-1 staining and histological bile duct damage (r =.58, P <.05) between day 3 and 28. Treatment with anti-ICAM-1 (but not anti-LFA-1) decreased both the mean grades of portal inflammation (P =.003) and NSDC (P =.002) lesions compared with control immunoglobulin G (IgG) treatments. Combined treatment with anti-ICAM-1 and anti-LFA-1 caused a further decrease in the amount of portal inflammation and bile duct damage compared with anti-ICAM-1, alone (P =.02). Anti-ICAM-1 treatment also decreased both the percentage of T cells and the production of interleukin-2 (IL-2) and IL-12 in the liver (P <.01), but had no effect on IL-4, IL-10, and interferon gamma. Neither anti-ICAM-1 nor anti-LFA-1 prevented lymphocytes from homing to the liver. These results indicate that both ICAM-1 and LFA-1 are important to the pathogenesis of NSDC.
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Affiliation(s)
- C D Howell
- The University of Maryland at Baltimore, School of Medicine, Baltimore, MD, USA.
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Knittel T, Dinter C, Kobold D, Neubauer K, Mehde M, Eichhorst S, Ramadori G. Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair. THE AMERICAN JOURNAL OF PATHOLOGY 1999; 154:153-67. [PMID: 9916930 PMCID: PMC1853435 DOI: 10.1016/s0002-9440(10)65262-5] [Citation(s) in RCA: 102] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Hepatic stellate cells (HSC), a pericyte-like nonparenchymal liver cell population, are regarded as the principal matrix-synthesizing cells of fibrotic liver. They might also play a role during liver inflammation. The present study analyzed (i) expression of cell adhesion molecules (CAMs) mediating cell infiltration, like intercellular adhesion molecule-1 (I-CAM-1) and vascular cell adhesion molecule-1 (V-CAM-1), by HSC, (ii) CAM regulation in HSC by growth factors and inflammatory cytokines, and (iii) CAM expression in situ during liver inflammation, using immunochemistry and Northern blot analysis. I-CAM-1 and V-CAM-1 expression was present in HSC in vitro and in cells located in the sinusoidal/perisinusoidal area of normal liver. Growth factors, eg, transforming growth factor-beta1, down-regulated I-CAM-1- and V-CAM-1-coding mRNAs and stimulated N-CAM expression of HSC. In contrast, inflammatory cytokines like tumor necrosis factor-alpha reduced N-CAM-coding mRNAs, whereas induction of I-CAM-1- and V-CAM-1-specific transcripts increased several fold. In situ, messengers specific for I-CAM-1 and V-CAM-1 were induced 3 hours after CCl4 treatment (thereby preceding mononuclear cell infiltration starting at 12 hours), were expressed at maximal levels 9-12 hours after CCl4 application, and decreased afterwards. I-CAM-1 and V-CAM-1 immunoreactivity increased in a linear fashion starting 3 hours after CCl4-induced liver injury, was detected in highest amounts at 24-48 hours characterized by maximal cell infiltration, and returned to baseline values at 96 hours. Interestingly, the induction/repression of CAM-specific messengers paralleled the time kinetics of tumor necrosis factor-alpha transforming growth factor-beta1 expression in injured liver. HSC might be important during the onset of hepatic tissue injury as proinflammatory elements and might interact with I-CAM-1 and V-CAM-1 ligand-bearing cells, namely lymphocyte function-associated antigen-1- or Mac-1/very late activation antigen-4-positive inflammatory cells, thereby modulating the recruitment and migration of mononuclear cells within the perisinusoidal space of diseased livers.
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Affiliation(s)
- T Knittel
- Department of Internal Medicine, University of Göttingen, Germany
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Abstract
BACKGROUND Sialyl Lewis-x (sLx) is a cellular adhesion molecule (CAM) that has been implicated in the inflammatory reaction and cancer metastasis. The sLx is the carbohydrate ligand of endothelial-selectin (E-selectin), an inducible vascular endothelial CAM. The role of sLx has been investigated in several cancers, and its presence has been correlated with advanced disease stage, decreased disease-free survival, and greater metastatic potential. A recent study has found that cultured head and neck (HN) squamous cell carcinoma (SCC) cell lines express sLx and that binding of these cells to cytokine activated endothelium correlates with the endothelial expression of E-selectin. The purpose of this study was to identify sLx in the tumors of patients with HNSCC and to see if the presence of sLx correlated with disease status. METHODS We performed immunohistochemical (IHC) staining to detect the sLx antigen using the monoclonal antibody (MAb) KM-93. Eighty-two specimens of HNSCC that were obtained at the time of resection or biopsy were analyzed for sLx staining patterns and intensities. The clinical outcomes of survival, disease-free interval, and incidence of distant metastasis were then assessed to determine whether there was a correlation with sLx tumor expression. In addition, we analyzed specimens from metastatic HNSCC sites for expression of sLx. RESULTS The sLx expression was identified in 62% of the primary tumor specimens and 87% of the metastatic tumor specimens analyzed by IHC. The staining pattern in the HNSCC tumors differed from that seen in normal squamous epithelium but was variable in both intensity and distribution. The sLx expression in the metastatic sites was higher than in the primary sites in 67% of the specimens (10 of 15). There was no correlation between sLx staining and disease status. CONCLUSIONS The results of this study demonstrate that sLx is present in HNSCC and supports the data that show that sLx may play a role in the metastasis of HNSCC. Future studies are warranted to evaluate the role of sLx, E-selectin, and other CAMs in HNSCC.
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Affiliation(s)
- R W Farmer
- Division of Otolaryngology-Head and Neck Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA
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Minnick KE, Kreisberg R, Dillon PW. Soluble ICAM-1 (sICAM-1) in biliary atresia and its relationship to disease activity. J Surg Res 1998; 76:53-6. [PMID: 9695739 DOI: 10.1006/jsre.1998.5285] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
BACKGROUND Intercellular adhesion molecule-1 (ICAM-1) is strongly expressed on the bile ducts and hepatic parenchyma of livers with biliary atresia. A soluble, circulating form of this membrane protein has been found to be elevated in a number of inflammatory hepatic disorders. However, its expression in biliary atresia is unknown. The purpose of this study was to assess the presence of soluble ICAM-1 in infants with biliary atresia in relation to disease activity, degree of cholestasis, and standard liver function tests. MATERIALS AND METHODS A total of nine patients (n = 9) with biliary atresia (seven) and neonatal hyperbilirubinemia (two) were studied (age range 6 weeks-9 years). Control samples were obtained from three healthy infants (2-10 months). Serum was collected from each patient and stored at -80 degrees C until assayed. Levels of sICAM-1 were measured in duplicate utilizing an ELISA method (Bioscource International). Standard liver function tests (conjugated bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase, alanine aminotransferase) were determined at the same time. Results are expressed as the means +/- SEM with statistical analysis by Mann-Whitney test. RESULTS sICAM-1 levels were significantly elevated in all patients with biliary atresia (997 +/- 56 ng/ml) when compared to controls (P < 0.001). No correlation was found between sICAM-1 levels and conjugated bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase, and alanine aminotransferase levels or with clinical assessment of disease severity. CONCLUSIONS sICAM-1 is markedly elevated in biliary atresia reflecting the immunopathology of the disease process but does not appear to correlate with markers of liver function. sICAM-1 may be useful in assessing the effects of immunomodulatory therapy.
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Affiliation(s)
- K E Minnick
- Department of Surgery, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey 17033, USA
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Gulubova MV. Intercellular adhesion molecule-1 (ICAM-1) expression in the liver of patients with extrahepatic cholestasis. Acta Histochem 1998; 100:59-74. [PMID: 9542581 DOI: 10.1016/s0065-1281(98)80006-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
ICAM-1 mediates the recruitment of neutrophils through the endothelium to the site of inflammation by the ICAM-1/Mac-1 and ICAM-1/LFA-1 adhesion pathways. In extrahepatic cholestasis, recruitment of neutrophils is a main feature of the inflammatory infiltrate in areas of parenchymal damage. The aim of the present study was to describe the light and electron microscopical localization of ICAM-1 expression in the liver of cholestatic patients. The peroxidase-antiperoxidase technique was used. Increased ICAM-1 expression was detected on sinusoidal endothelial and Kupffer cells. A de novo ICAM-1 expression was described on some Ito cells and the sinusoidal hepatocyte membrane in areas of parenchymal injury. In the portal areas of livers of cholestatic patients, ICAM-1 was observed on the endothelial surface of portal veins and on hepatic arteries. Occasionally, ICAM-1 was found on the surface of bile duct epithelia. It is suggested that ICAM-1 expression is up-regulated by cytokines like TNF-alpha, IL-1 and interferons released from activated Kupffer cells. The mechanisms of ICAM-1 upregulation and neutrophil recruitment in the liver during extrahepatic cholestasis are discussed.
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Affiliation(s)
- M V Gulubova
- Department of Pathology, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
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Affiliation(s)
- G W McCaughan
- A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital/University of Sydney, Australia.
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Broomé U, Nemeth A, Hultcrantz R, Scheynius A. Different expression of HLA-DR and ICAM-1 in livers from patients with biliary atresia and Byler's disease. J Hepatol 1997; 26:857-62. [PMID: 9126800 DOI: 10.1016/s0168-8278(97)80253-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS Extrahepatic biliary atresia (EHBA) and chronic progressive intra-hepatic cholestasis (Byler's disease) are two distinct disorders of unknown etiology in the neonate, characterized by profound cholestasis. The aim of the present study was to investigate the inflammatory reaction in liver tissue from patients with EHBA and Byler's disease. METHODS The expression of HLA-DR and ICAM-1 and the number of CD4+, CD8+ and gamma/delta+ T-cells were investigated with immunoperoxidase technique on cryostat sections of liver tissue from patients with EHBA (n=11), Byler's disease (n=7) and (healthy controls (n=5). RESULTS Only mild inflammation was seen, mainly with CD4+ cells, predominantly in the portal tracts in EHBA and throughout the lobuli in Byler's disease. Neither ICAM-1 nor HLA-DR was present on the bile duct cells or hepatocytes in the control patients. The bile duct cells in all EHBA patients expressed both ICAM-1 and HLA-DR. HLA-DR was expressed on the hepatocytes in five EHBA patients, but ICAM-1 was only found on the hepatocytes in two EHBA patients. In Byler's disease the bile duct cells did not express ICAM-1 or HLA-DR, but the hepatocytes from all Byler patients expressed both ICAM-1 and HLA-DR. CONCLUSIONS Although neither EHBA nor Byler's disease is characterized by intense inflammatory cell infiltration, an aberrant expression of ICAM-1 and HLA-DR was found in the liver in both patients with EHBA and patients with Byler's disease. The expression of HLA-DR and ICAM-1, was clearly distinct between the two disorders, indicating that it is not merely an unspecific event secondary to cholestasis.
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Affiliation(s)
- U Broomé
- Department of Medicine, Huddinge and Karolinska Hospital, Stockholm, Sweden
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Dillon PW, Belchis D, Minnick K, Tracy T. Differential expression of the major histocompatibility antigens and ICAM-1 on bile duct epithelial cells in biliary atresia. TOHOKU J EXP MED 1997; 181:33-40. [PMID: 9149337 DOI: 10.1620/tjem.181.33] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Aberrant expression on biliary epithelial cells of the major histocompatibility complex (MHC) antigens in association with adhesion molecule intercellular adhesion molecule-1 (ICAM-1) may be crucial to the immunopathogenesis of biliary atresia. The patterns of MHC class I and II expression in relation to ICAM-1 expression as well as the associated lymphocyte subpopulations were studied in frozen section liver biopsies from six infants with biliary atresia. Intense ICAM-1 expression was found on all ductal epithelial cells in association with MHC I. No ductal epithelial cells demonstrated MHC II expression. Lymphocyte populations within the portal tracts all expressed LFA-1 and were predominantly CD4 positive (> 70%). CD8 positive cells accounted for less than 30%. The expression of ICAM-1 appears to be important in the pathogenesis of biliary atresia but is not linked to the expression of MHC II determinants. This result suggests that different regulatory mechanisms govern the expression of these important immunological receptors on biliary epithelial cells.
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Affiliation(s)
- P W Dillon
- Department of Surgery, Pennsylvania State University College of Medicine, Hershey 17033, USA
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Abstract
BACKGROUND/AIMS Increase of serum levels of the soluble intercellular adhesion molecules in patients with the cholestatic liver diseases primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are known and have been thought to indicate activation of the immune system and the grade of the inflammatory process. In hepatitis and cholestatic diseases, expression of adhesion molecules was found on the surface of bile duct epithelia and hepatocytes. MATERIALS AND METHODS Serum levels of sICAM-1 in patients with intrahepatic cholestasis in PBC (n = 42) and extrahepatic cholestasis (n = 18) due to choledocholithiasis were investigated. sICAM-1 levels and "classical" cholestasis parameters as alkaline phosphatase (ALP), gamma-glutamyl-transpeptidase (gamma-GTP) and bilirubin levels were compared. Furthermore, sICAM-1 concentrations and "classical" cholestasis parameters were analysed before and after therapy with ursodeoxycholic acid (UDCA). In addition, sICAM-1 was detected in serum and bile fluid of four patients with cholestasis due to choledocholithiasis. Soluble ICAM-1 levels in sera and, if accessible, in bile fluids were determined using a commercially available ELISA system. Statistics were done by Wilcoxon's signed rank exact test and Spearman's rank correlation test. Sensitivity and specificity of cholestasis parameters and sICAM-1 concentrations was analysed by receiver operating characteristic (ROC) curves. RESULTS Increased sICAM-1 serum concentrations in a similar range were found in patients with PBC (range 251-2620 micrograms/l; median 966 micrograms/l) as well as in patients with extrahepatic cholestasis (257-2961 micrograms/l; median 760 micrograms/l) compared to healthy controls (n = 12; 220-500 micrograms/l; median 318 micrograms/l). sICAM-1 levels correlated significantly to histological stage I to IV (p < 0.001), ALP (range 107-1877 U/l; median 545 U/l; r = 0.496, p = 0.0008), bilirubin (range 0.3-26 mg/dl; median 0.8 mg/dl; r = 0.52; p < 0.0004) and gamma-GTP levels (range 43-705 U/l; median 221 U/l; r = 0.36; p = 0.02) in PBC patients. In PBC patients a histological stage III or IV (n = 21) could be predicted with high sensitivity (95%) and specificity (85%) if sICAM-1 levels were above 840 micrograms/l. After treatment of PBC patients with UDCA, sICAM-1 levels decreased significantly with decline of other "classical" cholestasis parameters. Increased sICAM-1 levels (range 257-2961, median 745 micrograms/l) in extrahepatic cholestasis correlated also significantly with serum concentrations of bilirubin (r = 0.8; p < 0.01; range 0.3-19.7, median 1.6 mg/dl), gamma-GTP (r = 0.55; p = 0.03; range 33-1401, median 179 U/l) and ALP (r = 0.61; p = 0.1; range 110-1378, median 562 U/l). sICAM-1 was detectable in bile fluid (264-919 micrograms/l) of four patients with extrahepatic cholestasis and nose-biliary catheterisation. CONCLUSIONS sICAM-1 concentrations were found to discriminate between histological stage I/II and stage III/IV of PBC with higher sensitivity and specificity than "classical" cholestasis parameters. Increased serum concentrations for sICAM-1 in intra- and in extrahepatic cholestasis and detection of sICAM-1 in the bile may indicate that sICAM-1 is eliminated through the bile. In other words, not only increased synthesis but also decreased elimination may be responsible for increased sICAM-1 serum levels in patients with cholestatic liver diseases.
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Affiliation(s)
- F Polzien
- Department of Internal Medicine, University of Göttingen, Germany
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