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Your search keyword '"David G, Bowen"' showing total 4 results
Start Over Author "David G, Bowen" Publisher public library of science (plos)
4 results on '"David G, Bowen"'

1. CD147 mediates intrahepatic leukocyte aggregation and determines the extent of liver injury.

Author

Christine Yee, Nathan M Main, Alexandra Terry, Igor Stevanovski, Annette Maczurek, Alison J Morgan, Sarah Calabro, Alison J Potter, Tina L Iemma, David G Bowen, Golo Ahlenstiel, Fiona J Warner, Geoffrey W McCaughan, Susan V McLennan, and Nicholas A Shackel

Subjects
Medicine, Science
Abstract

BackgroundChronic inflammation is the driver of liver injury and results in progressive fibrosis and eventual cirrhosis with consequences including both liver failure and liver cancer. We have previously described increased expression of the highly multifunctional glycoprotein CD147 in liver injury. This work describes a novel role of CD147 in liver inflammation and the importance of leukocyte aggregates in determining the extent of liver injury.MethodsNon-diseased, progressive injury, and cirrhotic liver from humans and mice were examined using a mAb targeting CD147. Inflammatory cell subsets were assessed by multiparameter flow cytometry.ResultsIn liver injury, we observe abundant, intrahepatic leukocyte clusters defined as ≥5 adjacent CD45+ cells which we have termed "leukocyte aggregates". We have shown that these leukocyte aggregates have a significant effect in determining the extent of liver injury. If CD147 is blocked in vivo, these leukocyte aggregates diminish in size and number, together with a marked significant reduction in liver injury including fibrosis. This is accompanied by no change in overall intrahepatic leukocyte numbers. Further, blocking of aggregation formation occurs prior to an appreciable increase in inflammatory markers or fibrosis. Additionally, there were no observed, "off-target" or unpredicted effects in targeting CD147.ConclusionCD147 mediates leukocyte aggregation which is associated with the development of liver injury. This is not a secondary effect, but a cause of injury as aggregate formation proceeds other markers of injury. Leukocyte aggregation has been previously described in inflammation dating back over many decades. Here we demonstrate that leukocyte aggregates determine the extent of liver injury.

Published
2019
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2. Circulating fibroblast activation protein activity and antigen levels correlate strongly when measured in liver disease and coronary heart disease.

Author

Shirley Uitte de Willige, Fiona M Keane, David G Bowen, Joyce J M C Malfliet, H Emma Zhang, Bharvi Maneck, Geoffrey W McCaughan, Frank W G Leebeek, Dingeman C Rijken, and Mark D Gorrell

Subjects
Medicine, Science
Abstract

BACKGROUND AND AIM:Circulating fibroblast activation protein (cFAP) is a constitutively active enzyme expressed by activated fibroblasts that has both dipeptidyl peptidase and endopeptidase activities. We aimed to assess the correlation between cFAP activity and antigen levels and to compare variations in levels. METHODS:In plasma of 465 control individuals, 368 patients with coronary heart disease (CHD) and 102 hepatitis C virus (HCV) infected patients with severe liver disease before and after liver transplant, cFAP activity levels were measured with a newly developed cFAP activity assay. In the same samples, cFAP antigen levels were measured using a commercially available cFAP ELISA. Correlation analyses between activity and antigen levels were performed by calculating Pearson's correlation coefficient (ρ). Additionally, normal ranges, determinants and differences between cohorts and between anticoagulants were investigated. RESULTS:cFAP activity and antigen levels significantly correlated in controls (ρ: 0.660, p

Published
2017
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3. Widespread GLI expression but limited canonical hedgehog signaling restricted to the ductular reaction in human chronic liver disease

Author

Jade Boland, Geoffrey W. McCaughan, Candice Alexandra Grzelak, D. Neil Watkins, Nicholas A. Shackel, Bharvi Maneck, David G. Bowen, Nicholas David Sigglekow, Devanshi Seth, Alessandra Warren, Luciano G. Martelotto, Elizabeth J. Hamson, Jinbiao Chen, Robert Cheng, B. Patkunanathan, and Janina E.E. Tirnitz-Parker

Subjects
Male, 0301 basic medicine, Immunofluorescence, lcsh:Medicine, Biochemistry, Diagnostic Radiology, Cell Signaling, Animal Cells, Leukocytes, Medicine and Health Sciences, lcsh:Science, education.field_of_study, Multidisciplinary, integumentary system, Liver Diseases, Stem Cells, Radiology and Imaging, Wnt signaling pathway, Nuclear Proteins, Middle Aged, Hedgehog signaling pathway, Cell biology, Liver, embryonic structures, Female, Cellular Types, Anatomy, Cellular Structures and Organelles, Signal transduction, Signal Transduction, Research Article, Adult, medicine.medical_specialty, Signal Inhibition, animal structures, Imaging Techniques, Population, Kruppel-Like Transcription Factors, Zinc Finger Protein Gli2, Biology, Research and Analysis Methods, 03 medical and health sciences, Tubulins, Diagnostic Medicine, Internal medicine, GLI2, medicine, Humans, Hedgehog Proteins, Cilia, Endothelium, Progenitor cell, Immunoassays, education, Hedgehog, Aged, lcsh:R, Biology and Life Sciences, Proteins, Cell Biology, Cytoskeletal Proteins, 030104 developmental biology, Endocrinology, Hepatocytes, Hedgehog Signaling, Immunologic Techniques, Gastrointestinal Imaging, lcsh:Q, Smoothened, Liver and Spleen Scan
Abstract

Canonical Hedgehog (Hh) signaling in vertebrate cells occurs following Smoothened activation/translocation into the primary cilia (Pc), followed by a GLI transcriptional response. Nonetheless, GLI activation can occur independently of the canonical Hh pathway. Using a murine model of liver injury, we previously identified the importance of canonical Hh signaling within the Pc+ liver progenitor cell (LPC) population and noted that SMO-independent, GLI-mediated signals were important in multiple Pc-ve GLI2+ intrahepatic populations. This study extends these observations to human liver tissue, and analyses the effect of GLI inhibition on LPC viability/gene expression. Human donor and cirrhotic liver tissue specimens were evaluated for SHH, GLI2 and Pc expression using immunofluorescence and qRT-PCR. Changes to viability and gene expression in LPCs in vitro were assessed following GLI inhibition. Identification of Pc (as a marker of canonical Hh signaling) in human cirrhosis was predominantly confined to the ductular reaction and LPCs. In contrast, GLI2 was expressed in multiple cell populations including Pc-ve endothelium, hepatocytes, and leukocytes. HSCs/myofibroblasts (>99%) expressed GLI2, with only 1.92% displaying Pc. In vitro GLI signals maintained proliferation/viability within LPCs and GLI inhibition affected the expression of genes related to stemness, hepatocyte/biliary differentiation and Hh/Wnt signaling. At least two mechanisms of GLI signaling (Pc/SMO-dependent and Pc/SMO-independent) mediate chronic liver disease pathogenesis. This may have significant ramifications for the choice of Hh inhibitor (anti-SMO or anti-GLI) suitable for clinical trials. We also postulate GLI delivers a pro-survival signal to LPCs whilst maintaining stemness.

Published
2017

4. Circulating fibroblast activation protein activity and antigen levels correlate strongly when measured in liver disease and coronary heart disease

Author

David G. Bowen, Fiona M. Keane, Geoffrey W. McCaughan, Mark D. Gorrell, Bharvi Maneck, H. Emma Zhang, Dingeman C. Rijken, Shirley Uitte de Willige, Frank W.G. Leebeek, Joyce J. M. C. Malfliet, and Hematology

Subjects
0301 basic medicine, RNA viruses, Physiology, medicine.medical_treatment, lcsh:Medicine, Coronary Disease, Hepacivirus, 030204 cardiovascular system & hematology, Liver transplantation, medicine.disease_cause, Vascular Medicine, Body Mass Index, Liver disease, 0302 clinical medicine, Fibroblast activation protein, alpha, Fibrosis, Animal Cells, Blood plasma, Medicine and Health Sciences, Coronary Heart Disease, Enzyme-Linked Immunoassays, lcsh:Science, Pathology and laboratory medicine, Connective Tissue Cells, 2. Zero hunger, Multidisciplinary, Hepatitis C virus, Serine Endopeptidases, Medical microbiology, Middle Aged, Hepatitis C, 3. Good health, Body Fluids, Blood, Infectious Diseases, Liver, Connective Tissue, Gelatinases, Viruses, Anatomy, Cellular Types, Pathogens, Research Article, Adult, medicine.medical_specialty, Infectious Disease Control, Adolescent, Cardiology, Surgical and Invasive Medical Procedures, Enzyme-Linked Immunosorbent Assay, Biology, Research and Analysis Methods, Microbiology, Blood Plasma, Citric Acid, 03 medical and health sciences, Digestive System Procedures, Sex Factors, Internal medicine, Endopeptidases, medicine, Humans, Immunoassays, Edetic Acid, Transplantation, Flaviviruses, lcsh:R, Case-control study, Organisms, Viral pathogens, Biology and Life Sciences, Anticoagulants, Membrane Proteins, Organ Transplantation, Cell Biology, Fibroblasts, medicine.disease, Hepatitis viruses, Liver Transplantation, Microbial pathogens, 030104 developmental biology, Endocrinology, Biological Tissue, Case-Control Studies, Immunology, Immunologic Techniques, lcsh:Q, Body mass index, Biomarkers, Developmental Biology
Abstract

Background and aim Circulating fibroblast activation protein (cFAP) is a constitutively active enzyme expressed by activated fibroblasts that has both dipeptidyl peptidase and endopeptidase activities. We aimed to assess the correlation between cFAP activity and antigen levels and to compare variations in levels. Methods In plasma of 465 control individuals, 368 patients with coronary heart disease (CHD) and 102 hepatitis C virus (HCV) infected patients with severe liver disease before and after liver transplant, cFAP activity levels were measured with a newly developed cFAP activity assay. In the same samples, cFAP antigen levels were measured using a commercially available cFAP ELISA. Correlation analyses between activity and antigen levels were performed by calculating Pearson’s correlation coefficient (ρ). Additionally, normal ranges, determinants and differences between cohorts and between anticoagulants were investigated. Results cFAP activity and antigen levels significantly correlated in controls (ρ: 0.660, p

Published
2017

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