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      Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis

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          Abstract

          Background

          Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD).

          Materials and Methods

          CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients.

          Results

          qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74).

          Conclusions

          Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.

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          Most cited references47

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          QuPath: Open source software for digital pathology image analysis

          QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath’s flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.
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            National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report.

            The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies.
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              Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment―A consensus report from the Pulmonary Council of the ISHLT

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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                25 May 2021
                2021
                : 12
                : 661761
                Affiliations
                [1] 1 Department of Chronic Diseases and Metabolism, Katholieke Universiteit , Leuven, Belgium
                [2] 2 Department of Pathology, University Hospital Leuven , Leuven, Belgium
                [3] 3 Department of Pathology, University Medical Center Utrecht , Utrecht, Netherlands
                [4] 4 Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit , Leuven, Belgium
                [5] 5 Department of Respiratory Diseases, Lung Transplant Unit, University Hospital Leuven , Leuven, Belgium
                [6] 6 Department of Thoracic Surgery University Hospital Leuven , Leuven, Belgium
                [7] 7 Department of Cardiovascular Sciences, Katholieke Universiteit , Leuven, Belgium
                [8] 8 Department of Anesthesiology, University Hospital Leuven , Leuven, Belgium
                [9] 9 Department of Hematology, University Hospital Leuven , Leuven, Belgium
                Author notes

                Edited by: Hao Wang, Tianjin Medical University General Hospital, China

                Reviewed by: Antoine Magnan, Université de Nantes, France; Caigan Du, University of British Columbia, Canada

                *Correspondence: Robin Vos, robin.vos@ 123456uzleuven.be

                This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2021.661761
                8187127
                34122421
                f7ab8c82-6017-429b-a3c6-be25d7a653b7
                Copyright © 2021 Vanstapel, Goldschmeding, Broekhuizen, Nguyen, Sacreas, Kaes, Heigl, Verleden, De Zutter, Verleden, Weynand, Verbeken, Ceulemans, Van Raemdonck, Neyrinck, Schoemans, Vanaudenaerde and Vos

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 31 January 2021
                : 07 May 2021
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 47, Pages: 14, Words: 6015
                Categories
                Immunology
                Original Research

                Immunology
                gvhd,ras,bos,lung transplantation,fibrosis,ctgf,clad
                Immunology
                gvhd, ras, bos, lung transplantation, fibrosis, ctgf, clad

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