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      Differential expression of RNA-binding proteins in bronchial epithelium of stable COPD patients

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          Abstract

          Purpose

          Inflammatory gene expression is modulated by posttranscriptional regulation via RNA-binding proteins (RBPs), which regulate mRNA turnover and translation by binding to conserved mRNA sequences. Their role in COPD is only partially defined. This study evaluated RBPs tristetraprolin (TTP), human antigen R (HuR), and AU-rich element-binding factor 1 (AUF-1) expression using lung tissue from COPD patients and control subjects and probed their function in epithelial responses in vitro.

          Patients and methods

          RBPs were detected by immunohistochemistry in bronchial and peripheral lung samples from mild-to-moderate stable COPD patients and age/smoking history-matched controls; RBPs and RBP-regulated genes were evaluated by Western blot, ELISA, protein array, and real-time PCR in human airway epithelial BEAS-2B cell line stimulated with hydrogen peroxide, cytokine combination (cytomix), cigarette smoke extract (CSE), and following siRNA-mediated silencing. Results were verified in a microarray database from bronchial brushings of COPD patients and controls. RBP transcripts were measured in peripheral blood mononuclear cell samples from additional stable COPD patients and controls.

          Results

          Specific, primarily nuclear immunostaining for the RBPs was detected in structural and inflammatory cells in bronchial and lung tissues. Immunostaining for AUF-1, but not TTP or HuR, was significantly decreased in bronchial epithelium of COPD samples vs controls. In BEAS-2B cells, cytomix and CSE stimulation reproduced the RBP pattern while increasing expression of AUF-1-regulated genes, interleukin-6, CCL2, CXCL1, and CXCL8. Silencing expression of AUF-1 reproduced, but not enhanced, target upregulation induced by cytomix compared to controls. Analysis of bronchial brushing-derived transcriptomic confirmed the selective decrease of AUF-1 in COPD vs controls and revealed significant changes in AUF-1-regulated genes by genome ontology.

          Conclusion

          Downregulated AUF-1 may be pathogenic in stable COPD by altering posttranscriptional control of epithelial gene expression.

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          Most cited references 65

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          RNA regulons: coordination of post-transcriptional events.

           Jack Keene (2007)
          Recent findings demonstrate that multiple mRNAs are co-regulated by one or more sequence-specific RNA-binding proteins that orchestrate their splicing, export, stability, localization and translation. These and other observations have given rise to a model in which mRNAs that encode functionally related proteins are coordinately regulated during cell growth and differentiation as post-transcriptional RNA operons or regulons, through a ribonucleoprotein-driven mechanism. Here I describe several recently discovered examples of RNA operons in budding yeast, fruitfly and mammalian cells, and their potential importance in processes such as immune response, oxidative metabolism, stress response, circadian rhythms and disease. I close by considering the evolutionary wiring and rewiring of these combinatorial post-transcriptional gene-expression networks.
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            Immunology of asthma and chronic obstructive pulmonary disease.

             Peter Barnes (2008)
            Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive airway diseases that involve chronic inflammation of the respiratory tract, but the type of inflammation is markedly different between these diseases, with different patterns of inflammatory cells and mediators being involved. As described in this Review, these inflammatory profiles are largely determined by the involvement of different immune cells, which orchestrate the recruitment and activation of inflammatory cells that drive the distinct patterns of structural changes in these diseases. However, it is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations. This has important implications for the development of new therapies.
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              • Record: found
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              The cytokine network in asthma and chronic obstructive pulmonary disease.

               Peter Barnes (2008)
              Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases.
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                Author and article information

                Journal
                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                1176-9106
                1178-2005
                2018
                12 October 2018
                : 13
                : 3173-3190
                Affiliations
                [1 ]Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Salerno, Italy, cstellato@ 123456unisa.it
                [2 ]Interdepartmental Study Center for Inflammatory and Smoke-related Airway Diseases (CEMICEF), Cardiorespiratory and Internal Medicine Section, University of Ferrara, Ferrara, Italy
                [3 ]Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, cstellato@ 123456unisa.it
                [4 ]Department of Biomedical Sciences, Dentistry and Morphological and Functional Imaging (BIOMORF), University of Messina, Messina, Italy
                Author notes
                Correspondence: Cristiana Stellato, Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvador Allende, 84081 Baronissi, Salerno, Italy, Tel +39 08 996 5024, Email cstellato@ 123456unisa.it
                [*]

                These authors contributed equally to this work

                Article
                copd-13-3173
                10.2147/COPD.S166284
                6190813
                © 2018 Ricciardi et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Respiratory medicine

                airway epithelium, auf-1, copd, inflammation, posttranscriptional gene regulation

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