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      Identification of novel target genes in human lung tissue involved in chronic obstructive pulmonary disease

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          Abstract

          Introduction

          As part of a study aimed at illuminating at least some of the complex molecular events taking place in COPD, we screened tissues by means of transcriptome analyses.

          Materials and methods

          Tissues were subjected to transcriptome analysis. Candidate genes were identified and validated by immunohistochemistry. Primary human lung cells were subjected to stimulation with cigarette smoke extract for further validation by real time PCR.

          Results

          Six candidate genes were selected for further investigations: Aquaporin 3 ( AQP3), extracellular matrix protein 1 ( ECM1), four and a half LIM domain 1 ( FHL1), milk fat globule epidermal growth factor 8 ( MFGE8, lactadherin), phosphodiesterase 4D-interacting protein ( PDE4DIP), and creatine transporter SLC6A8. All six proteins were allocated to distinct cell types by immunohistochemistry. Upon stimulation with cigarette smoke extract, human type II pneumocytes showed a dose-dependent down-regulation of MFGE8, while ECM1 and FHL1 also tended to be down-regulated. Although present, none of the candidates was regulated by cigarette smoke extract in primary human macrophages.

          Discussion

          MFGE8 turned out to be an interesting new candidate gene in COPD deserving further studies.

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          Most cited references 6

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          Extracellular matrix protein 1 (ECM1) is over-expressed in malignant epithelial tumors.

          The extracellular matrix protein 1 (ECM1) is a secreted protein that has been implicated with cell proliferation, angiogenesis and differentiation. In the present study, we used immunohistochemical staining to examine the expression of ECM1 in a panel of human tumors and found that it was closely correlated with some types of tumors including: invasive breast ductal carcinoma (83%), esophageal squamous carcinoma (73%), gastric cancer (88%) and colorectal cancer (78%). Significantly, ECM1expression was correlated with the metastatic properties of the tumors. Primary breast cancers that had formed metastases were 76% positive while those that had not metastasized were only 33% positive. ECM1 expression was also correlated with PCNA a marker for proliferation, but not with CD34, a marker for endothelial cells. These results indicate that ECM1 tends to be preferentially expressed by metastatic epithelial tumors.
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            Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction.

            Airway obstruction is a hallmark of allergic asthma and is caused primarily by airway smooth muscle (ASM) hypercontractility. Airway inflammation leads to the release of cytokines that enhance ASM contraction by increasing ras homolog gene family, member A (RhoA) activity. The protective mechanisms that prevent or attenuate the increase in RhoA activity have not been well studied. Here, we report that mice lacking the gene that encodes the protein Milk Fat Globule-EGF factor 8 (Mfge8(-/-)) develop exaggerated airway hyperresponsiveness in experimental models of asthma. Mfge8(-/-) ASM had enhanced contraction after treatment with IL-13, IL-17A, or TNF-α. Recombinant Mfge8 reduced contraction in murine and human ASM treated with IL-13. Mfge8 inhibited IL-13-induced NF-κB activation and induction of RhoA. Mfge8 also inhibited rapid activation of RhoA, an effect that was eliminated by an inactivating point mutation in the RGD integrin-binding site in recombinant Mfge8. Human subjects with asthma had decreased Mfge8 expression in airway biopsies compared with healthy controls. These data indicate that Mfge8 binding to integrin receptors on ASM opposes the effect of allergic inflammation on RhoA activity and identify a pathway for specific inhibition of ASM hypercontractility in asthma.
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              Aquaporin-3 potentiates allergic airway inflammation in ovalbumin-induced murine asthma

              Oxidative stress plays a pivotal role in the pathogenesis of asthma. Aquaporin-3 (AQP3) is a small transmembrane water/glycerol channel that may facilitate the membrane uptake of hydrogen peroxide (H2O2). Here we report that AQP3 potentiates ovalbumin (OVA)-induced murine asthma by mediating both chemokine production from alveolar macrophages and T cell trafficking. AQP3 deficient (AQP3−/−) mice exhibited significantly reduced airway inflammation compared to wild-type mice. Adoptive transfer experiments showed reduced airway eosinophilic inflammation in mice receiving OVA-sensitized splenocytes from AQP3−/− mice compared with wild-type mice after OVA challenge, consistently with fewer CD4+ T cells from AQP3−/− mice migrating to the lung than from wild-type mice. Additionally, in vivo and vitro experiments indicated that AQP3 induced the production of some chemokines such as CCL24 and CCL22 through regulating the amount of cellular H2O2 in M2 polarized alveolar macrophages. These results imply a critical role of AQP3 in asthma, and AQP3 may be a novel therapeutic target.
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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
                26 July 2018
                : 13
                : 2255-2259
                Affiliations
                [1 ]Pathology of the University Medical Center Schleswig-Holstein (UKSH), Campus Luebeck and Research Center Borstel, Borstel, Germany, lheinbockel@ 123456fz-borstel.de
                [2 ]Airway Research Center North (ARCN), German Center for Lung Research (DZL), Großhansdorf, Germany, lheinbockel@ 123456fz-borstel.de
                [3 ]Immunobiophysics, Research Center Borstel, Borstel, Germany
                [4 ]Pulmonary Research Institute at LungenClinic Grosshansdorf, Grosshansdorf, Germany
                [5 ]LungenClinic Grosshansdorf, Grosshansdorf, Germany
                [6 ]Institute of Human Genetics, University Medical Center Ulm, Ulm, Germany
                [7 ]Medical Clinic III, Pulmonology/Infectious Diseases, University Hospital Schleswig-Holstein, Campus Luebeck, Luebeck, Germany
                Author notes
                Correspondence: Lena Heinbockel, Pathology of the University Medical Center Schleswig-Holstein (UKSH), Campus Luebeck Research Center Borstel, Parkallee 3, D-23845 Borstel, Germany, Tel +49 453 7188 6273, Email lheinbockel@ 123456fz-borstel.de
                Article
                copd-13-2255
                10.2147/COPD.S161958
                6065552
                © 2018 Heinbockel 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

                copd, transcriptome, mfge8, cse, cigarette smoke extract, ets2

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