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Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin

OBJECTIVE: Dysregulated repair following epithelial injury is a key forerunner of disease in many organs, and the acquisition of a mesenchymal phenotype by the injured epithelial cells (epithelial to mesenchymal transition, EMT) may serve as a source of fibrosis. The macrolide antibiotic azithromyci...

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Autores principales: Banerjee, Balarka, Musk, Michael, Sutanto, Erika N., Yerkovich, Stephanie T., Hopkins, Peter, Knight, Darryl A., Lindsey-Temple, Suzanna, Stick, Stephen M., Kicic, Anthony, Chambers, Daniel C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528745/
https://www.ncbi.nlm.nih.gov/pubmed/23284981
http://dx.doi.org/10.1371/journal.pone.0052309
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author Banerjee, Balarka
Musk, Michael
Sutanto, Erika N.
Yerkovich, Stephanie T.
Hopkins, Peter
Knight, Darryl A.
Lindsey-Temple, Suzanna
Stick, Stephen M.
Kicic, Anthony
Chambers, Daniel C.
author_facet Banerjee, Balarka
Musk, Michael
Sutanto, Erika N.
Yerkovich, Stephanie T.
Hopkins, Peter
Knight, Darryl A.
Lindsey-Temple, Suzanna
Stick, Stephen M.
Kicic, Anthony
Chambers, Daniel C.
author_sort Banerjee, Balarka
collection PubMed
description OBJECTIVE: Dysregulated repair following epithelial injury is a key forerunner of disease in many organs, and the acquisition of a mesenchymal phenotype by the injured epithelial cells (epithelial to mesenchymal transition, EMT) may serve as a source of fibrosis. The macrolide antibiotic azithromycin and the DNA synthesis inhibitor mycophenolate are in clinical use but their mechanism of action remains unknown in post-transplant bronchiolitis obliterans syndrome (BOS). Here we determined if regional variation in the EMT response to TGFβ1 underlies the bronchiolocentric fibrosis leading to BOS and whether EMT could be inhibited by azithromycin or mycophenolate. METHODS/RESULTS: We found that small and large airway epithelial cells from stable lung transplant patients underwent EMT when stimulated with TGFβ1, however mesenchymal protein expression was higher and loss of epithelial protein expression more complete in small airway epithelial cells. This regional difference was not mediated by changes in expression of the TGFβRII or Smad3 activation. Azithromycin potentially inhibited EMT in both small and large airway epithelial cells by inhibiting Smad3 expression, but not activation. CONCLUSION: Collectively, these observations provide a biologic basis for a previously unexplained but widely observed clinical phenomena, and a platform for the development of new approaches to fibrotic diseases.
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spelling pubmed-35287452013-01-02 Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin Banerjee, Balarka Musk, Michael Sutanto, Erika N. Yerkovich, Stephanie T. Hopkins, Peter Knight, Darryl A. Lindsey-Temple, Suzanna Stick, Stephen M. Kicic, Anthony Chambers, Daniel C. PLoS One Research Article OBJECTIVE: Dysregulated repair following epithelial injury is a key forerunner of disease in many organs, and the acquisition of a mesenchymal phenotype by the injured epithelial cells (epithelial to mesenchymal transition, EMT) may serve as a source of fibrosis. The macrolide antibiotic azithromycin and the DNA synthesis inhibitor mycophenolate are in clinical use but their mechanism of action remains unknown in post-transplant bronchiolitis obliterans syndrome (BOS). Here we determined if regional variation in the EMT response to TGFβ1 underlies the bronchiolocentric fibrosis leading to BOS and whether EMT could be inhibited by azithromycin or mycophenolate. METHODS/RESULTS: We found that small and large airway epithelial cells from stable lung transplant patients underwent EMT when stimulated with TGFβ1, however mesenchymal protein expression was higher and loss of epithelial protein expression more complete in small airway epithelial cells. This regional difference was not mediated by changes in expression of the TGFβRII or Smad3 activation. Azithromycin potentially inhibited EMT in both small and large airway epithelial cells by inhibiting Smad3 expression, but not activation. CONCLUSION: Collectively, these observations provide a biologic basis for a previously unexplained but widely observed clinical phenomena, and a platform for the development of new approaches to fibrotic diseases. Public Library of Science 2012-12-21 /pmc/articles/PMC3528745/ /pubmed/23284981 http://dx.doi.org/10.1371/journal.pone.0052309 Text en © 2012 Banerjee et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Banerjee, Balarka
Musk, Michael
Sutanto, Erika N.
Yerkovich, Stephanie T.
Hopkins, Peter
Knight, Darryl A.
Lindsey-Temple, Suzanna
Stick, Stephen M.
Kicic, Anthony
Chambers, Daniel C.
Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
title Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
title_full Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
title_fullStr Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
title_full_unstemmed Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
title_short Regional Differences in Susceptibiity of Bronchial Epithelium to Mesenchymal Transition and Inhibition by the Macrolide Antibiotic Azithromycin
title_sort regional differences in susceptibiity of bronchial epithelium to mesenchymal transition and inhibition by the macrolide antibiotic azithromycin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528745/
https://www.ncbi.nlm.nih.gov/pubmed/23284981
http://dx.doi.org/10.1371/journal.pone.0052309
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