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In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury
The pathophysiological mechanism involved in side effects of radiation therapy, and especially the role of the endothelium remains unclear. Previous results showed that plasminogen activator inhibitor-type 1 (PAI-1) contributes to radiation-induced intestinal injury and suggested that this role coul...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625166/ https://www.ncbi.nlm.nih.gov/pubmed/26510580 http://dx.doi.org/10.1038/srep15738 |
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author | Rannou, Emilie François, Agnès Toullec, Aurore Guipaud, Olivier Buard, Valérie Tarlet, Georges Mintet, Elodie Jaillet, Cyprien Iruela-Arispe, Maria Luisa Benderitter, Marc Sabourin, Jean-Christophe Milliat, Fabien |
author_facet | Rannou, Emilie François, Agnès Toullec, Aurore Guipaud, Olivier Buard, Valérie Tarlet, Georges Mintet, Elodie Jaillet, Cyprien Iruela-Arispe, Maria Luisa Benderitter, Marc Sabourin, Jean-Christophe Milliat, Fabien |
author_sort | Rannou, Emilie |
collection | PubMed |
description | The pathophysiological mechanism involved in side effects of radiation therapy, and especially the role of the endothelium remains unclear. Previous results showed that plasminogen activator inhibitor-type 1 (PAI-1) contributes to radiation-induced intestinal injury and suggested that this role could be driven by an endothelium-dependent mechanism. We investigated whether endothelial-specific PAI-1 deletion could affect radiation-induced intestinal injury. We created a mouse model with a specific deletion of PAI-1 in the endothelium (PAI-1KO(endo)) by a Cre-LoxP system. In a model of radiation enteropathy, survival and intestinal radiation injury were followed as well as intestinal gene transcriptional profile and inflammatory cells intestinal infiltration. Irradiated PAI-1KO(endo) mice exhibited increased survival, reduced acute enteritis severity and attenuated late fibrosis compared with irradiated PAI-1(flx/flx) mice. Double E-cadherin/TUNEL labeling confirmed a reduced epithelial cell apoptosis in irradiated PAI-1KO(endo). High-throughput gene expression combined with bioinformatic analyses revealed a putative involvement of macrophages. We observed a decrease in CD68(+)cells in irradiated intestinal tissues from PAI-1KO(endo) mice as well as modifications associated with M1/M2 polarization. This work shows that PAI-1 plays a role in radiation-induced intestinal injury by an endothelium-dependent mechanism and demonstrates in vivo that the endothelium is directly involved in the progression of radiation-induced enteritis. |
format | Online Article Text |
id | pubmed-4625166 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-46251662015-11-03 In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury Rannou, Emilie François, Agnès Toullec, Aurore Guipaud, Olivier Buard, Valérie Tarlet, Georges Mintet, Elodie Jaillet, Cyprien Iruela-Arispe, Maria Luisa Benderitter, Marc Sabourin, Jean-Christophe Milliat, Fabien Sci Rep Article The pathophysiological mechanism involved in side effects of radiation therapy, and especially the role of the endothelium remains unclear. Previous results showed that plasminogen activator inhibitor-type 1 (PAI-1) contributes to radiation-induced intestinal injury and suggested that this role could be driven by an endothelium-dependent mechanism. We investigated whether endothelial-specific PAI-1 deletion could affect radiation-induced intestinal injury. We created a mouse model with a specific deletion of PAI-1 in the endothelium (PAI-1KO(endo)) by a Cre-LoxP system. In a model of radiation enteropathy, survival and intestinal radiation injury were followed as well as intestinal gene transcriptional profile and inflammatory cells intestinal infiltration. Irradiated PAI-1KO(endo) mice exhibited increased survival, reduced acute enteritis severity and attenuated late fibrosis compared with irradiated PAI-1(flx/flx) mice. Double E-cadherin/TUNEL labeling confirmed a reduced epithelial cell apoptosis in irradiated PAI-1KO(endo). High-throughput gene expression combined with bioinformatic analyses revealed a putative involvement of macrophages. We observed a decrease in CD68(+)cells in irradiated intestinal tissues from PAI-1KO(endo) mice as well as modifications associated with M1/M2 polarization. This work shows that PAI-1 plays a role in radiation-induced intestinal injury by an endothelium-dependent mechanism and demonstrates in vivo that the endothelium is directly involved in the progression of radiation-induced enteritis. Nature Publishing Group 2015-10-29 /pmc/articles/PMC4625166/ /pubmed/26510580 http://dx.doi.org/10.1038/srep15738 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Rannou, Emilie François, Agnès Toullec, Aurore Guipaud, Olivier Buard, Valérie Tarlet, Georges Mintet, Elodie Jaillet, Cyprien Iruela-Arispe, Maria Luisa Benderitter, Marc Sabourin, Jean-Christophe Milliat, Fabien In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury |
title | In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury |
title_full | In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury |
title_fullStr | In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury |
title_full_unstemmed | In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury |
title_short | In vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury |
title_sort | in vivo evidence for an endothelium-dependent mechanism in radiation-induced normal tissue injury |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625166/ https://www.ncbi.nlm.nih.gov/pubmed/26510580 http://dx.doi.org/10.1038/srep15738 |
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