Cargando…

HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis

BACKGROUND & AIMS: Radiation therapy in the pelvic area is associated with side effects that impact the quality of life of cancer survivors. Interestingly, the gastrointestinal tract is able to adapt to significant changes in oxygen availability, suggesting that mechanisms related to hypoxia sen...

Descripción completa

Detalles Bibliográficos
Autores principales: Toullec, Aurore, Buard, Valérie, Rannou, Emilie, Tarlet, Georges, Guipaud, Olivier, Robine, Sylvie, Iruela-Arispe, M. Luisa, François, Agnès, Milliat, Fabien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738457/
https://www.ncbi.nlm.nih.gov/pubmed/29276749
http://dx.doi.org/10.1016/j.jcmgh.2017.08.001
_version_ 1783287697471700992
author Toullec, Aurore
Buard, Valérie
Rannou, Emilie
Tarlet, Georges
Guipaud, Olivier
Robine, Sylvie
Iruela-Arispe, M. Luisa
François, Agnès
Milliat, Fabien
author_facet Toullec, Aurore
Buard, Valérie
Rannou, Emilie
Tarlet, Georges
Guipaud, Olivier
Robine, Sylvie
Iruela-Arispe, M. Luisa
François, Agnès
Milliat, Fabien
author_sort Toullec, Aurore
collection PubMed
description BACKGROUND & AIMS: Radiation therapy in the pelvic area is associated with side effects that impact the quality of life of cancer survivors. Interestingly, the gastrointestinal tract is able to adapt to significant changes in oxygen availability, suggesting that mechanisms related to hypoxia sensing help preserve tissue integrity in this organ. However, hypoxia-inducible factor (HIF)-dependent responses to radiation-induced gut toxicity are unknown. Radiation-induced intestinal toxicity is a complex process involving multiple cellular compartments. Here, we investigated whether epithelial or endothelial tissue-specific HIF-1α deletion could affect acute intestinal response to radiation. METHODS: Using constitutive and inducible epithelial or endothelial tissue-specific HIF-1α deletion, we evaluated the consequences of epithelial or endothelial HIF-1α deletion on radiation-induced enteritis after localized irradiation. Survival, radiation-induced tissue injury, molecular inflammatory profile, tissue hypoxia, and vascular injury were monitored. RESULTS: Surprisingly, epithelium-specific HIF-1α deletion does not alter radiation-induced intestinal injury. However, irradiated VECad-Cre(+/-)HIF-1α(FL/FL) mice present with lower radiation-induced damage, showed a preserved vasculature, reduced hypoxia, and reduced proinflammatory response compared with irradiated HIF-1α(FL/FL) mice. CONCLUSIONS: We demonstrate in vivo that HIF-1α impacts radiation-induced enteritis and that this role differs according to the targeted cell type. Our work provides a new role for HIF-1α and endothelium-dependent mechanisms driving inflammatory processes in gut mucosae. Results presented show that effects on normal tissues have to be taken into account in approaches aiming to modulate hypoxia or hypoxia-related molecular mechanisms.
format Online
Article
Text
id pubmed-5738457
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Elsevier
record_format MEDLINE/PubMed
spelling pubmed-57384572017-12-22 HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis Toullec, Aurore Buard, Valérie Rannou, Emilie Tarlet, Georges Guipaud, Olivier Robine, Sylvie Iruela-Arispe, M. Luisa François, Agnès Milliat, Fabien Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Radiation therapy in the pelvic area is associated with side effects that impact the quality of life of cancer survivors. Interestingly, the gastrointestinal tract is able to adapt to significant changes in oxygen availability, suggesting that mechanisms related to hypoxia sensing help preserve tissue integrity in this organ. However, hypoxia-inducible factor (HIF)-dependent responses to radiation-induced gut toxicity are unknown. Radiation-induced intestinal toxicity is a complex process involving multiple cellular compartments. Here, we investigated whether epithelial or endothelial tissue-specific HIF-1α deletion could affect acute intestinal response to radiation. METHODS: Using constitutive and inducible epithelial or endothelial tissue-specific HIF-1α deletion, we evaluated the consequences of epithelial or endothelial HIF-1α deletion on radiation-induced enteritis after localized irradiation. Survival, radiation-induced tissue injury, molecular inflammatory profile, tissue hypoxia, and vascular injury were monitored. RESULTS: Surprisingly, epithelium-specific HIF-1α deletion does not alter radiation-induced intestinal injury. However, irradiated VECad-Cre(+/-)HIF-1α(FL/FL) mice present with lower radiation-induced damage, showed a preserved vasculature, reduced hypoxia, and reduced proinflammatory response compared with irradiated HIF-1α(FL/FL) mice. CONCLUSIONS: We demonstrate in vivo that HIF-1α impacts radiation-induced enteritis and that this role differs according to the targeted cell type. Our work provides a new role for HIF-1α and endothelium-dependent mechanisms driving inflammatory processes in gut mucosae. Results presented show that effects on normal tissues have to be taken into account in approaches aiming to modulate hypoxia or hypoxia-related molecular mechanisms. Elsevier 2017-08-16 /pmc/articles/PMC5738457/ /pubmed/29276749 http://dx.doi.org/10.1016/j.jcmgh.2017.08.001 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Research
Toullec, Aurore
Buard, Valérie
Rannou, Emilie
Tarlet, Georges
Guipaud, Olivier
Robine, Sylvie
Iruela-Arispe, M. Luisa
François, Agnès
Milliat, Fabien
HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis
title HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis
title_full HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis
title_fullStr HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis
title_full_unstemmed HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis
title_short HIF-1α Deletion in the Endothelium, but Not in the Epithelium, Protects From Radiation-Induced Enteritis
title_sort hif-1α deletion in the endothelium, but not in the epithelium, protects from radiation-induced enteritis
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738457/
https://www.ncbi.nlm.nih.gov/pubmed/29276749
http://dx.doi.org/10.1016/j.jcmgh.2017.08.001
work_keys_str_mv AT toullecaurore hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT buardvalerie hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT rannouemilie hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT tarletgeorges hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT guipaudolivier hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT robinesylvie hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT iruelaarispemluisa hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT francoisagnes hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis
AT milliatfabien hif1adeletionintheendotheliumbutnotintheepitheliumprotectsfromradiationinducedenteritis