Cargando…
The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice
Total body irradiation (TBI) leads to dose- and tissue-specific lethality. In the current study, we demonstrate that a mitochondrion-targeted nitroxide JP4-039 given once 24 hours after 9–10 Gy TBI significantly improves mouse survival, and the recovery of intestinal barrier, differentiation and ste...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794877/ https://www.ncbi.nlm.nih.gov/pubmed/29391546 http://dx.doi.org/10.1038/s41598-018-20370-9 |
_version_ | 1783297186434383872 |
---|---|
author | Wei, Liang Leibowitz, Brian J. Epperly, Michael Bi, Cheng Li, Allen Steinman, Justin Wipf, Peter Li, Song Zhang, Lin Greenberger, Joel Yu, Jian |
author_facet | Wei, Liang Leibowitz, Brian J. Epperly, Michael Bi, Cheng Li, Allen Steinman, Justin Wipf, Peter Li, Song Zhang, Lin Greenberger, Joel Yu, Jian |
author_sort | Wei, Liang |
collection | PubMed |
description | Total body irradiation (TBI) leads to dose- and tissue-specific lethality. In the current study, we demonstrate that a mitochondrion-targeted nitroxide JP4-039 given once 24 hours after 9–10 Gy TBI significantly improves mouse survival, and the recovery of intestinal barrier, differentiation and stem cell functions. The GI-protective effects are associated with rapid and selective induction of tight junction proteins and cytokines including TGF-β, IL-10, IL-17a, IL-22 and Notch signaling long before bone marrow depletion. However, no change was observed in crypt death or the expression of prototypic pro-inflammatory cytokines such as TNF-α, IL-6 or IL-1β. Surprisingly, bone marrow transplantation (BMT) performed 24 hours after TBI improves intestinal barrier and stem cell recovery with induction of IL-10, IL-17a, IL-22, and Notch signaling. Further, BMT-rescued TBI survivors display increased intestinal permeability, impaired ISC function and proliferation, but not obvious intestinal inflammation or increased epithelial death. These findings identify intestinal epithelium as a novel target of radiation mitigation, and potential strategies to enhance ISC recovery and regeneration after accidental or medical exposures. |
format | Online Article Text |
id | pubmed-5794877 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-57948772018-02-12 The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice Wei, Liang Leibowitz, Brian J. Epperly, Michael Bi, Cheng Li, Allen Steinman, Justin Wipf, Peter Li, Song Zhang, Lin Greenberger, Joel Yu, Jian Sci Rep Article Total body irradiation (TBI) leads to dose- and tissue-specific lethality. In the current study, we demonstrate that a mitochondrion-targeted nitroxide JP4-039 given once 24 hours after 9–10 Gy TBI significantly improves mouse survival, and the recovery of intestinal barrier, differentiation and stem cell functions. The GI-protective effects are associated with rapid and selective induction of tight junction proteins and cytokines including TGF-β, IL-10, IL-17a, IL-22 and Notch signaling long before bone marrow depletion. However, no change was observed in crypt death or the expression of prototypic pro-inflammatory cytokines such as TNF-α, IL-6 or IL-1β. Surprisingly, bone marrow transplantation (BMT) performed 24 hours after TBI improves intestinal barrier and stem cell recovery with induction of IL-10, IL-17a, IL-22, and Notch signaling. Further, BMT-rescued TBI survivors display increased intestinal permeability, impaired ISC function and proliferation, but not obvious intestinal inflammation or increased epithelial death. These findings identify intestinal epithelium as a novel target of radiation mitigation, and potential strategies to enhance ISC recovery and regeneration after accidental or medical exposures. Nature Publishing Group UK 2018-02-01 /pmc/articles/PMC5794877/ /pubmed/29391546 http://dx.doi.org/10.1038/s41598-018-20370-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Wei, Liang Leibowitz, Brian J. Epperly, Michael Bi, Cheng Li, Allen Steinman, Justin Wipf, Peter Li, Song Zhang, Lin Greenberger, Joel Yu, Jian The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice |
title | The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice |
title_full | The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice |
title_fullStr | The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice |
title_full_unstemmed | The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice |
title_short | The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice |
title_sort | gs-nitroxide jp4-039 improves intestinal barrier and stem cell recovery in irradiated mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794877/ https://www.ncbi.nlm.nih.gov/pubmed/29391546 http://dx.doi.org/10.1038/s41598-018-20370-9 |
work_keys_str_mv | AT weiliang thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT leibowitzbrianj thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT epperlymichael thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT bicheng thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT liallen thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT steinmanjustin thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT wipfpeter thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT lisong thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT zhanglin thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT greenbergerjoel thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT yujian thegsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT weiliang gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT leibowitzbrianj gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT epperlymichael gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT bicheng gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT liallen gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT steinmanjustin gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT wipfpeter gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT lisong gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT zhanglin gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT greenbergerjoel gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice AT yujian gsnitroxidejp4039improvesintestinalbarrierandstemcellrecoveryinirradiatedmice |