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Sci Rep. 2018 Feb 1;8(1):2072. doi: 10.1038/s41598-018-20370-9.

The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice.

Author information

1
Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
2
Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.
3
Department of Bioengineering, University of Pittsburgh, Swanson School of Engineering, Pittsburgh, USA.
4
Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
5
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
6
Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
7
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
8
Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA. yuj2@upmc.edu.
9
Department of Radiation Oncology, UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA. yuj2@upmc.edu.

Abstract

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.

PMID:
29391546
PMCID:
PMC5794877
DOI:
10.1038/s41598-018-20370-9
[Indexed for MEDLINE]
Free PMC Article

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