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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Radiation Syndrome / drug therapy*
  • Acute Radiation Syndrome / therapy
  • Adult Stem Cells / cytology
  • Adult Stem Cells / physiology
  • Adult Stem Cells / radiation effects*
  • Animals
  • Bone Marrow Transplantation
  • Cell Differentiation
  • Cell Proliferation
  • Cytokines / metabolism
  • Female
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / radiation effects*
  • Mice
  • Mice, Inbred C57BL
  • Nitrogen Oxides / pharmacology*
  • Nitrogen Oxides / therapeutic use
  • Radiation-Protective Agents / pharmacology*
  • Radiation-Protective Agents / therapeutic use
  • Tight Junction Proteins / metabolism


  • Cytokines
  • JP4-039
  • Nitrogen Oxides
  • Radiation-Protective Agents
  • Tight Junction Proteins