Purpose: To examined if Mn (Ⅲ) meso-tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+), a superoxide dismutase mimetic and potent antioxidant, can mitigate TBl-induced long-term BM injury in a mouse model.Materials and methods: Male C57BL/6-Ly-5.2 mice were exposed to a sublethal dose (6.5 Gy) of total body irradiation (TBI).Six hours after TBI, they were treated with vehicle (PBS) or MnTE-2-PyP5+ (6 mg/kg) by s.c.injection and then the injection was repeated every day for 30 days.Immediately after the last injection, bone marrow (BM) cells were harvested from normal control mice and irradiated mice receiving vehicle or MnTE-2-PyP5+ treatment after euthanization.The cells were analyzed for: (1) ROS production by flow cytometry after DCF staining; (2) DNA damage by 8-OHdG and γ-H2AX immunofluorescent microscopy; (3) clonogenic function by colony-forming cell (CFC) and cobblestone area-forming cell (CAFC) assays; (4) frequencies of HSCs and hematopoietic progenitor cells (HPCs) by flow cytometry after immunostaining with antibodies against lineage markers, c-kit and Scal; and (5) expression of p 16Ink4a by real-time RT-PCR.Results: Post-TBI treatment with MnTE-2-PyP5+ significantly inhibited TBI-induced increases in ROS production and DNA damage in HSCs and HPCs.The reduction of oxidative stress was associated with a significant increase in HSC frequency and clonogenic function.In fact, the clonogenic function of HSCs from irradiated mice after MnTE-2-PyP5+ treatment was comparable to that of HSCs from normal controls on a per HSC basis, suggesting that MnTE-2-PyP5+ treatment inhibited the induction of HSC senescence by TBI.This suggestion is supported by the finding that MnTE-2-PyP5+ treatment also reduced the expression ofpl6 Ink4a mRNA in HSCs induced by TBI.Conclusions: MnTE-2-PyP5+ has the potential to be used as a therapeutic agent to mitigate TBI-induced long-term BM suppression by inhibition of IR-induced HSC senescence through the ROS-p 16 pathway.