Abstract
BackgroundExposure to a moderate to high dose of ionizing radiation (IR) not only causes acute radiation syndrome but also induces long-term (LT) bone marrow (BM) injury. The latter effect of IR is primarily attributed to the induction of hematopoietic stem cell (HSC) senescence. Granulocyte colony-stimulating factor (G-CSF) is the only treatment recommended to be given to radiation victims soon after IR. However, clinical studies have shown that G-CSF used to treat the leukopenia induced by radiotherapy or chemotherapy in patients can cause sustained low white blood cell counts in peripheral blood. It has been suggested that this adverse effect is caused by HSC and hematopoietic progenitor cell (HPC) proliferation and differentiation stimulated by G-CSF, which impairs HSC self-renewal and may exhaust the BM capacity to exacerbate IR-induced LT-BM injury.MethodsC57BL/6 mice were exposed to 4 Gy γ-rays of total body irradiation (TBI) at a dose-rate of 1.08 Gy per minute, and the mice were treated with G-CSF (1 μg/each by ip) or vehicle at 2 and 6 h after TBI on the first day and then twice every day for 6 days. All mice were killed one month after TBI for analysis of peripheral blood cell counts, bone marrow cellularity and long-term HSC (CD34-lineage-sca1+c-kit+) frequency. The colony-forming unit-granulocyte and macrophage (CFU-GM) ability of HPC was measured by colony-forming cell (CFC) assay, and the HSC self-renewal capacity was analyzed by BM transplantation. The levels of ROS production, the expression of phospho-p38 mitogen-activated protein kinase (p-p38) and p16INK4a (p16) mRNA in HSCs were measured by flow cytometry and RT-PCR, respectively.ResultsThe results of our studies show that G-CSF administration mitigated TBI-induced decreases in WBC and the suppression of HPC function (CFU-GM) (p < 0.05), whereas G-CSF exacerbated the suppression of long-term HSC engraftment after transplantation one month after TBI (p < 0.05); The increase in HSC damage was associated with increased ROS production, activation of p38 mitogen-activated protein kinase (p38), induction of senescence in HSCs.ConclusionOur findings suggest that although G-CSF administration can reduce ARS, it can also exacerbate TBI-induced LT-BM injury in part by promoting HSC senescence via the ROS-p38-p16 pathway.
Highlights
Exposure to a moderate to high dose of ionizing radiation (IR) causes acute radiation syndrome and induces long-term (LT) bone marrow (BM) injury
Granulocyte colony-stimulating factor (G-CSF) treatment alone had no effect on peripheral blood counts compared with control mice, whereas G-CSF administration attenuated the reduction in the number of white blood cells (WBC) in 4 Gy total body irradiation (TBI) group, and it almost recovered the number of WBCs after exposure to 4 Gy TBI
There was no significant difference in the number of bone marrow mononuclear cells (BMMNCs) among all groups, as shown in Fig. 1c, suggesting that bone marrow cells recovered to normal levels 1 month after 4 Gy TBI
Summary
Exposure to a moderate to high dose of ionizing radiation (IR) causes acute radiation syndrome and induces long-term (LT) bone marrow (BM) injury. The latter effect of IR is primarily attributed to the induction of hematopoietic stem cell (HSC) senescence. Even though some irradiated patients recover from IR-induced acute myelosuppression, they may develop long-term BM injury manifested by decreasing the HSC reserves and damaging HSC selfrenewal ability subsequently. Unlike acute bone marrow suppression, residual BM damage is larvaceous, and under homeostatic conditions, patients with residual BM damage usually have a prolonged period of normal blood cell counts despite decreasing in HSC reserves. The risk of residual BM damage has been failed to consider by the seemingly normal blood cell counts and BM cellularity, especially after HGFs treatment
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.