Ionizing radiation induces ferroptosis in granulocyte-macrophage hematopoietic progenitor cells of murine bone marrow.

Purpose: To study whether radiation-induced bleeding in the bone marrow induced iron accumulation, and subsequently caused ferroptosis in granulocyte-macrophage hematopoietic progenitor cells.Materials and methods: Male mice were subjected to different doses (0, 4, 8, or 10 Gy) of gamma radiation from a 137Cs source. The changes in iron metabolism or ferroptosis-related parameters of irradiated bone marrow were accessed with biochemical, histopathological, and antibody methods. Hematocytes were detected with a hematology analyzer. The counts of granulocyte-macrophage hematopoietic progenitor cells were measured with the granulocyte-macrophage colony-forming unit.Results: Iron accumulation occurred in the bone marrow, which caused by radiation-induced hemorrhage. The iron accumulation triggered an iron regulatory protein-ferroportin 1 axis to increase serum iron levels. Using LDN193189, radiation-induced iron accumulation was demonstrated to decrease white blood cell counts at least partly through a decrease in the counts of granulocyte-macrophage hematopoietic progenitor cells. The reduction in the counts of granulocyte-macrophage hematopoietic progenitor cells was subsequently demonstrated to attribute to ferroptosis with the use of ferroptosis inhibitors and through the detection of ferroptosis related-parameters. The survival rate of irradiated mice was improved using Ferrostatin-1 or LDN193189.Conclusions: These findings suggest that radiation-induced hemorrhage in the bone marrow causes ferroptosis in granulocyte-macrophage hematopoietic progenitor cells, and anti-ferroptosis has the potential to be a radioprotective strategy to ameliorate radiation-induced hematopoietic injury.

Evaluation of potential ionizing irradiation protectors and mitigators using clonogenic survival of human umbilical cord blood hematopoietic progenitor cells.

We evaluated the use of colony formation (colony-forming unit-granulocyte macrophage [CFU-GM], burst-forming unit erythroid [BFU-E], and colony-forming unit-granulocyte-erythroid-megakaryocyte-monocytes [CFU-GEMM]) by human umbilical cord blood (CB) hematopoietic progenitor cells for testing novel small molecule ionizing irradiation protectors and mitigators. The following compounds were added before (protection) or after (mitigation) ionizing irradiation: GS-nitroxides (JP4-039 and XJB-5-131), the bifunctional sulfoxide MMS-350, the phosphoinositol-3-kinase inhibitor LY29400, triphenylphosphonium-imidazole fatty acid, the nitric oxide synthase inhibitor (MCF-201-89), the p53/mdm2/mdm4 inhibitor (BEB55), methoxamine, isoproterenol, propranolol, and the adenosine triphosphate-sensitive potassium channel blocker (glyburide). The drugs XJB-5-131, JP4-039, and MMS-350 were radiation protectors for CFU-GM. JP4-039 was also a radiation protector for CFU-GEMM. The drugs XJB-5-131, JP4-039, and MMS-350 were radiation mitigators for BFU-E, MMS-350 and JP4-039 were mitigators for CFU-GM, and MMS350 was a mitigator for CFU-GEMM. In contrast, other drugs were effective in murine assays; TTP-IOA, LY294002, MCF201-89, BEB55, propranolol, isoproterenol, methoxamine, and glyburide but showed no significant protection or mitigation in human CB assays. These data support the testing of new candidate clinical radiation protectors and mitigators using human CB clonogenic assays early in the drug discovery process, thus reducing the need for animal experiments.

Effects of 900-MHz microwave radiation on gamma-ray-induced damage to mouse hematopoietic system.

Exposure of humans simultaneously to microwave and gamma-ray irradiation may be a commonly encountered phenomenon. In a previous study data showed that low-dose microwave radiation increased the survival rate of mice irradiated with 8Gy gamma-ray; however, the mechanisms underlying these findings remain unclear. Consequently, studies were undertaken to examine the effects of microwave exposure on hematopoietic system adversely altered by gamma-ray irradiation in mice. Preexposure to low-dose microwaves attenuated the damage produced by gamma-ray irradiation as evidenced by less severe pathological alterations in bone marrow and spleen. The protective effects of microwaves were postulated to be due to up-expression of some hematopoietic growth factors, stimulation of proliferation of the granulocyte-macrophages in bone marrow, and inhibition of the gamma-ray induced suppression of hematopoietic stem cells/hematopoietic progenitor cells. Data thus indicate that prior exposure to microwaves may be beneficial in providing protection against injuries produced by gamma-ray on the hematopoietic system in mice.

Scorpion venom peptides accelerate hematopoietic recovery of myelosuppression in irradiated mice.

Sublethally irradiated mice were administered with scorpion venom peptides (SVP) or with PBS in the saline control group, 3 days before and 7 consecutive days after irradiation. Hematopoietic recovery was assessed by bone marrow (BM) cell proliferation index (PI) and colony forming unit-granulocyte/macrophage (CFU-GM), spleen weight index (SI) and thymus weight index (TI), colony-forming unit-spleen (CFU-S) and peripheral leukocyte counts. In addition, IL-1alpha and SCF levels in BM, IL-6 and GM-CSF levels in serum were determined. In SVP treated groups, PI was improved dramatically versus control mice on day 22 after irradiation. The number of CFU-GM colonies in all SVP treated groups was higher than the control groups. The difference of the number of CFU-GM colonies between SVPV group (0.2 mg/kg) and the control was significant on day 5 and 10 after irradiation (p < 0.05). SVPIV (0.2 mg/kg) could activate the CFU-S formation on day 10 after irradiation. SI was in peak value on day 15 after irradiation in all groups and the SI value of SVPV treated group was higher than control group (p < 0.05). Our results suggest that SVP may be valuable natural peptides that relieve myelosuppression caused by radiation. The effect of SVP accelerating the hematopoietic recovery was potentially through a mechanism of stimulating the release of cytokines.

[The study of low dose radiation inducing hormesis effect on hematopoietic system].

OBJECTIVE: To study the hormesis effect on hematopoietic system induced by low dose radiation. METHOD: CFU-GM and BFU-E were cultured in methylcellulose semi-solid culture system, levels of GM-CSF and IL-3 were assayed by ELISA and mRNA levels of GM-CSF, G-CSF, IL-3 by in situ hybridization, narrow line hybridization and Northern blot. RESULTS: (1) The in vitro yields of CFU-GM and BFU-E from radiated mice was higher than that from the control. (2) The serum protein level of GM-CSF increased obviously than that of controls; (3) mRNA levels of GM-CSF and G-CSF were also increased. CONCLUSION: There is hormesis effect on hematopoietic system induced by low dose radiation, which may be related to the increasing of cytokines.