| Remedy of acute radiation sickness (ARS)is the crucial step in emergency medical process of nuclear accidents, then scientist home and abroad paid much attention to it. Learning from that applying hematopoietic factors to cure hematopoietic disorder diseases induced by radiotherapy or chemotherapy to tumor, we observed some promotive effect to hematopoiesis recovery for the past few years by using hematopoietic factors on ARS patients who suffered form nuclear accidents. But because of not enough knowledge about the therapy effect and abuse of hematopoietic factors, during the therapy, it came out short effect,no effect even minus effect.Owing to the development and permeation to each other of preclinical medicine,biotechnology and clinical therapy in the present years, the level of remedy, recognition and treatment to ARS was raised obviously. The patients subjected to moderate hematopoietic ARS survived on the whole, and the patients subjected to severe hematopoietic ARS could survive on the overwhelming majority, and the infection and hemorrhage complication were not so severe. As to the extremely myeloid ARS patients, they generally needed bone marrow transplantation and could extend the survival time to some extent, but finally succumbed to multiple organ failure, none survived.Great expectations were focus on bone marrow and/or peripheral blood hematopoietic stem cell transplantation (HSCT) to extremely severe hematopoietic ARS patients, however, the results turned out not so ideal by practices. Then, through comprehensive analysis of vsARS in nuclear accidents and by literature study, we think it is a key point in ARS therapy to application cytokine reasonably for reconstitution of haematogenesis.Nevertheless, most of the accidental exposure were asymmetrical, and part of the bone marrow cells which have hematopoietic function were shielded and so free of radiation impairment, plus the hematopoietic stem cells in resting phase have some radiation resistance and so these cells can survive. Therefore, there are still some hematopoietic stem cells in the bone marrow of the patients who subjected to the accidental vsARS, and these cells are the"seeds"for reconstitution of hematopoietic function and they are the foundation for applying hematopoietic cell growth factors. When the body suffered large dose of radiation, although there was no change in endogenous hematopoietic cell growth factors, but the number of the hematopoietic cells reduced sharply, simultaneously the hematopoietic cells proliferative response to hematopoietic cell growth factors declined, so the body needed much more cytokine to stimulate hematopoiesis, thus it provided an opportunity for applying exogenous hematopoietic cell growth factors.For the purpose of reasonably applying hematopoitic factors to cure ARS patients, our laboratory systematically researched the therapy effects of rhG-CSF, rhTPO, rhIL-11, rhIL-6 and so forth on different degree of ARS on mice,beagle dog and monkey model and raised the best dosage schedule. We found that the earlier to apply the hematopoietic factors, the better hematopoietic recovery effect we could get. Basing on mentioned above, this study explored the therapeutic effect and possible mechanism when administered large single dose of rhG-CSF to mice early after irradiation. We hope to provide a new way and approach for remedy of acute radiation sickness.Firstly, we investigated the effect of early administration of large dose of rhG-CSF on survival rate and average survival time of mice which were exposed to 8.0Gy ofγray. The results indicated that early administration of large dose of rhG-CSF could effectively increase 30d survival rate of mice which were subjected to lethal dose of radiation and prolong the average survival time and show some dosage effect. But the dosage of rhG-CSF was not the higher, the better. The optimum dosage of rhG-CSF was 1.0mg/kg which may probably due to toxic and side effect of the chemokine. To improve the schedule, we explored the effect of various protocols of rhG-CSF administration on recovery of peripheral blood counts in the mice after 6.0 Gy 60Coγradiation. The results suggested a single injection of rhG-CSF (1mg/kg) at 30 minutes after irradiation was an optimal administration schedule. So we applied this schedule in the afterward study.Then, we further researched the effect of a single injection of rhG-CSF at various doses (0.25,0.5 and 1 mg/kg) on peripheral blood counts and bone marrow nucleated cell counts of irradiated mice . The results shown that a single injection of rhG-CSF at large dose accelerated platelet(PLT), red blood cell (RBC), and white blood cell (WBC) recovery in a dose-dependent fashion.The results mentioned above indicated that early administration of large single dose of rhG-CSF could protect and promote the self rudimental bone marrow hematopoietic stem cells proliferation and further mature. But whether large dose of rhG-CSF would cause exhaustion of hematopoietic stem cells and affect the long-term hematopoietic function when it induced hematopoietic stem cells proliferation and differentiation? So in order to verify the security of early administration of large single dose of rhG-CSF, we designed twice irradiated (both 6Gy) mice model, and investigated the effect of early administration of large single dose of rhG-CSF on the recovery of haematogenesis. The results turned out that the recovery of hemogram in rhG-CSF treatment group was faster than that in control group, indicating that early administration of large single dose of rhG-CSF would not cause exhaustion of hematopoietic stem cells, except to promote the recovery of the short time hematopoietic function, it could also improve the long-term recovery of haematogenesis.After determine the therapeutic effect of early administration of large single dose of rhG-CSF onγray irradiated mice, we went on to explore the possible mechanism. The study found out that (1) A single injection of rhG-CSF at large doses could greatly improve the recovery of hemogram in the nonmyeloablative bone marraw transplanted mice. (2)A single injection of rhG-CSF at large doses could also promote the implantation of exogenous stem cells into the transplanted mice, indicating that rhG-CSF could protect and support both exogenous and endogenous stem cells.Thus, we presumed a single injection of rhG-CSF at large doses may probably promote the recovery of blood producing function by improve the bone marrow hematopoietc microenvironment. But, two other kind of cytokine, SCF and IL-11, which were usually applied in ARS experimental therapy had no such effect. (3) The effect of AMD3100 (antagonist of CXCR4) on recovery of hemogram in irradiated mice was different from the rhG-CSF. AMD3100 had transient white blood cell mobilization early after administration, but no else effect afterwards. This indicated that rhG-CSF promoted the recovery of hematopoietc function in irradiated mice may not though mobilization mechanism.All the results show that (1) Early administration of rhG-CSF at large dose can greatly improve the survival rate and prolong the survival time of lethal irradiated mice. (2) A single injection of rhG-CSF (1mg/kg) at 30 minutes after irradiation was an optimal administration schedule. (3) A single early injection of rhG-CSF (1mg/kg) can promote the recovery of hematopoietic function in 6.0 Gy 60Coγray irradiated mice. (4) A single early injection of rhG-CSF (1mg/kg) also enhance the recovery of hematopoietic function in bone marraw transplanted mice. (5) To some extent, rhG-CSF can advance the implantation of stem cells into bone marraw transplanted mice. (6) The commonly used mobilizing agent AMD3100, different from rhG-CSF, has transient white blood cell mobilization in 60Coγray irradiated mice, but has no effect on the recovery of peripheral blood.This study indicates that a single early injection of rhG-CSF (1mg/kg) has good therapeutic effect on 60Coγray irradiated mice and provides a new way and experimental basis for the treatment of ARS.
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