The Therapeutic Effect Of High Dose Recombinant Human Granulocyte Colony-stimulating Factor On Acute Radiation Sickness

Currently, patients under severe degree bone marrow form acute radiation sickness(ARS) can be successfully cured and long-term survival can be achieved through utilization of cytokines, especially hematopoietic growth factors(HGFs). Nevertheless, when exposure dose is >10Gy, none of the ARS victims can achieve long-term survival despite advanced therapeutic strategys including hematopoietic stem cell transplantation(HSCT).Reconstitution of hematopoietic and immune functions determines whether lethally irradiated injuries can be restored. It is widely recognized that HGFs can promote hematopoietic reconstitution. Whether an ARS patient should receive hematopoietic growth factor or HSCT treatment depends on residual hematopoietic stem cells (HSCs) in his bone marrow. If there are sufficient residual HSCs, hematopoietic growth factor treatment would be superior to HSCT, owing to the fact that exogenous hematopoietic growth factors can recuperate hematosis, and side effects of HSCT, such as multiple organ failure(MOF), can be avoided. To investigate the possible threshold dose of HGF treatment, C57BL/6 mice were exposed to 8.0Gy and rhesus macaques to 10.0Gyγ-ray radiation to establish ARS models. Therapeutic effects based on hematopoietic growth factors were observed, with the aim of providing reference data for clinic management of ARS.Murine G-CSF is 73% homologous to human counterpart, so recombinant human granulocyte colony-stimulating factor (rhG-CSF) is equipotent to mice models. Firstly, we observed therapeutic effect of high dose rhG-CSF on ARS mice exposed to 8.0Gy 60Coγray. Hematopoietic and immune measurements were simultaneously determined on 300th day post irradiation. Results showed that: 1) all animals from irradiation control group died (12.1±3.0d). On 30th and 300th day post irradiation, survival rates of animals from 1000μg/kg rhG-CSF group were 86.7% and 80%, respectively. 2) early greying of the hair was observed in some animals, which is common in mice receiving high dose irradiation. 3) colony-forming unit of spleen(CFU-S), colony forming unit (CFU) of bone marrow, peripheral blood analysis and histopathological evaluation demonstrated that hematopoietic function hasn't recovered to normal level yet, so did indexs of immune function such as peripheral blood lymphocyte subsets, reproductive activity of spleen T/B cell, ratio of spleen/ thymus to body weight. However, the high dose rhG-CSF treatment (1000μg/kg) was superior to the lower dose (250μg/kg). Moreover, we investigated therapeutic effect of high dose rhG-CSF treatment (200μg/kg) on rhesus macaques exposed to 10.0Gy 60Coγray. We found that high dose rhG-CSF could enable the rhesus macaques survival with 60% survival rate(3/5). Two irradiation control animals died of haemorrhages of intestinal tract and heart at 12th and 15th day respectively. RhG-CSF can promote the recovery of hematopoiesis, mobilize bone marrow stem cells(BMSCs) to peripheral blood(PB), and thus offer seeds for regeneration of multilineage hematopoietic cells.In summary, we found that intensive dose of rhG-CSF could not only decurtate administration time for ARS, but also accelerate recovery of hematopoiesis and improve prognosis by increasing the counts of WBC, NEUT, RET, and PLT, and mobilizing BMSCs to peripheral blood. Meanwhile, stem cells from autologous"HSCT"may spontaneously migrate to damaged tissues, differentiate, then restore the function of these damaged tissues. High dose rhG-CSF protocol may turn into new management strategy for severe ARS victims.