P38 MAPK抑制剂联合G-CSF对全身γ射线照射小鼠辐射损伤的实验治疗研究
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摘要
核事故受照人员以及临床上因各种疾病而接受放射治疗的患者,会出现各种辐射损伤。其中造血系统对辐射高度敏感,其辐射损伤治疗是放射病预防诊治研究中的关键,目前尚无有效治疗手段。因此研发造血系统辐射损伤预防和治疗药物具有重要的社会意义和临床价值。
P38丝裂原活化激酶(p38mitogen-activated protein kinases, p38MAPK)通路在造血细胞发育、衰老和凋亡中具有重要作用,在造血细胞受照后激活。抑制P38MAPK通路能降低造血祖干细胞的凋亡,缓解再生性障碍贫血和骨髓增生异常综合征病人的病情。SB203580(SB)为p38MAPK抑制剂,其作为辐射预防药的研究尚未见报道。
为探索p38MAPK抑制剂作为小鼠辐射损伤预防药物的可行性,我们首先进行了小鼠30天生存率实验。在小鼠接受7.2Gy全身照射前半小时腹腔注射SB(15mg/kg)一次,随后隔日给药,共给药6次。结果表明P38MAPK抑制能显著提高受照小鼠30天生存率。进行小鼠6Gy全身照射体内实验表明,SB能提高小鼠外周血及单侧股骨有核细胞计数,增强小鼠造血祖细胞增殖能力,降低骨髓细胞中活性氧(ROS)水平。本课题首次证实P38MAPK通路可能作为辐射损伤预防治疗的靶点。
粒细胞集落刺激因子(granulocyte colony-stimulating factor, G-CSF)是已经批准用于临床治疗肿瘤患者放、化疗后白细胞低下的造血细胞因子,但临床上提倡用于治疗急性放射病的G-CSF给药剂量都较小,且持续给药时间长,用于重度以上急性放射病治疗作用不明显。临床上在放疗后使用G-CSF治疗发现,G-CSF能够诱发骨髓细胞功能耗竭。因此本课题进一步开展了SB联合G—CSF对不同剂量(2,4,6Gy)γ射线全身照射小鼠造血免疫系统辐射损伤的治疗作用研究。
SB治疗组小鼠于照射后24小时第1次腹腔注射给药,以后隔天注射1次,共给药5次。G-CSF治疗组小鼠于照射后2小时和6小时后腹腔注射给药,剂量为1μg/只,以后每天注射两次,共6天。联合用药组小鼠同时腹腔注射两种药物。照射组和未照射组小鼠腹腔注射等体积的含30%DMSO的无菌对照溶液。
在小鼠接受7.2Gy全身照射后观察生存率,发现SB与G-CSF联合应用能显著提高小鼠生存率。利用粒—巨噬细胞集落形成实验(colony forming units-granulocyte-macrophage,CFU-GM)对小鼠造血祖细胞功能进行检测,发现联合用药组小鼠骨髓细胞的克隆形成能力均高于SB或者G-CSF单独用药组。利用鹅卵石样区域形成细胞实验(cobblestone area-forming cell, CAFC)检测4Gy受照小鼠骨髓造血干细胞的功能,发现联合用药组小鼠第4周CAFC数高于照射组,SB或者G-CSF单独用药组。
对SB辐射损伤保护作用机制进行初步探索。检测小鼠骨髓细胞ROS水平,发现SB,G-CSF单独给药,以及联合给药组小鼠骨髓细胞ROS水平均低于照射组小鼠。体外实验在发现SB提高受照小鼠骨髓细胞克隆能力的基础上,利用MAPK信号转导通路PCR芯片筛选出p38在辐射损伤中16个可能调节的下游靶基因。SB除抑制MAPK信号通路外,还能调节CDK4/6, CyclinD2等周期蛋白及一些转录因子的表达来起作用。
综上所述,首次发现SB作为预防药物预防辐射损伤有一定疗效,而与G-CSF联合后,可缓解G-CSF的副作用,对辐射损伤尤其4Gy全身照射小鼠具有更好的治疗效果,研究结果为开发临床放射疾病预防和治疗新方法提供了实验依据。SB可能是通过降低骨髓细胞ROS水平,提高造血系统功能来实现辐射保护作用,具体作用机制仍需进一步深入研究。
The patients received radiotherapy for various diseases in clinic and the victims of nuclear events might develop different irradiation injuries. It is well known that hematopoietic system is hypersensitive to irradiation, so hematopoietic injury is the key of the radiation protection and therapy. The prevention and therapy of hematopoietic radiation injury is very essential for the clinic and society.
P38mitogen-activated protein kinases (p38MAPK, p38) play important role in the development, senescence and apoptosis of the hematopoietic cells, and are over activated after irradiation. Inhibition of p38either with pharmacological inhibitors or by genetic approaches has been shown to reduce the severity of acquired aplastic anemia and myelodysplastic syndromes by inhibiting apoptosis of hematopoietic stem and progenitor cells. So in the present study, we discussed whether inhibition of p38with SB203580(SB) alone could prevent TBI-induced BM injury.
The feasibility of SB as radiation prevention drug was evaluated by the30-day survival rates of the mice exposed to radiation. Mice were given SB at15mg/kg via intraperitoneal injection (ip)30min before irradiation, and then thereafter every other day for a total of6injections. Our results showed that p38inhibition with SB had significant effect on the30-day survival rates of the mice exposed to7.2Gy TBI. In addition, SB could elevate the white blood cells (WBC) and bone marrow mononucleated cells (BMNCs) count, enhance the hematopoietic progenitor cells colony ability by decreasing the reactive oxygen species (ROS) levels in bone marrow cells of the mice exposed to6Gy TBI. We proved firstly that p38might be used as the targets of radioprotection.
Granulocytes colony-stimulating factor (G-CSF) has been approved to be used on the low WBCs patients caused by radio and chemo-therapy in clinic. But in clinic, the G-CSF used in acute radiation syndrome was low dosage and continued long time, had no obvious effects on patients received high irradiation doses. The clinical trials demonstrated G-CSF during radiotherapy could exhaust the bone marrow capacity, probably via promoting HSPC proliferation and differentiation to negatively affect the self-renewal of HSCs. So in the present study, we examined whether inhibition of p38with SB in combination with G-CSF can mitigate TBI-induced BM injury.For SB treatment, mice were given SB at15mg/kg via ip24h after irradiation, and then thereafter every other day for a total of5injections. For G-CSF treatment, mice were administered with G-CSF at a dose of1μg/each by ip at2h and6h after irradiation on the first day, and then twice every day for5days. For combination therapy, mice were given both SB and G-CSF as described above. As a control, mice were irradiated and then treated with vehicle in a similar manner as described for SB and/or G-CSF.
To test the effects of SB and/or G-CSF on TBI-induced lethality in mice, we first observed the survival rates of mice after exposure of them to7.2Gy TBI. Our results showed that p38inhibition with SB had no significant effect on the30-day survival rates of the mice exposed to7.2Gy TBI when it was used alone but increased the survival of the mice when it was combined with G-CSF. To determine whether SB and/or G-CSF increase hematopoiesis after TBI by stimulating hematopoietic progenitor cells, we examined the effects of SB and/or G-CSF on CFU-GM. The effect of SB plus G-CSF on CFU-GM frequencies was greater than either agent alone. The effects of SB and/or G-CSF on the hematopoietic function of mouse BM HSCs received4Gy TBI were analyzed by a CAFC assay. The effects of SB plus G-CSF on CAFC frequencies were higher than IR, SB or G-CSF alone.
The mechanism of SB radioprotection was explored. The bone marrow cells ROS levels were detected; our results suggested that SB and/or G-CSF might decrease the ROS level of bone marrow cells. SB could mitigate the CAFC ability of bone marrow cells in vitro experiments. The16genes regulated by IR and p38were screened out by Mouse MAP Kinases Signaling Pathway PCR Array. In addition to the MAPK related genes, the CDK4/6, CyclinD2cell cycle genes and other translation factors genes were also regulated by IR and SB.
In summary, SB alone showed preventive effects on the hematopoietic irradiation injury. After combined with G-CSF, the shortcomings of G-CSF were attenuated, the combination showed better therapeutic effects than each alone especially after4Gy TBI, which provides new experiments results for the development of new radiation prevention and treatment methods in clinic. SB might enhance the hematopoietic system function by decreasing bone marrow cells ROS levels to elevate the30-day survival rates of the mice exposed to7.2Gy TBI, the detailed mechanism still needed to be further explored.
P38丝裂原活化激酶(p38mitogen-activated protein kinases, p38MAPK)通路在造血细胞发育、衰老和凋亡中具有重要作用,在造血细胞受照后激活。抑制P38MAPK通路能降低造血祖干细胞的凋亡,缓解再生性障碍贫血和骨髓增生异常综合征病人的病情。SB203580(SB)为p38MAPK抑制剂,其作为辐射预防药的研究尚未见报道。
为探索p38MAPK抑制剂作为小鼠辐射损伤预防药物的可行性,我们首先进行了小鼠30天生存率实验。在小鼠接受7.2Gy全身照射前半小时腹腔注射SB(15mg/kg)一次,随后隔日给药,共给药6次。结果表明P38MAPK抑制能显著提高受照小鼠30天生存率。进行小鼠6Gy全身照射体内实验表明,SB能提高小鼠外周血及单侧股骨有核细胞计数,增强小鼠造血祖细胞增殖能力,降低骨髓细胞中活性氧(ROS)水平。本课题首次证实P38MAPK通路可能作为辐射损伤预防治疗的靶点。
粒细胞集落刺激因子(granulocyte colony-stimulating factor, G-CSF)是已经批准用于临床治疗肿瘤患者放、化疗后白细胞低下的造血细胞因子,但临床上提倡用于治疗急性放射病的G-CSF给药剂量都较小,且持续给药时间长,用于重度以上急性放射病治疗作用不明显。临床上在放疗后使用G-CSF治疗发现,G-CSF能够诱发骨髓细胞功能耗竭。因此本课题进一步开展了SB联合G—CSF对不同剂量(2,4,6Gy)γ射线全身照射小鼠造血免疫系统辐射损伤的治疗作用研究。
SB治疗组小鼠于照射后24小时第1次腹腔注射给药,以后隔天注射1次,共给药5次。G-CSF治疗组小鼠于照射后2小时和6小时后腹腔注射给药,剂量为1μg/只,以后每天注射两次,共6天。联合用药组小鼠同时腹腔注射两种药物。照射组和未照射组小鼠腹腔注射等体积的含30%DMSO的无菌对照溶液。
在小鼠接受7.2Gy全身照射后观察生存率,发现SB与G-CSF联合应用能显著提高小鼠生存率。利用粒—巨噬细胞集落形成实验(colony forming units-granulocyte-macrophage,CFU-GM)对小鼠造血祖细胞功能进行检测,发现联合用药组小鼠骨髓细胞的克隆形成能力均高于SB或者G-CSF单独用药组。利用鹅卵石样区域形成细胞实验(cobblestone area-forming cell, CAFC)检测4Gy受照小鼠骨髓造血干细胞的功能,发现联合用药组小鼠第4周CAFC数高于照射组,SB或者G-CSF单独用药组。
对SB辐射损伤保护作用机制进行初步探索。检测小鼠骨髓细胞ROS水平,发现SB,G-CSF单独给药,以及联合给药组小鼠骨髓细胞ROS水平均低于照射组小鼠。体外实验在发现SB提高受照小鼠骨髓细胞克隆能力的基础上,利用MAPK信号转导通路PCR芯片筛选出p38在辐射损伤中16个可能调节的下游靶基因。SB除抑制MAPK信号通路外,还能调节CDK4/6, CyclinD2等周期蛋白及一些转录因子的表达来起作用。
综上所述,首次发现SB作为预防药物预防辐射损伤有一定疗效,而与G-CSF联合后,可缓解G-CSF的副作用,对辐射损伤尤其4Gy全身照射小鼠具有更好的治疗效果,研究结果为开发临床放射疾病预防和治疗新方法提供了实验依据。SB可能是通过降低骨髓细胞ROS水平,提高造血系统功能来实现辐射保护作用,具体作用机制仍需进一步深入研究。
The patients received radiotherapy for various diseases in clinic and the victims of nuclear events might develop different irradiation injuries. It is well known that hematopoietic system is hypersensitive to irradiation, so hematopoietic injury is the key of the radiation protection and therapy. The prevention and therapy of hematopoietic radiation injury is very essential for the clinic and society.
P38mitogen-activated protein kinases (p38MAPK, p38) play important role in the development, senescence and apoptosis of the hematopoietic cells, and are over activated after irradiation. Inhibition of p38either with pharmacological inhibitors or by genetic approaches has been shown to reduce the severity of acquired aplastic anemia and myelodysplastic syndromes by inhibiting apoptosis of hematopoietic stem and progenitor cells. So in the present study, we discussed whether inhibition of p38with SB203580(SB) alone could prevent TBI-induced BM injury.
The feasibility of SB as radiation prevention drug was evaluated by the30-day survival rates of the mice exposed to radiation. Mice were given SB at15mg/kg via intraperitoneal injection (ip)30min before irradiation, and then thereafter every other day for a total of6injections. Our results showed that p38inhibition with SB had significant effect on the30-day survival rates of the mice exposed to7.2Gy TBI. In addition, SB could elevate the white blood cells (WBC) and bone marrow mononucleated cells (BMNCs) count, enhance the hematopoietic progenitor cells colony ability by decreasing the reactive oxygen species (ROS) levels in bone marrow cells of the mice exposed to6Gy TBI. We proved firstly that p38might be used as the targets of radioprotection.
Granulocytes colony-stimulating factor (G-CSF) has been approved to be used on the low WBCs patients caused by radio and chemo-therapy in clinic. But in clinic, the G-CSF used in acute radiation syndrome was low dosage and continued long time, had no obvious effects on patients received high irradiation doses. The clinical trials demonstrated G-CSF during radiotherapy could exhaust the bone marrow capacity, probably via promoting HSPC proliferation and differentiation to negatively affect the self-renewal of HSCs. So in the present study, we examined whether inhibition of p38with SB in combination with G-CSF can mitigate TBI-induced BM injury.For SB treatment, mice were given SB at15mg/kg via ip24h after irradiation, and then thereafter every other day for a total of5injections. For G-CSF treatment, mice were administered with G-CSF at a dose of1μg/each by ip at2h and6h after irradiation on the first day, and then twice every day for5days. For combination therapy, mice were given both SB and G-CSF as described above. As a control, mice were irradiated and then treated with vehicle in a similar manner as described for SB and/or G-CSF.
To test the effects of SB and/or G-CSF on TBI-induced lethality in mice, we first observed the survival rates of mice after exposure of them to7.2Gy TBI. Our results showed that p38inhibition with SB had no significant effect on the30-day survival rates of the mice exposed to7.2Gy TBI when it was used alone but increased the survival of the mice when it was combined with G-CSF. To determine whether SB and/or G-CSF increase hematopoiesis after TBI by stimulating hematopoietic progenitor cells, we examined the effects of SB and/or G-CSF on CFU-GM. The effect of SB plus G-CSF on CFU-GM frequencies was greater than either agent alone. The effects of SB and/or G-CSF on the hematopoietic function of mouse BM HSCs received4Gy TBI were analyzed by a CAFC assay. The effects of SB plus G-CSF on CAFC frequencies were higher than IR, SB or G-CSF alone.
The mechanism of SB radioprotection was explored. The bone marrow cells ROS levels were detected; our results suggested that SB and/or G-CSF might decrease the ROS level of bone marrow cells. SB could mitigate the CAFC ability of bone marrow cells in vitro experiments. The16genes regulated by IR and p38were screened out by Mouse MAP Kinases Signaling Pathway PCR Array. In addition to the MAPK related genes, the CDK4/6, CyclinD2cell cycle genes and other translation factors genes were also regulated by IR and SB.
In summary, SB alone showed preventive effects on the hematopoietic irradiation injury. After combined with G-CSF, the shortcomings of G-CSF were attenuated, the combination showed better therapeutic effects than each alone especially after4Gy TBI, which provides new experiments results for the development of new radiation prevention and treatment methods in clinic. SB might enhance the hematopoietic system function by decreasing bone marrow cells ROS levels to elevate the30-day survival rates of the mice exposed to7.2Gy TBI, the detailed mechanism still needed to be further explored.
引文
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