The Effects of p38 MAPK Inhibition Combined with G-CSF Administration on the Hematoimmune System in Mice with Irradiation Injury

Li, Deguan; Wang, Yueying; Wu, Hongying; Lu, Lu; Wang, Xiaochun; Zhang, Junling; Zhang, Heng; Fan, Saijun; Fan, Feiyue; Zhou, Daohong; Meng, Aimin

doi:10.1371/journal.pone.0062921

Cited by 15 publications

(15 citation statements)

References 31 publications

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“…1 a. Peripheral blood was obtained via the orbital sinus 1 month after 4 Gy TBI, and WBCs, platelets, and hematocrit were measured as described previously [ 25 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Twenty four male mice were divided into four groups randomly: (a) control group; (b) 4 Gy group; (c) G-CSF group; (d) G-CSF + 4 Gy group. Mice from G-CSF + 4 Gy group and 4 Gy group were exposure to 4 Gy γ-rays (dose rate:1.08 Gy per minute) using an Exposure Instrument Cammacell-40 (Atomic Energy of Canada Lim), and then administered with G-CSF or vehicle (saline in 100 ul volume) twice a day for 7 days with intraperitoneal injections at an dose of 1 μg/mouse [ 25 , 39 ]. The mice from G-CSF group and control group were not exposure to irradiation, and were treated in a manner similar to that described above.…”

Section: Methodsmentioning

confidence: 99%

“…The numbers of peripheral blood cells included white blood cells (WBCs), red blood cells, platelets, and the hemoglobin (HGB) were measured by an MEK-7222 K (Nihonkohden, Japan). BM cells were harvested as previously described [ 25 ]. The number of viable BMNCs was counted and expressed as ×10 7 /femur.…”

Section: Methodsmentioning

confidence: 99%

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Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation

Lu²,

Zhang

et al. 2015

Cell Biosci

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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.

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“…1 a. Peripheral blood was obtained via the orbital sinus 1 month after 4 Gy TBI, and WBCs, platelets, and hematocrit were measured as described previously [ 25 ]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation

Lu²,

Zhang

et al. 2015

Cell Biosci

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“…In this study, we first confirmed that MLA could increase the survival rate of mice exposed to 7.2 Gy total body irradiation (TBI). Second, we examined the protective effects of MLA on the hematopoietic system in mice exposed to 6 Gy TBI, which could result in virtually no lethality for up to 30 days post-irradiation [ 14 ]. Finally, we investigated the mechanism by which MLA provides protection against IR injury.…”

Section: Introductionmentioning

confidence: 99%

The Protective Effects of 5-Methoxytryptamine-α-lipoic Acid on Ionizing Radiation-Induced Hematopoietic Injury

Tian

Tang

et al. 2016

IJMS

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Antioxidants are prospective radioprotectors because of their ability to scavenge radiation-induced reactive oxygen species (ROS). The hematopoietic system is widely studied in radiation research because of its high radiosensitivity. In the present study, we describe the beneficial effects of 5-methoxytryptamine-α-lipoic acid (MLA), which was synthesized from melatonin and α-lipoic acid, against radiation-induced hematopoietic injury. MLA administration significantly enhanced the survival rate of mice after 7.2 Gy total body irradiation. The results showed that MLA not only markedly increased the numbers and clonogenic potential of hematopoietic cells but also decreased DNA damage, as determined by flow cytometric analysis of histone H2AX phosphorylation. In addition, MLA decreased the levels of ROS in hematopoietic cells by inhibiting NOX4 expression. These data demonstrate that MLA prevents radiation-induced hematopoietic syndrome by increasing the number and function of and by inhibiting DNA damage and ROS production in hematopoietic cells. These data suggest MLA is beneficial for the protection of radiation injuries.

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“…Previous studies have demonstrated that exposure to sub-lethal doses of 137 Cs γ ray TBI led to long-term BM suppression and induced a decrease in the peripheral blood cell counts [ 14 , 15 ]. To investigate the SB203580 treatment effects on IR-induced hematopoietic system injury, the numbers of peripheral blood cells were analyzed 80 days after 6 Gy TBI.…”

Section: Resultsmentioning

confidence: 99%

p38 MAPK Inhibitor Insufficiently Attenuates HSC Senescence Administered Long-Term after 6 Gy Total Body Irradiation in Mice

Wang

Zhang

et al. 2016

IJMS

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Senescent hematopoietic stem cells (HSCs) accumulate with age and exposure to stress, such as total-body irradiation (TBI), which may cause long-term myelosuppression in the clinic. However, the methods available for long-term myelosuppression remain limited. Previous studies have demonstrated that sustained p38 mitogen-activated protein kinases (p38 MAPK) activation in HSCs following exposure to TBI in mice and the administration of its inhibitor twenty-four hours after TBI may partially prevent long-term myelosuppression. However, long-term myelosuppression is latent and identified long after the administration of radiation. In this study, we investigated the effects of SB203580 (a small molecule inhibitor of p38 MAPK) on long-term myelosuppression induced by TBI. Mice with hematopoietic injury were injected intraperitoneally with SB203580 every other day five times beginning 70 days after 6 Gy of 137Cs γ ray TBI. Our results at 80 days demonstrated that SB203580 did not significantly improve the TBI-induced long-term reduction of peripheral blood cell and bone marrow nucleated cell (BMNC) counts, or defects in hematopoietic progenitor cells (HPCs) and HSC clonogenic function. SB203580 reduced reactive oxygen species (ROS) production and p-p38 expression; however, SB203580 had no effect on p16 expression in the HSCs of mice. In conclusion, these findings suggest that treatment with SB203580 70 days after TBI in mice inhibits the ROS-p38 oxidative stress pathway; however, it has no therapeutic effect on long-term myelosuppression induced by TBI.

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The Effects of p38 MAPK Inhibition Combined with G-CSF Administration on the Hematoimmune System in Mice with Irradiation Injury

Cited by 15 publications

References 31 publications

Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation

Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation

The Protective Effects of 5-Methoxytryptamine-α-lipoic Acid on Ionizing Radiation-Induced Hematopoietic Injury

p38 MAPK Inhibitor Insufficiently Attenuates HSC Senescence Administered Long-Term after 6 Gy Total Body Irradiation in Mice

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