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

<div><p></p><p>The acute and residual (or long-term) bone marrow (BM) injury induced by ionizing radiation (IR) is a major clinic concern for patients receiving conventional radiotherapy and victims accidentally exposed to a moderate-to-high dose of IR. In this study, we investigated the effects of the treatment with the p38 inhibitor SB203580 (SB) and/or granulocyte colony-stimulating factor (G-CSF) on the hematoimmune damage induced by IR in a mouse model. Specifically, C57BL/6 mice were exposed to a sublethal dose (6 Gy) of total body irradiation (TBI) and then treated with vehicle, G-CSF, SB, and G-CSF plus SB. G-CSF (1 µg/mouse) was administrated to mice by intraperitoneal (ip) injection twice a day for six successive days; SB (15 mg/kg) by ip injection every other day for 10 days. It was found that the treatment with SB and/or G-CSF significantly enhanced the recovery of various peripheral blood cell counts and the number of BM mononuclear cells 10 and 30 days after the mice were exposed to TBI compared with vehicle treatment. Moreover, SB and/or G-CSF treatment also increased the clonogenic function of BM hematopoietic progenitor cells (HPCs) and the frequency of BM lineage<b>⁻</b>Sca1⁺c-kit⁺ cells (LSK cells) and short-term and long term hematopoietic stem cells (HSCs) 30 days after TBI, in comparison with vehicle treated controls. However, the recovery of peripheral blood B cells and CD4⁺ and CD8⁺ T cells was not significantly affected by SB and/or G-CSF treatment. These results suggest that the treatment with SB and/or G-CSF can reduce IR-induced BM injury probably in part via promoting HSC and HPC regeneration.</p></div

Effects of SB and/or G-CSF treatment on BMMNC counts.

<p>Mice were treated with ip injection of vehicle (V), SB 203580 (SB), G-CSF (CSF), or both (C+S) after exposure to 6Gy TBI as described in the Methods. A group of sham-irradiated control mice was included as a control (Ctr). BMMNCs were numerated after the mice were euthanized 10 days (A) and 30 days (B) after TBI. The data are expressed as mean± SD (n = 5). a, <i>p</i><0.05, vs. Ctr; b, <i>p</i><0.05, vs. V;c, <i>p</i><0.05, vs. CSF; d, <i>p</i><0.05, vs. SB.</p

Peripheral blood cell counts at 30d after 6Gy TBI.

<p>Mice were treated with ip injection of vehicle (V), SB 203580 (SB), G-CSF (CSF), or both (C+S) after exposure to 6Gy TBI as described in the Methods. A group of sham-irradiated control mice was included as a control (Ctr). Blood were collected after the mice were euthanized 30 days after 6Gy TBI to count various blood cells. The data are expressed as mean± SD. a, <i>p</i><0.05, vs. Ctr; b, <i>p</i><0.05, vs. V; c, <i>p</i><0.05, vs. CSF; d, <i>p</i><0.05, vs. SB.</p

Effects of SB and/or G-CSF treatment on immune organ coefficients.

<p>Mice were treated with ip injection of vehicle (V), SB 203580 (SB), G-CSF (CSF), or both (C+S) after exposure to 6Gy TBI as described in the Methods. A group of sham-irradiated control mice was included as a control (Ctr). The spleen and thymus were collected and weighted after the mice were euthanized 10 days (A,B) and 30 days(C,D) after TBI. The organ coefficients were calculated by organ weight (mg)/mice weight (g). The data are expressed as mean± SD (n = 5). a, <i>p</i><0.05, vs. Ctr; b, <i>p</i><0.05, vs. V; c, <i>p</i><0.05, vs. CSF; d, <i>p</i><0.05, vs. SB.</p