There is still a need for better protection against or mitigation of the effects of ionizing radiation following conventional radiotherapy or accidental exposure. The objective of our current study was to investigate the possible roles of matrix metalloproteinase inhibitor, ilomastat, in the protection of mice from total body radiation (TBI), and the underlying protective mechanisms. Ilomastat treatment increased the survival of mice after TBI. Ilomastat pretreatment promoted recovery of hematological and immunological cells in mice after 6 Gy γ-ray TBI. Our findings suggest the potential of ilomastat to protect against or mitigate the effects of radiation.
Acute Radiation Syndrome ; blood ; immunology ; prevention & control ; Animals ; Blood Cells ; drug effects ; radiation effects ; Dose-Response Relationship, Drug ; Gamma Rays ; adverse effects ; Hydroxamic Acids ; therapeutic use ; Indoles ; therapeutic use ; Matrix Metalloproteinase Inhibitors ; therapeutic use ; Mice ; Radiation Injuries, Experimental ; blood ; immunology ; prevention & control ; Radiation-Protective Agents ; therapeutic use ; Spleen ; drug effects ; immunology ; radiation effects ; Survival Analysis ; Whole-Body Irradiation

OBJECTIVEThe purpose of the present study was to observe the changes in CD4+CD25+Nrp1+Treg cells after irradiation with different doses and explore the possible molecular mechanisms involved.

METHODSICR mice and mouse lymphoma cell line (EL-4 cells) was used. The expressions of CD4, CD25, Nrp1, calcineurin and PKC-α were detected by flow cytometry. The expressions of TGF-β1, IL-10, PKA and cAMP were estimated with ELISA.

RESULTSAt 12 h after irradiation, the expression of Nrp1 increased significantly in 4.0 Gy group, compared with sham-irradiation group (P<0.05) in the spleen and thymus, respectively, when ICR mice received whole-body irradiation (WBI). Meanwhile the synthesis of Interleukin 10 (IL-10) and transforming growth factor-β1 (TGF-β1) increased significantly after high dose irradiation (HDR) (> or = 1.0 Gy). In addition, the expression of cAMP and PKA protein increased, while PKC-α, calcineurin decreased at 12h in thymus cells after 4.0 Gy X-irradiation. While TGF-β1 was clearly inhibited when the PLC-PIP2 signal pathway was stimulated or the cAMP-PKA signal pathway was blocked after 4.0 Gy X-irradiation, this did not limit the up-regulation of CD4+CD25+Nrp1+Treg cells after ionizing radiation.

CONCLUSIONThese results indicated that HDR might induce CD4+CD25+Nrp1+Treg cells production and stimulate TGF-β1 secretion by regulating signal molecules in mice.

Animals ; Calcineurin ; genetics ; metabolism ; Cyclic AMP ; metabolism ; Dose-Response Relationship, Radiation ; Female ; Gene Expression Regulation ; radiation effects ; Immunosuppression ; Interleukin-10 ; genetics ; metabolism ; Lymphocyte Subsets ; physiology ; Male ; Mice ; Neuropilin-1 ; genetics ; metabolism ; Phosphoinositide Phospholipase C ; genetics ; metabolism ; Protein Kinases ; genetics ; metabolism ; Signal Transduction ; Transforming Growth Factor beta ; genetics ; metabolism ; Whole-Body Irradiation ; adverse effects

BACKGROUNDRadiation-induced injury after accidental or therapeutic total body exposure to ionizing radiation has serious pathophysiological consequences, and currently no effective therapy exists. This study was designed to investigate whether transplantation of allogeneic murine compact bone derived-mesenchymal stem cells (CB-MSCs) could improve the survival of mice exposed to lethal dosage total body irradiation (TBI), and to explore the potential immunoprotective role of MSCs.

METHODSBALB/c mice were treated with 8 Gy TBI, and then some were administered CB-MSCs isolated from C57BL/6 mice. Survival rates and body weight were analyzed for 14 days post-irradiation. At three days post-irradiation, we evaluated IFN-γ and IL-4 concentrations; CD4(+)CD25(+)Foxp3(+) regulatory T cell (Treg) percentage; CXCR3, CCR5, and CCR7 expressions on CD3(+) T cells; and splenocyte T-bet and GATA-3 mRNA levels. CB-MSC effects on bone marrow hemopoiesis were assessed via colony-forming unit granulocyte/macrophage (CFU-GM) assay.

RESULTSAfter lethal TBI, compared to non-transplanted mice, CB-MSC-transplanted mice exhibited significantly increased survival, body weight, and CFU-GM counts of bone marrow cells (P < 0.05), as well as higher Treg percentages, reduced IFN-γ, CXCR3 and CCR5 down-regulation, and CCR7 up-regulation. CB-MSC transplantation suppressed Th1 immunity. Irradiated splenocytes directly suppressed CFU-GM formation from bone marrow cells, and CB-MSC co-culture reversed this inhibition.

CONCLUSIONAllogeneic CB-MSC transplantation attenuated radiation-induced hematopoietic toxicity, and provided immunoprotection by alleviating lymphocyte-mediated CFU-GM inhibition, expanding Tregs, regulating T cell chemokine receptor expressions, and skewing the Th1/Th2 balance toward anti-inflammatory Th2 polarization.

Animals ; Bone and Bones ; cytology ; Cytokines ; metabolism ; Female ; Granulocyte-Macrophage Progenitor Cells ; cytology ; Male ; Mesenchymal Stem Cell Transplantation ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Whole-Body Irradiation ; adverse effects

The purpose of the study was to investigate the influencing factors of mortality rate in the bone marrow transplantation in mice. The recipient mice receiving whole-body irradiation of gamma-ray were infused with the same strain of bone marrow cells or the mixture of the bone marrow cells and splenocytes respectively. Experiments were carried out in four batches, with different strains of mice used, respectively. The manifestations and the appearance of graft-versus-host disease (GVHD) were observed, as well as the mortality rate within 35 d of the transplantation in the recipient mice. The mortality rate of the first group of recipient mice was the lowest, the mortality rate of the second group of recipient mice was the highest and the obvious GVHD performance was observed before death. In the third group, the mortality rate declined and there was statistical significance compared to that of the second group. The mortality rate of the fourth group of mice was higher than that of the third group, but still lower than that of the second group of mice and there is a statistical significance. This evidence suggested that mouse genetic purity, splenocytes, the ratio of the bone marrow cells and splenocytes and the week-old of the mouse could be the important influencing factors of the mortality rate in mouse bone marrow transplantation.
Animals ; Bone Marrow Transplantation ; adverse effects ; methods ; mortality ; Cell Transplantation ; Female ; Graft vs Host Disease ; immunology ; mortality ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred ICR ; Mice, Transgenic ; Spleen ; cytology ; Survival Rate ; Whole-Body Irradiation

OBJECTIVETo evaluate the different concentrate of tea polyphenols (TP) and its compound for irradiation-protection and investigate its mechanism.

METHODTo evaluate the radioprotective activity, mice were exposed to whole body gamma irradiation. TP 80 and TP 50 (50, 10 mg x kg(-1)) and its major constituent epigallocatechin gallate (EGCG) (50, 10 mg x kg(-1)) were administered after irradiation to examine its inhibition against irradiation-induced injury.

RESULTThis study indicate that in comparison with non-irradiated controls, irradiation resulted in a significant reduction the spleen index (spleen weight/body weight 100), haematological parameters (RBC, WBC and PLT), activity of superoxide dismutase (SOD), and increase of malondialdehde (MDA) level in 28 days. Oral administration of TP (50 mg x kg(-1)) shown the best effect on reducing the irradiation-induced injury on mice studied, and showed a protective effect against irradiation-induced haematological parameters (RBC, WBC and PLT), the spleen index and MDA level significant reduction, and antioxidase activity (SOD) decrease.

CONCLUSIONThe results suggest that TP 50 mg x kg(-1) and EGCG have in vivo antioxidant potential and radioprotective activity against whole body gamma irradiation in mice. It may be concluded that TP (50% EGCG) possess good irradiation-protective and antioxidant effect.

Animals ; Camellia sinensis ; chemistry ; Catechin ; administration & dosage ; analogs & derivatives ; Disease Models, Animal ; Female ; Flavonoids ; administration & dosage ; Humans ; Male ; Mice ; Phenols ; administration & dosage ; Plant Extracts ; administration & dosage ; Polyphenols ; Radiation Injuries ; drug therapy ; enzymology ; prevention & control ; Radiation-Protective Agents ; administration & dosage ; Random Allocation ; Superoxide Dismutase ; blood ; Whole-Body Irradiation ; adverse effects

Long-term survivors of hematopoietic stem cell transplantation (HSCT) during childhood and adolescence are at risk of developing endocrine complications. The purpose of this study was to evaluate the long-term endocrine complications and their associated risk factors among such patients. We reviewed the data from 111 patients (59 males and 52 females) who underwent HSCT at the mean age of 8.3+/-4.1 yr. Thirty patients (27.0%) had growth impairment, and seven (21.2%) out of 33 patients who attained final height reached final height below 2 standard deviation (SD). The final height SD score of the patients conditioned with total body irradiation (TBI) was significantly lower than that of the patients conditioned without TBI (-1.18+/-1.14 vs. -0.19+/-0.78, P=0.011). Thirteen patients (11.7%) developed hypothyroidism (11 subclinical, 2 central) 3.8+/-1.8 (range 1.6-6.2) yr after HSCT. Nineteen (65.5%) out of 29 females had evidence of gonadal dysfunction, and 18 (64.3%) out of 28 males had evidence of gonadal dysfunction. The risk for gonadal dysfunction was significantly higher in females conditioned with busulfan/cyclophosphamide (P=0.003). These results suggest that the majority of patients treated with HSCT during childhood and adolescence have one or more endocrine complications. Therefore, multiple endocrine functions should be monitored periodically after HSCT until they reach adult age.
Adolescent ; Adult ; Body Height ; Child ; Child, Preschool ; Endocrine System Diseases/*etiology/physiopathology ; Female ; Gonadal Disorders/etiology ; Growth Disorders/etiology ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Infant ; Male ; Thyroid Diseases/etiology ; Transplantation Conditioning/adverse effects ; Whole-Body Irradiation/adverse effects

The objective of this study was to investigate the function and mechanism of hyperbaric oxygen (HBO) in antagonizing acute graft-versus-host disease (aGVHD) and improving the rate of survival. The lethally irradiated C57BL/6 recipients were injected with bone marrow and lymphocyte of spleen from BALB/c donors and were treated with HBO, cyclosporine A (CsA) and methotrexate (MTX). T lymphocytes and subsets, adhesion molecules and cytokines were detected by flow cytometry, ELISA and RT-PCR respectively. The results showed that the survival rate in HBO group was much higher than that in allogenetic bone marrow transplantation (allo-BMT) group and CsA + MTX group; the numbers of CD3(+), CD4(+), CD8(+), CD4(+)CD11a(+), CD4(+)CD18(+), CD8(+)CD11a(+), CD8(+)CD18(+) lymphocytes in spleen were decreased markedly by HBO and CsA + MTX (p < 0.05); the levels of IL-2 and TNFalpha mRNA and their serum concentrations in HBO group were much lower than those in allo-BMT group but were higher than those in CsA + MTX group; the levels of IL-4 and IL-10 mRNA in HBO group were much higher than those in allo-BMT group and CsA + MTX group. It is concluded that HBO has more remarkable advantage in improving the rate of survival than CsA + MTX, its mechanism of anti-aGVHD is tightly correlated with the transform of T cell and its subsets and the expression of adhesion molecules and cytokines.
Acute Disease ; Animals ; Bone Marrow Transplantation ; adverse effects ; Cytokines ; biosynthesis ; Female ; Graft vs Host Disease ; etiology ; therapy ; Hyperbaric Oxygenation ; Lymphocyte Transfusion ; adverse effects ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; T-Lymphocytes ; immunology ; Whole-Body Irradiation

This study was aimed to investigate a new method of avoiding graft-vs-host disease (GVHD) through selective elimination of alloreactive donor lymphocytes by using total body irradiation (TBI) and cyclophosphamide (Cy). Female (BALB/c x C57BL/6) F1 mice (H-2(d/b)) as recipients received (60)Co gamma-ray sublethal TBI of 4 Gy on day 0 followed by being inoculated with P388D1 leukemia cell line on day 1, injection of allogeneic splenocytes from C57BL/6 male mice (H-2(b)) was carried out for induction of graft-vs-leukemia (GVL) effect prior to stem cell transplantation (SCT), intraperitoneally injection of cyclophosphamide (Cy) (200 mg/kg) and TBI (9 Gy) was given on day 6. One day later, treated mice were rescued with bone marrow hematopoietic stem cells from (BALB/c x C57BL/6) F1 male mice (H-2(d/b)). The results showed that recipients had no occurrence of leukemia and GVHD through selective elimination of alloreactive donor lymphocytes by Cy and TBI, survived more than 210 days, the complete-donor chimerism occurred on day 21 after transplantation. The ratio of chimerism descended subsequently, but still displayed mixed-chimerism at 90 days. Control mice died of GVHD, leukemia or other death-related-transplantation within 20 to 36 days (P<0.01). It is concluded that to induce GVL effects by MHC mismatched splenocytes given before syngeneic bone marrow transplantation followed by selective elimination of alloreactive donor lymphocytes through TBI and Cy, graft-vs-host disease was thus avoided.
Animals ; Cyclophosphamide ; therapeutic use ; Female ; Graft vs Host Disease ; prevention & control ; Graft vs Tumor Effect ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Leukemia P388 ; therapy ; Lymphocyte Depletion ; Lymphocytes ; immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Whole-Body Irradiation

This study was aimed to explore whether the graft-versus-host disease (GVHD) could be alleviated by intra-bone marrow (IBM) infusion of allogeneic hematopoietic stem cells. Female C57BL/6 mice as recipients received total body irradiation (TBI) 4 Gy on day 0, followed by injection of peripheral hematopoietic stem cells (1 x 10(7)) from mobilized male BALB/c with granulocyte-colony stimulating factor (rhG-CSF), and cyclophosphamide (200 mg/kg) was injected intraperitoneally two days later. The results showed that the incidence and severity of GVHD were more low and alleviative in group IBM-PBSCT than that in group TV-PBSCT (p < 0.05). Y chromosome of donor mice could be detected in the bone marrow of recipient mice. It is concluded that the method of intra-bone marrow infusion is superior to injection via the tail vein in the engraftment of hematopoietic stem cells in terms of stem cell homing while the frequency and severity of GVHD in allogeneic mice decrease.
Animals ; Cyclophosphamide ; therapeutic use ; Female ; Graft vs Host Disease ; prevention & control ; Granulocyte Colony-Stimulating Factor ; therapeutic use ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Animal ; Peripheral Blood Stem Cell Transplantation ; adverse effects ; methods ; Recombinant Proteins ; Whole-Body Irradiation

OBJECTIVETo study the radioprotective effect of catechines against radiation injury in mice.

METHODSCatechines were administered in mice intragastrically at the daily dose of 200 mg/kg for 10 consecutive days before whole body irradiation with 6 Gy X-rays. The body weight changes, survival time, 30-day survival rate, and counts of peripheral white blood cells were recorded.

RESULTSThe mice with catechine pre-treatment before X-ray exposure suffered less body weight loss than those without the treatment before exposure. Catechines markedly increased the survival time of the irradiated mice, and raised the 30-d survival rate of the irradiated mice to 53.33% as compared with the rate of 13.33% in the radiated mice without catechine pre-treatment. Catechines significantly promoted recovery of peripheral white blood cells.

CONCLUSIONCatechines have definite radioprotective effect against radiation injury in mice.

Animals ; Catechin ; pharmacology ; Female ; Leukocyte Count ; Mice ; Radiation Injuries, Experimental ; blood ; mortality ; prevention & control ; Radiation-Protective Agents ; pharmacology ; Random Allocation ; Survival Analysis ; Survival Rate ; Time Factors ; Whole-Body Irradiation ; adverse effects