Medical Countermeasures for Radiation Combined Injury: Radiation with Burn, Blast, Trauma and/or Sepsis. Report of an NIAID Workshop, March 26–27, 2007

Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Radiation Research (Impact Factor: 2.91). 07/2008; 169(6):712-21. DOI: 10.1667/RR1295.1
Source: PubMed


Non-clinical human radiation exposure events such as the Hiroshima and Nagasaki bombings or the Chernobyl accident are often coupled with other forms of injury, such as wounds, burns, blunt trauma, and infection. Radiation combined injury would also be expected after a radiological or nuclear attack. Few animal models of radiation combined injury exist, and mechanisms underlying the high mortality associated with complex radiation injuries are poorly understood. Medical countermeasures are currently available for management of the non-radiation components of radiation combined injury, but it is not known whether treatments for other insults will be effective when the injury is combined with radiation exposure. Further research is needed to elucidate mechanisms behind the synergistic lethality of radiation combined injury and to identify targets for medical countermeasures. To address these issues, the National Institute of Allergy and Infectious Diseases convened a workshop to make recommendations on the development of animal models of radiation combined injury, possible mechanisms of radiation combined injury, and future directions for countermeasure research, including target identification and end points to evaluate treatment efficacy.

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    • "Additionally, biological factors such as age may further complicate not only the extent or development of injury, but also the strategies used to manage the consequences of single or combined insults. Given the growing worldwide threat of radiological/nuclear terrorism, the concept of radiation combined injury (RCI) has been identified as a high priority research area (Pellmar and Rockwell 2005, DiCarlo et al. 2008). "
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    ABSTRACT: Purpose: Uncontrolled radiation exposure due to radiological terrorism, industrial accidents or military circumstances is a continuing threat for the civilian population. Age plays a major role in the susceptibility to radiation; younger children are at higher risk of developing cognitive deterioration when compared to adults. Our objective was to determine if an exposure to radiation affected the vulnerability of the juvenile hippocampus to a subsequent moderate traumatic injury. Materials and methods: Three-week-old (juvenile) and eight-week-old young adult C57BL/J6 male mice received whole body cesium-137 (137Cs) irradiation with 4 gray (Gy). One month later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Two months post-irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains frozen for immunohistochemical assessment of activated microglia and neurogenesis in the hippocampal dentate gyrus. Results: All animals were able to learn the water maze task; however, treatment effects were seen when spatial memory retention was assessed. Animals that received irradiation as juveniles followed by a moderate traumatic brain injury one month later did not show spatial memory retention, i.e., were cognitively impaired. In contrast, all groups of animals that were treated as adults showed spatial memory retention in the probe trials. Conclusion: Although the mechanisms involved are not clear, our results suggest that irradiation enhanced a young animal's vulnerability to develop cognitive injury following a subsequent traumatic injury.
    International Journal of Radiation Biology 10/2013; 90(3). DOI:10.3109/09553002.2014.859761 · 1.69 Impact Factor
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    • "The few studies performed on radiation combined injury involving infection as the second insult have used common gram negative organisms such as Klebsiella pneumoniae or enteric contents using cecal ligation and puncture [4], [5], [12], [13] However, a recent National Institutes of Health consensus meeting explicitly stated that staphylococcal infections should be anticipated in the wake of a radiation event and recommended further study of IR followed by this common gram positive organism [14]. While staphylococcal infections can be sensitive or resistant to methicillin, the incidence of methicillin-resistant Staphylococcus aureus (MRSA) is becoming increasingly common [15]. "
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    ABSTRACT: World conditions place large populations at risk from ionizing radiation (IR) from detonation of dirty bombs or nuclear devices. In a subgroup of patients, ionizing radiation exposure would be followed by a secondary infection. The effects of radiation combined injury are potentially more lethal than either insult in isolation. The purpose of this study was to determine mechanisms of mortality and possible therapeutic targets in radiation combined injury. Mice were exposed to IR with 2.5 Gray (Gy) followed four days later by intratracheal methicillin-resistant Staphylococcus aureus (MRSA). While either IR or MRSA alone yielded 100% survival, animals with radiation combined injury had 53% survival (p = 0.01). Compared to IR or MRSA alone, mice with radiation combined injury had increased gut apoptosis, local and systemic bacterial burden, decreased splenic CD4 T cells, CD8 T cells, B cells, NK cells, and dendritic cells, and increased BAL and systemic IL-6 and G-CSF. In contrast, radiation combined injury did not alter lymphocyte apoptosis, pulmonary injury, or intestinal proliferation compared to IR or MRSA alone. In light of the synergistic increase in gut apoptosis following radiation combined injury, transgenic mice that overexpress Bcl-2 in their intestine and wild type mice were subjected to IR followed by MRSA. Bcl-2 mice had decreased gut apoptosis and improved survival compared to WT mice (92% vs. 42%; p<0.01). These data demonstrate that radiation combined injury results in significantly higher mortality than could be predicted based upon either IR or MRSA infection alone, and that preventing gut apoptosis may be a potential therapeutic target.
    PLoS ONE 10/2013; 8(10):e77203. DOI:10.1371/journal.pone.0077203 · 3.23 Impact Factor
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    • "Wound inflictions along with radiation exposure are of even more serious concern because the immune system is extremely radiosensitive. Since immunosupp ressed individuals are highly susceptibl e to opportunistic infections [2], protection of hematopoieti c tissue from acute radiation injury is an important criterion in developing radiation countermea sures. This need has prompted research among government laboratories, academic institutions and pharmaceuti cal companies to identify potential radiation countermeasure candidates. "
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    ABSTRACT: This study aimed to determine the role of granulocyte colony-stimulating factor (G-CSF), induced by a promising radiation countermeasure, gamma tocotrienol (GT3), in protecting mice from lethal doses of ionizing radiation. CD2F1 mice were injected with an optimal dose of GT3 and a G-CSF antibody, and their 30-d survival was monitored. An appropriate antibody isotype was used as a control. Multiplex Luminex was used to analyze GT3-induced cytokines. G-CSF neutralization by exogenous administration of a G-CSF antibody was confirmed by analyzing serum cytokine levels. Our results demonstrate that GT3 significantly protected mice against ionizing radiation, and induced high levels of G-CSF in peripheral blood 24h after administration. Injection of a G-CSF neutralizing antibody to the GT3-treated mice resulted in complete neutralization of G-CSF and abrogation of its protective efficacy. Administration of a G-CSF antibody did not affect levels of other cytokines induced by GT3. Histopathology of bone marrow from GT3-treated and -irradiated mice demonstrated protection of the hematopoietic tissue, and also that such protection was abrogated by administering a G-CSF antibody. Our results suggest that induction of high levels of G-CSF by GT3 administration is responsible for its protective efficacy against radiation injury.
    Cytokine 04/2013; 62(2). DOI:10.1016/j.cyto.2013.03.009 · 2.66 Impact Factor
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