Medical countermeasures for radiation combined injury: radiation with burn, blast, trauma and/or sepsis. report of an NIAID Workshop, March 26-27, 2007.
ABSTRACT 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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ABSTRACT: ABSTRACT Purpose: Concern regarding radiation effects on human health continues to increase world-wide. Given that infection is a major cause of morbidity and mortality after exposure, the goal of this study was to evaluate decrements in immune cell populations using a mammalian model subjected to a live bacterial infection. Materials & Methods: C57BL/6 mice were exposed to total-body irradiation (TBI) with 3 Gy protons (70 cGy/min). One, 2, 4, 8 or 16 days later, subsets of mice were injected intraperitoneally with live Escherichia coli [055:K59(B5)]. Control groups received no radiation and vehicle (no bacteria). The mice were euthanized for analyses 90-120 minutes after injection of the bacteria. Results: There were no unexpected effects of radiation or E. coli alone. Despite dramatic radiation-induced decreases in all leukocyte populations in both the blood and spleen, irradiated mice were still able to respond to an immune challenge based on capacity to generate an oxidative burst and secrete inflammatory cytokines, i.e. tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). However, these responses were generally elevated above control values. Conclusions: Together, these results suggest the possibility for enhanced inflammation-associated tissue injury and increased risk for chronic inflammation.International Journal of Radiation Biology 03/2014; · 1.84 Impact Factor
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ABSTRACT: The authors demonstrate the efficacy of a bridging therapy in a preclinical animal model that allows the lymphohematopoietic system of severely immunocompromised individuals exposed to acute, high-dose ionizing irradiation to recover and to survive. CD2F1 mice were irradiated acutely with high doses causing severe, potentially fatal hematopoietic or gastrointestinal injuries and then transfused intravenously with progenitor-enriched, whole blood, or peripheral blood mononuclear cells from mice injected with tocopherol succinate- and AMD3100- (a chemokine receptor anatogonist used to improve the yield of mobilized progenitors). Survival of these mice over a 30-d period was used as the primary measured endpoint of therapeutic effectiveness. The authors demonstrate that tocopherol succinate and AMD3100 mobilize progenitors into peripheral circulation and that the infusion of mobilized progenitor enriched blood or mononuclear cells acts as a bridging therapy for lymphohematopoietic system recovery in mice exposed to whole-body ionizing irradiation. The results demonstrate that infusion of whole blood or blood mononuclear cells from tocopherol succinate (TS)- and AMD3100-injected mice improved the survival of mice receiving high radiation doses significantly. The efficacy of TS-injected donor mice blood or mononuclear cells was comparable to that of blood or cells obtained from mice injected with granulocyte colony-stimulating factor. Donor origin-mobilized progenitors were found to localize in various tissues. The authors suggest that tocopherol succinate is an optimal agent for mobilizing progenitors with significant therapeutic potential. The extent of progenitor mobilization that tocopherol succinate elicits in experimental mice is comparable quantitatively to clinically used drugs such as granulocyte-colony stimulating factor and AMD3100. Therefore, it is proposed that tocopherol succinate be considered for further translational development and ultimately for use in humans.Health physics 06/2014; 106(6):689-98. · 0.92 Impact Factor
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ABSTRACT: The possibility of a public health radiological or nuclear emergency in the United States remains a concern. Media attention focused on lost radioactive sources and international nuclear threats, as well as the potential for accidents in nuclear power facilities (e.g., Windscale, Three Mile Island, Chernobyl, and Fukushima) highlight the need to address this critical national security issue. To date, no drugs have been licensed to mitigate/treat the acute and long-term radiation injuries that would result in the event of large-scale, radiation, or nuclear public health emergency. However, recent evaluation of several candidate radiation medical countermeasures (MCMs) has provided initial proof-of-concept of efficacy. The goal of the Radiation Nuclear Countermeasures Program (RNCP) of the National Institute of Allergy and Infectious Diseases (National Institutes of Health) is to help ensure the government stockpiling of safe and efficacious MCMs to treat radiation injuries, including, but not limited to, hematopoietic, gastrointestinal, pulmonary, cutaneous, renal, cardiovascular, and central nervous systems. In addition to supporting research in these areas, the RNCP continues to fund research and development of decorporation agents targeting internal radionuclide contamination, and biodosimetry platforms (e.g., biomarkers and devices) to assess the levels of an individual's radiation exposure, capabilities that would be critical in a mass casualty scenario. New areas of research within the program include a focus on special populations, especially pediatric and geriatric civilians, as well as combination studies, in which drugs are tested within the context of expected medical care management (e.g., antibiotics and growth factors). Moving forward, challenges facing the RNCP, as well as the entire radiation research field, include further advancement and qualification of animal models, dose conversion from animal models to humans, biomarker identification, and formulation development. This paper provides a review of recent work and collaborations supported by the RNCP.Drug Development Research 02/2014; 75(1):23-8. · 0.73 Impact Factor