Abstract
The range of radiation threats we face today includes everything from individual radiation exposures to mass casualties resulting from a terrorist incident, and many of these exposure scenarios include the likelihood of additional traumatic injury as well. Radiation injury is defined as an ionizing radiation exposure inducing a series of organ injury within a specified time. Severity of organ injury depends on the radiation dose and the duration of radiation exposure. Organs and cells with high sensitivity to radiation injury are the skin, the hematopoietic system, the gastrointestinal (GI) tract, spermatogenic cells, and the vascular system. In general, acute radiation syndrome (ARS) includes DNA double strand breaks (DSB), hematopoietic syndrome (bone marrow cells and circulatory cells depletion), cutaneous injury, GI death, brain hemorrhage, and splenomegaly within 30 days after radiation exposure. Radiation injury sensitizes target organs and cells resulting in ARS. Among its many effects on tissue integrity at various levels, radiation exposure results in activation of the iNOS/NF-kB/NF-IL6 and p53/Bax pathways; and increases DNA single and double strand breaks, TLR signaling, cytokine concentrations, bacterial infection, cytochrome c release from mitochondria to cytoplasm, and possible PARP-dependent NAD and ATP-pool depletion. These alterations lead to apoptosis and autophagy and, as a result, increased mortality. In this review, we summarize what is known about how radiation exposure leads to the radiation response with time. We also describe current and prospective countermeasures relevant to the treatment and prevention of radiation injury.
Highlights
Reports on mortality in the life span study (LSS) cohort of atomic bomb survivors followed by the radiation effects research foundation indicates that (1) the risk of all causes of death is positively associated with radiation doses; (2) conventional dose-threshold analysis suggests no threshold; (3) the risk from cancer mortality increases significantly for most major organs, (4) an increased risk of non-neoplastic diseases including circulatory, respiratory and digestive systems are associated with radiation effects [1]
Because exposure to ionizing radiation combined with wound or hemorrhage trauma enhances inducible nitric oxide synthase (iNOS) gene expression and iNOS protein levels, due to activation of both NF-kB and nuclear factor-IL6 (NF-IL6) and increases in serum cytokines [15, 27, 33], greater production of peroxynitrite anion and more protein nitration is anticipated relative to that seen after radiation exposure alone
Radiation combined with wound trauma results in a decrease in the levels of lymphocytes, macrophages, neutrophils, platelets, cell adhesion molecules, tissue integrity, and stem cells, but leads to an increase in the activity of the iNOS/NF-kB/NF-IL6 and p53/Bax pathways, toll-like receptors (TLRs) signaling, cytokine concentrations [134], bacterial infection, cytochrome c release from mitochondria to cytoplasm, and DNA single and double strand breaks
Summary
Reports on mortality in the life span study (LSS) cohort of atomic bomb survivors followed by the radiation effects research foundation indicates that (1) the risk of all causes of death is positively associated with radiation doses; (2) conventional dose-threshold analysis suggests no threshold; (3) the risk from cancer mortality increases significantly for most major organs, (4) an increased risk of non-neoplastic diseases including circulatory, respiratory and digestive systems are associated with radiation effects [1]. Whether cells survive or die after ionizing radiation alone or when combined with other trauma depends on the number and severity of organ lesions, which determines the extent to which signal transduction pathways responsible for triggering cell death by apoptosis and autophagy are activated. Signal transduction pathway activation in response to DNA damage DNA repair proteins including RAD50, MRE11, NBS1, RAD17, RAD1, RAD9, and HUS1 bind to ionizing radiation-induced DSBs to form complexes, which are detected by ataxia telangiectasia mutated (ATM) kinases. The NF-kB signaling network includes DNA repair, cell cycle check regulation, mitochondrial antioxidants, survival and apoptosis, and cytokine and chemokine expression in response to ionizing radiationinduced damage [15] Additional trauma such as wounding potentiates gene expression induced by ionizing radiation. MMP3 and MMP13 significantly increase after combined injury more than after wounding, whereas irradiation does not induce such increase
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