title: Pharmacological countermeasures for the acute radiation syndrome.
abstract: The acute radiation syndrome (ARS) is defined as the signs and symptoms that occur within several months after exposure to ionizing radiation (IR). This syndrome develops after total- or partial-body irradiation at a relatively high dose (above about 1 Gy in humans) and dose rate. Normal tissue injuries induced by IR differ depending on the target organ and cell type. Organs and cells with high sensitivity to radiation include the skin, the hematopoietic system, the gut, the spermatogenic cells and the vascular system. Exposure to IR causes damage to DNA, protein, and lipids in mammalian cells, as well as increased mitochondria-dependent generation of reactive oxygen species (ROS), with subsequent cell cycle checkpoint arrest, apoptosis, and stress-related responses. DNA double strand breaks (DSBs) are a primary lethal lesion induced by IR. The cellular response to damage is complex and relies on simultaneous activation of a number of signaling networks. Among these, the activation of DNA non-homologous end-joining (NHEJ) and homologous recombination (HR), and signaling pathways containing ataxia telangiectasia mutated (ATM), play important roles. The transcription factor NFkappaB has emerged as a pro-survival actor in response to IR in ATM and p53-induced protein with a death domain (PIDD) cascades. Although radiation-induced ARS has been well documented at the clinical level, and mechanistic information is accumulating, successful prophylaxis and treatment for ARS is problematic, even with the use of supportive care and growth factors. There is a pressing need to develop radiation countermeasures that can be used both in the clinic, for small-scale incidents, and outside the clinic, in mass casualty scenarios. In this review we summarize recent information on intracellular and extracellular signaling pathways relevant to radiation countermeasure research.
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA. xiao@afrri.usuhs.mil
authors.forename: Mang
authors.initials: M
authors.lastname: Xiao
authors.forename: Mark H
authors.initials: MH
authors.lastname: Whitnall
mesh_terms: D054508:Acute Radiation Syndrome / Q000188:drug therapy / Q000378:metabolism*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases