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.

Ferulic acid induces heme oxygenase-1 <i>via</i> activation of ERK and Nrf2

“…There has been considerable public and scientifi c interest in the use of phytochemicals derived from dietary components to combat oxidative stress (3,4). Ferulic acid (FA) is a phytochemical commonly found in many herbs used in traditional Chinese medicine (5).…”

Contemporary Radiation Countermeasure

“…Overt doses of radiation can cause both immediate and delayed effects. The effect of ionising radiation on the whole-body system may result in acute radiation syndrome (ARS) 7,8 . This syndrome encompasses dose-dependent damages that affect the hematopoietic, gastrointestinal, cerebrovascular, pulmonary, and cutaneous systems in the body 9 .…”

Models for the Development of Radiation Countermeasures

“…Since many signalling pathway and their regulators are involved in the cellular responses to radiation damage, systematically dissecting them to identify critical targets in different organs under different circumstances, requires investigations on a large number of cell systems with defined genetic alterations. Creation of isogenic cells with well-defined genetic alterations coupled with high through-put screening (HTS) has greatly facilitated the identification of certain critical molecular targets as well as the evaluation of potential countermeasure agents [14][15][16] .…”