The overall goal of this project is to develop a new strategy to protect, ameliorate and treat radiation (RT)-induced normal tissue injury by using a novel synthetic manganese(Mn)-porphyrins as potent scavengers of reactive oxygen species (ROS) and reactive nitrogen species (RNS). The strategy is based on our current mechanistic studies implicating chronic oxidative stress as an important contributing factor in the development of RT-induced normal tissue injury. We hypothesize that exposure to ionizing radiation results in chronic oxidative stress which is associated with continuous production of ROS/RNS and expression/activation of damaging cytokines involved in development of RT-induced normal tissue injury. Several lines of evidence from our group support this hypothesis. Using electron spin resonance (ESR) and spin trapping we have demonstrated the presence of ROS in rat lungs 13 weeks after irradiation. In a transgenic mouse model we have shown that overexpression of extracellular superoxide dismutase (EC-SOD), an important scavenger of ROS, ameliorates RT-induced lung injury. In addition, our studies show that Mn(III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP5+) compound can be used to target ROS and reduce RT-induced lung damage if given prior to radiation exposure. This proposal is designed to test already established and further develop/optimize new catalytic Mn-porphyrin compounds, to document their ability to prevent/ameliorate or treat RT-induced normal tissue injury after exposure to photons or mixed neutron/photon type of ionizing radiation. With the growing threats from radiation exposure after terrorist attack, the development of effective radioprotective compounds as proposed in this project will be an important contribution for establishment of effective medical countermeasures against radiation.