The response of lung to irradiation is complex, involving killing of lung cells, death of endothelial cells, influx of inflammatory cells and waves of inflammatory cytokines and ROS production. Two major functional outcomes are observed, radiation pneumonitis and radiation fibrosis. Protection against functional and histopathological damage has been demonstrated for a number of different agents when given before irradiation but the extent to which radiation-induced lung damage can be mitigated or treated by agents given only after irradiation is uncertain. The goal of the present proposal is to develop and investigate agents capable of such mitigation and treatment based on the hypothesis that inflammatory cytokines and consequent ROS production play a major role in the development of lung damage. Our previous work in rats has demonstrated that partial volume irradiation of the lower lung can induce damage in the upper (shielded) lung suggesting an inflammatory component to radiation-induced damage. The project has three specific aims.
The first aim i s to extend our preliminary studies with SOD/catalase mimetics to determine their effects when given over different time periods after irradiation. This work will be done in collaboration with the company Eukarion Inc (Core component). The second specific aim is to investigate the mitigating/treatment potential of compounds that can block the induction of the inflammatory response by blocking specific inflammatory signaling pathways. This work will build on our preliminary work demonstrating that Genistein, a protein tyrosine kinase inhibitor, that is a well known dietary supplement and can block the activation of the transcription factor NFkappaB, can mitigate lung damage when given after irradiation.
This aim will determine an optimal treatment protocol for Genistein and will investigate the response of the lung in mice knocked out for specific genes involved in the innate inflammatory response to pinpoint which specific parts of the pathway are important for radiation-induced inflammation in lung. Drugs targeting these specific parts of the pathway will then be tested for their efficacy in mitigating and treating radiation-induced lung injury.
Specific Aim 3 will build on the work undertaken in the previous two aims to study the efficacy of combinations of agents that block ROS and inflammation with the ACE inhibitors and AT blockers being investigated in other projects in this program.
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