Mitigating and treating the effects of radiation on lung tissue

肺对辐射的反应是复杂的，包括肺细胞的杀伤、内皮细胞的死亡、炎性细胞的内流以及炎性细胞因子和ROS的产生。观察到两种主要的功能结局，放射性肺炎和放射性纤维化。已经证明，在照射前给予一些不同的药剂可以防止功能和组织病理学损伤，但仅在照射后给予的药剂在多大程度上可以减轻或治疗辐射引起的肺损伤尚不确定。本提案的目标是基于炎症细胞因子和随后的ROS产生在肺损伤的发展中起主要作用的假设，开发和研究能够进行这种缓解和治疗的试剂。我们以前在大鼠中的工作已经证明，下肺的部分体积照射可以诱导上（屏蔽）肺的损伤，这表明辐射诱导的损伤的炎症成分。 该项目有三个具体目标。第一个目的是扩展我们的初步研究与SOD/过氧化氢酶模拟物，以确定其影响时，在不同的时间段照射后。这项工作将与Eukarion Inc（核心组件）公司合作完成。第二个具体目标是研究可以通过阻断特定炎症信号传导途径来阻断炎症反应诱导的化合物的缓解/治疗潜力。这项工作将建立在我们的初步工作，证明金雀异黄素，蛋白酪氨酸激酶抑制剂，这是一个众所周知的膳食补充剂，可以阻止转录因子NF κ B的激活，可以减轻肺损伤时，给予照射后。这一目标将确定染料木黄酮的最佳治疗方案，并将研究先天免疫缺陷相关的特定基因敲除小鼠肺的反应。 炎症反应，以查明哪些特定部分的途径是重要的辐射诱导的炎症在肺部。然后将测试针对这些特定部分的药物在减轻和治疗辐射诱导的肺损伤方面的功效。具体目标3将建立在前两个目标中进行的工作的基础上，以研究阻断ROS和炎症的药物与ACE抑制剂和AT阻断剂的组合的疗效，这些药物正在本项目的其他项目中进行研究。

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 is 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.