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、炎性细胞的涌入、炎性细胞因子的波动和ROS的产生。观察到两种主要的功能结果，放射性肺炎和放射性纤维化。许多不同的药物在照射前给予对功能和组织病理损伤的保护作用已被证明，但只有在照射后给予的药物在多大程度上可以减轻或治疗辐射所致的肺损伤尚不确定。本提案的目的是基于炎症细胞因子和随后产生的ROS在肺损伤的发展中起主要作用的假设，开发和研究能够减轻和治疗这种疾病的药物。我们以前在大鼠身上的工作已经证明，下肺的部分体积照射可以导致上肺(屏蔽的)损伤，提示辐射诱导的损伤中存在炎症成分。 该项目有三个具体目标。第一个目标是扩展我们对超氧化物歧化酶/过氧化氢酶模拟物的初步研究，以确定在照射后的不同时间段给予它们的影响。这项工作将与Eukarion公司(核心组件)合作完成。第二个具体目的是研究化合物的缓解/治疗潜力，这些化合物可以通过阻断特定的炎症信号通路来阻断炎症反应的诱导。这项工作将建立在我们的初步工作的基础上，证明Genistein是一种蛋白酪氨酸激酶抑制剂，是一种众所周知的膳食补充剂，可以阻断转录因子NFkappaB的激活，在照射后给予可以减轻肺损伤。这一目标将确定金雀异黄素的最佳治疗方案，并将调查先天参与的特定基因敲除小鼠的肺反应。 炎症反应，以确定路径的哪些特定部分对于辐射引起的肺部炎症是重要的。然后，针对这些特定途径部分的药物将被测试其在减轻和治疗放射性肺损伤方面的效果。具体目标3将在前两个目标中开展的工作的基础上，研究阻断ROS和炎症的药物与ACE抑制剂和AT阻滞剂的组合的有效性，该计划的其他项目正在研究这些药物。

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.