Pulmonary response to external and internal exposure: model for dispersion event

该项目的总体目标是更深入地了解低外剂量时在肺中观察到的正常组织迟发效应以及放射性和（或）核弥散事件导致的内照射对全身造成的迟发效应的依据。这类事件的一个重要但未得到充分处理的方面是，辐射照射可能发生在内部，可能是全身性的，也可能是高度局部性的，这取决于所涉放射性物质的物理和化学性质。在这些事件中产生的颗粒将包括很大比例的超细或纳米材料，这些材料具有与较大直径颗粒不同的物理和化学性质 和表面积。在计算粒子暴露后的剂量和潜在靶器官系统时，需要考虑这种现象，这将在本项目的具体目标2中解决。我们以前的工作与外部束照射的肺导致我们的辐射迟发效应的范例是依赖于“对话”发生在一些受伤的细胞，而不是一个单一的靶细胞的经典概念。在本提案的具体目标中，我们将继续对肺部进行研究，将我们的检查范围扩大到放射性装置爆炸后人群中更有可能看到的较低剂量（具体目标1）。在具体目标2的研究中，我们将确定吸入放射性核素纳米颗粒的影响，并开发一种模型，将这种暴露与单独外部肺照射后观察到的暴露以及全身暴露进行比较。在特定目标3的研究中，我们将使用有关辐射暴露后发生的细胞和分子事件的信息，特别是促炎和促纤维化细胞因子和生长因子表达的改变及其遗传背景，以设计和测试可用于改善肺辐射毒性效应的药物。最后，在具体目标4的实验中，我们计划通过检查出生后生长期间外部束和内部辐射暴露后的肺反应来解决发育中生物体敏感性改变的可能性问题。

The overall goal of this project is directed at gaining a deeper understanding of the basis for the normal tissue late effects that are observed in the lung at low external doses and in the whole body from the internal exposure that occurs as a result of a radiological and/or nuclear dispersion event. An important, but inadequately addressed, aspect of such an event is that radiation exposure can occur internally, and may be either systemic or highly localized depending on the physical and chemical nature of the radioactive material involved. Particles generated in such events will include a significant proportion of ultra-fine or nano-materials, which have different physical and chemical properties from particles of larger diameter and surface area. This phenomenon needs to be considered when calculating dose and potential target organ systems following particle exposure, and this will be addressed in Specific Aim 2 of this project. Our previous work with external beam irradiation of the lung has led to our paradigm of radiation late effects being dependent upon the "conversation" which takes place between a number of injured cells, rather than the classic concept of a single target cell. In the specific aims for this proposal, we will continue our studies of the lung, extending our examination to the lower doses more likely to be seen in the population after the detonation of a radiological device (Specific Aim 1). In the studies in Specific Aim 2, we will determine the effects of inhaled radionuclide nanoparticles and develop a model that compares such exposures to those observed after external lung irradiation alone, as well as whole body exposures. In the studies in Specific Aim 3, we will use information about the cellular and molecular events that occur following radiation exposure, particularly in terms of the alterations in expression of proinflammatory and profibrotic cytokines and growth factors in conjunction with their genetic context, to design and test agents that could be used to ameliorate the toxic effects of radiation in the lung. Finally, in the experiments in Specific Aim 4, we plan to address the question of the potential for altered sensitivity in the developing organism by examining the pulmonary responses following external beam and internal radiation exposures during postnatal growth.