Mitigation and Modeling of Radiation Effects in the Context of Multi-Organ/Model

多器官/模型背景下辐射效应的缓解和建模

• 批准号: 8009997
• 负责人: Jacob N Finkelstein
• 金额: $ 50.57万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009997
• 关键词: Address; Adult; Aerosols; Affect; Age; Alveolitis; Blood Vessels; Bone Marrow; Breathing; Cells; Cesium; Child; Childhood; Chronic; Cicatrix; Collagen; Complex; Data; Defense Mechanisms; Deposition; Development; Devices; Dose; Drug Formulations; Effectiveness; Environment; Event; Face; Fibrosis; Frequencies; Functional disorder; Generations; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knowledge; Late Effects; Lead; Light; Lung; Lymphocyte; Modeling; Multiple Trauma; Nature; Nuclear; Organ; Organ Model; Particulate; Pharmaceutical Preparations; Phase; Population; Predisposition; Process; Production; Radiation; Radiation Injuries; Radiation Pneumonitis; Radioactive; Radioisotopes; Reactive Oxygen Species; Recovery; Recruitment Activity; Regimen; Research Personnel; Route; Source; System; Time; Toxic effect; Trauma; Work; base; cytokine; injured; internal radiation; irradiation; pulmonary function; radiation effect; response; response to injury

Effective mitigation of the pulmonary response to radiation is based on the knowledge of the specific effects of radiation on the various cellular components of the lung and on the context of the exposure. It is clear from the many studies of the pulmonary radiation response that there are two distinct components, radiation pneumonitis, a lymphocytic alveolitis that develops 2 to 3 months after irradiation, and a chronic fibrosis characterized by collagen deposition and scarring. These have been reasonably well characterized in various species and potential targets of mitigation have been identified. What is less well understood is how these processes may be modulated in an environment in which the lung is not the only system that has been damaged. How would the pulmonary inflammatory response be affected when the bone marrow, the source of cells recruited into the lung, has itself been injured? Would processes that enhance bone marrow recovery exacerbate the pulmonary response? Would processes identified as components of the pulmonary response, activation of inflammation, generation of reactive oxygen species (ROS) or vascular leak be somehow affected during multi-organ injury? This is one of the key questions that the current work seeks to address. Radiation exposure during an RDD or IND event is likely to result in damage to multiple system and thus mitigation of any one of them needs to be considered in the context of the other. Equally important is the concept of pulmonary injury being manifested as a result of combined or multiple injury. Does radiation damage to the lung alter the normal pulmonary defense mechanisms so as to exacerbate susceptibility to a secondary insult? Existing information suggests this to be the case. Thus, an important question that we plan to address is whether agents that effectively mitigate radiation pneumonitis and/or fibrosis are effective in restoring this component of pulmonary function. Both of the issues raised above bring to light a number of additional questions including identification of the most effective time to initiate administration of a mitigating agent and its duration of delivery, and best route of administration. We will also consider the feasibility of combining agents to take advantage of synergies that would arise from multiple mitigation targets. Finally, this proposal will continue to explore the question of internal radionuclide contamination and its effects of the lung as well as the potential unique susceptibility to radiation that may exist when exposure occurs in a pediatric population.

有效缓解肺部对辐射的反应是基于对辐射对肺部各种细胞成分的特定影响和暴露背景的了解的知识。从许多关于肺辐射反应的研究可以清楚地看出，有两个不同的成分：放射性肺炎，一种淋巴细胞肺泡炎，在辐照后2至3个月发展，以及以胶原蛋白沉积和疤痕为特征的慢性纤维化。这些在各种物种中都得到了很好的特征，并且已经确定了缓解的潜在靶标。不太了解的是，如何在肺不是唯一受损的系统的环境中调制这些过程。当骨髓（募集到肺部的细胞来源）本身受伤时，肺部炎症反应将如何影响？增强骨髓恢复的过程会加剧肺反应吗？在多器官损伤期间，是否会以某种方式影响被确定为肺反应，炎症激活，活性氧（ROS）或血管渗漏的过程？这是当前工作寻求解决的关键问题之一。 RDD或IND事件期间的辐射暴露可能会导致多个系统损坏，因此需要在另一个情况下进行减轻。同样重要的是，肺部损伤的概念是由于合并或多重损伤而表现出来的。辐射对肺部是否会改变正常的肺防御机制，从而加剧对继发性损伤的敏感性？现有信息表明是这种情况。因此，我们计划解决的一个重要问题是，有效减轻肺炎和/或纤维化的药物是否有效地恢复了肺功能的这一组成部分。上面提出的两个问题都揭示了许多其他问题，包括确定最有效的时间来启动缓解剂的管理及其交付时间以及最佳的管理途径。我们还将考虑将代理相结合以利用由多个缓解靶标产生的协同作用的可行性。最后，该提案将继续探讨内部放射性核素污染的问题及其对肺部的影响，以及在小儿种群中发生暴露时可能存在的潜在独特的辐射易感性。