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了解辐射对肺部各种细胞成分的具体影响以及暴露的情况。从许多关于肺部放射反应的研究中可以清楚地看出，有两种不同的成分：放射性肺炎、照射后 2 至 3 个月发生的淋巴细胞性肺泡炎，以及以胶原沉积和疤痕为特征的慢性纤维化。这些已经在不同物种中得到了相当好的描述，并且已经确定了潜在的缓解目标。不太了解的是，在肺部不是唯一受损系统的环境中，如何调节这些过程。当骨髓（招募到肺部的细胞来源）本身受到损伤时，肺部炎症反应会受到怎样的影响？增强骨髓恢复的过程会加剧肺部反应吗？在多器官损伤期间，被确定为肺部反应、炎症激活、活性氧（ROS）生成或血管渗漏的组成部分的过程是否会受到某种影响？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，因此需要在另一个系统的背景下考虑减轻其中任何一个系统的影响。同样重要的是肺损伤的概念，表现为联合或多发损伤的结果。肺部的辐射损伤是否会改变正常的肺部防御机制，从而加剧对二次损伤的敏感性？现有信息表明情况确实如此。因此，我们计划解决的一个重要问题是，有效减轻放射性肺炎和/或纤维化的药物是否能有效恢复肺功能的这一组成部分。上述两个问题都揭示了许多其他问题，包括确定开始施用缓解剂的最有效时间及其递送持续时间以及最佳施用途径。我们还将考虑合并代理以利用多个缓解目标产生的协同效应的可行性。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，以及儿科人群发生暴露时可能存在的潜在的独特辐射敏感性。