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

有效减轻肺部对辐射的反应是建立在了解辐射对肺部各种细胞成分的具体影响和照射环境的基础上的。从许多关于肺部辐射反应的研究中可以清楚地看出，有两个不同的组成部分，放射性肺炎，一种在照射后2至3个月发生的淋巴细胞肺泡炎，以及一种以胶原沉积和瘢痕形成为特征的慢性纤维化。这些问题已在不同物种中得到了相当好的表征，并已确定了潜在的缓解目标。不太清楚的是，在肺部不是唯一受损系统的环境中，这些过程是如何被调节的。当骨髓（肺细胞的来源）本身受到损伤时，肺部的炎症反应会受到怎样的影响？增强骨髓恢复的过程会加重肺反应吗？在多器官损伤过程中，被确定为肺反应组分、炎症激活、活性氧（ROS）的产生或血管泄漏的过程是否会以某种方式受到影响？这是当前工作试图解决的关键问题之一。在RDD或IND事件期间的辐射暴露可能会对多个系统造成损害，因此需要在考虑减轻其中任何一个系统的情况下考虑另一个系统。同样重要的是肺损伤的概念表现为合并或多重损伤的结果。肺部的辐射损伤是否会改变正常的肺防御机制，从而加剧对二次损伤的易感性？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有效地恢复肺功能的这一组成部分。上述两个问题都揭示了一些其他问题，包括确定开始给药缓解剂的最有效时间及其交付时间，以及最佳给药途径。我们还将考虑联合使用各种药剂以利用多个缓解目标产生的协同效应的可行性。最后，本提案将继续探讨内部放射性核素污染问题及其对肺部的影响，以及儿科人群暴露时可能存在的潜在独特的辐射易感性。

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.