Combined Target Therapy for the Pulmonary Syndrome

描述（由申请人提供）：鉴于目前恐怖主义风险加剧的状况，迫切需要快速获得和易于分发的对策，作为大规模放射性或核事件后的缓解措施。由于我们对急性意外（或故意）暴露受害者的护理能力增强，这意味着暴露者更有可能在全身暴露导致的即时血液学危机中幸存下来，尽管如此，作为多器官功能障碍综合征的一部分，晚期发病率仍将发生。因此，肺等器官在该综合征进展中所起的下游作用越来越受到关注。 虽然肺晚期效应（肺炎和纤维化）的总体进展是公认的，但导致其发展的途径的复杂性，包括细胞，分子和时间成分，导致我们小组的论点是，没有单一的药物或策略可能是有效的缓解剂或治疗这些潜在的致命终点。因此，我们设计了一个系统的实验设计，使用相关的“2株”小鼠模型，其中我们将评估联合治疗，包括广泛的抗炎药以及许多替代药物，每一种药物都是根据其在肺部晚期效应进展中的已知靶标选择的。此外，将根据急性与慢性治疗方法评估这些联合治疗。我们预计，到资助期结束时，我们将确定一种或多种联合疗法，每种疗法都有明确的给药方法，可能会开发用于放射性事件后的即刻和延迟期。

DESCRIPTION (provided by applicant): In light of the current state of heightened terrorism risk, rapidly accessible and easily distributed countermeasures are urgently required as mitigators following a mass radiological or nuclear event. Since our increased ability to care for victims of acute accidental (or intentional) exposure means that exposed persons are more likely to survive the immediate hematological crises which result from whole body exposure, nonetheless late morbidities will still occur as part of a multi-organ dysfunction syndrome. Therefore, the downstream roles played by such organs as the lung in this syndrome's progression are of increasing concern. Although the overall progression to pulmonary late effects (pneumonitis and fibrosis) is well recognized, the complex nature of the pathways leading to their development, which includes cellular, molecular and temporal components, has led to our group's contention that no single agent or strategy is likely to be an effective mitigator or treatment against these potentially lethal endpoints. We have therefore devised a systematic experimental design, using a pertinent "2-strain" murine model, in which we will assess combination therapies that include a broad-based anti-inflammatory together with a number of alternative agents, each of which has been chosen for its known target within the pulmonary late effect progression. In addition, these combinations will be assessed in terms of an acute versus a chronic treatment approach. We anticipate that by the end of the funding period, we will have identified one or more combination therapies, each with defined dosing approaches, that could potentially be developed for use in both the immediate and delayed periods following a radiological event.