Initial characterization of a non-pharmacological radiation countermeasure

描述(申请人提供)：放射性恐怖袭击(例如，简易核装置的引爆)可能导致数千名平民和急救人员暴露在致命或潜在致命剂量的电离辐射(IR)中。不幸的是，如果在暴露后给药，现有的对策通常是无效的，或者只在很小的剂量范围内有效。此外，使用现有方法处理大规模伤亡还存在后勤问题。因此，美国正在努力开发有效的对策，如果在辐射后使用，涉及到容易部署和使用方案，并且是无毒的。我们已经确定了一种新的非药理学策略，它在减轻IR对女性的致命影响方面非常有效 小鼠模型，如果在暴露后给药，并满足理想辐射对策的许多标准。我们的方法包括在照射后一段确定的时间内在小鼠身上创建一个小的皮下切口(1厘米)。我们的初步数据表明，照射后几分钟的皮下损伤极大地防止了致命性损伤。IR效应和急性辐射综合征的缓解可能是通过调节特定的细胞因子或促进造血恢复来实现的。然而，创建伤口以获得最大辐射防护的最佳参数以及创伤预防辐射致死的机制尚不清楚。在这一探索性应用中，我们寻求实现两个主要目标。第一个目标是确定照射后皮下损伤的最佳参数(伤口的长度、照射后保护损伤的时间窗)，以及可提供保护的最大剂量。为了确定“保护性伤害”策略作为辐射对策的有效性及其在治疗大规模伤亡中的有效性，我们将确定是否在照射后最多48小时的窗口内提供针对致命性的保护。为了确定适用性，我们将在不同年龄和性别的小鼠身上测试我们的策略，并评估是否所有年龄组和性别都得到了类似的保护，使其免受IR的致命影响。要做到这一点，将比较受过伤的小鼠和未受过伤的小鼠的30天存活率。第二个目标将是确定辐射后创伤提高存活率的潜在机制。具体地说，我们将比较受伤和对照照射小鼠细胞因子谱调节的时间模式，以及血液成分(和前体)和胃肠道的损伤和恢复，并将这些观察与生存联系起来。除了证明这种非衰弱的保护性损伤策略的有效性和普遍适用性外，拟议的实验还应该导致非药理学和药理学辐射对策的进一步发展。 与公共卫生有关：涉及简易核装置引爆的放射性恐怖袭击可能导致数千人暴露在致命或危及生命的剂量的电离辐射中。不幸的是，现有的辐射对策如果在照射后给予，通常是无效的，仅在很小的剂量范围内有效，或者受到后勤问题的困扰，这些问题限制了它们对治疗大规模伤亡的有效性。我们已经确定并建议进一步开发一种新的无毒和非药理的策略，如果在暴露后给予，这种策略在减轻辐射的致命影响方面非常有效，并且满足理想辐射对策的许多标准。

DESCRIPTION (provided by applicant): A radiological terrorist attack (e.g., the detonation of an improvised nuclear device) could result in the exposure of thousands of civilians and first responders to lethal or potentially lethal doses of ionizing radiation (IR). Unfortunately, existin countermeasures are generally ineffective if administered after exposure or are effective only within a narrow dose range. In addition, there are logistical problems associated with the treatment of mass casualties using existing approaches. Thus, there is a major effort in the U.S. to develop countermeasures that would be effective if administered after irradiation, involve easy deployment and use protocols, and are non-toxic. We have identified a novel non-pharmacological strategy which is very effective at mitigating the lethal effects of IR in a female mouse model if administered after exposure, and satisfies many of the criteria of an ideal radiation countermeasure. Our approach involves the creation of a small subcutaneous incision (1 cm) in the mouse within a defined period of time post-irradiation. Our preliminary data suggest that subcutaneous wounding several minutes after irradiation greatly protects against lethality. Mitigation of IR effects and the acute radiation syndrome may be mediated by the modulation of specific cytokines or enhanced recovery of hematopoiesis. However, the optimal parameters for creating the wound to derive maximal radioprotection and the mechanism by which wounding protects against radiation lethality have yet to be elucidated. In this exploratory application, we seek to accomplish two main objectives. The first objective will be to determine the optimal parameters for subcutaneous wounding after irradiation (length of the wound, window of time after irradiation during which wounding is protective), and the maximum dose for which protection may be afforded. To establish the validity of the "protective wounding" strategy as a radiation countermeasure, and its usefulness in the treatment of mass casualties, we shall determine whether protection against lethality is afforded within a window of up to 48 h post-irradiation. To determine applicability, we will test our strategy on mice of both sexes and of various ages, and assess whether all age groups and both sexes are protected similarly from the lethal effects of IR. To accomplish this, the 30-day survival of mice that have received a wound will be compared with that of mice which were not wounded. The second objective will be to identify potential mechanisms by which wounding after irradiation enhances survival. Specifically we shall compare the temporal pattern of modulation of cytokine profiles, and damage to and recovery of blood elements (and precursors) and the gastrointestinal tract, in wounded and control irradiated mice, and correlate these observations with survival. In addition to demonstrating the validity and general applicability of this non- debilitating protective wounding strategy, the experiments proposed should lead to further development of both non-pharmacological and pharmacological radiation countermeasures. PUBLIC HEALTH RELEVANCE: A radiological terrorist attack involving the detonation of an improvised nuclear device, could lead to the exposure of thousands of people to lethal or life-threatening doses of ionizing radiation. Unfortunately, existing radiation countermeasures are generally ineffective if administered after exposure, are effective only within a narrow dose range, or are plagued by logistical issues that limit their usefulness for the treatment of mass casualties. We have identified, and propose to further develop, a novel non-toxic and non-pharmacological strategy which is very effective at mitigating the lethal effects of radiation if administered after exposure, and which satisfies many of the criteria of an ideal radiation countermeasure.