Inflammatory response after combined insult of radiation and burn injury

描述(由申请人提供)：拟议研究的总体目标是确定辐射暴露和烧伤合并损伤导致的急性肺损伤(ALI)比单独损伤更严重的机制。肺是一个关键器官，对远程损伤特别敏感。这在一定程度上是因为器官广泛的血管床和精致的肺泡结构。急性肺损伤是由促炎细胞因子的过度产生引起的，这些细胞因子是全身和局部(在肺中)对烧伤和辐射损伤的反应而产生的，并且在复合伤害后很可能被放大。我们假设，全身炎症介质引发的过度活跃的肺部炎症反应是由全身炎症介质引发的过度活跃的肺部炎症反应触发的，这些并发症发生在遭受辐射的人身上。因此，在本申请的R21部分中，我们将确定烧伤小鼠的肺部病理程度和持续时间是否增加，与单独受到任何一种侮辱的动物相比，这些小鼠也受到辐射损伤，是否存在更大的功能损害。这将使用建立的小鼠背部烫伤(烧伤)损伤结合亚致死辐射暴露的模型来实现。如果我们看到对联合损伤的反应不同，那么我们将继续确定关键的促炎和致纤维化细胞因子的作用，这些细胞因子是在损伤早期和后期局部和系统产生的。在R33阶段，我们将探索导致肺异常反应的机制，包括这些因子的细胞来源和启动它们表达的信号级联，以确定肺泡巨噬细胞通过其细胞因子产生能力决定结果的程度。此外，我们将使用抗趋化因子受体和抗黏附分子受体抗体来确定旨在减少肺部炎症的治疗干预措施是否改善肺部病理，以及降低肺和肠道关键屏障的通透性是否有益。综上所述，预计拟议的实验将提供有关放射和烧伤复合损伤后组织损伤水平上升的机制的有价值的信息。此外，后续实验将探索旨在减少损伤后肺部炎症反应的治疗干预措施。

DESCRIPTION (provided by applicant): The overall objective of the proposed studies is to determine the mechanism by which the combined insult of radiation exposure and burn injury cause greater acute lung injury (ALI) than either insult alone. The lung is a critical organ, which is particularly sensitive to remote injury. This is, in part, because of the organ's extensive vascular bed and delicate alveolar architecture. Acute lung injury results from the overproduction of pro- inflammatory cytokines, which are generated both systemically and locally (in the lung) in response to injury, such as burn and radiation injury, and is likely to be amplified after a combined insult. We hypothesize that the complications which arise in radiation-exposed individuals who sustain burn injury are triggered by an overexuberant pulmonary inflammatory response which is triggered by systemic inflammatory mediators. Herein, during the R21 component of this application, we will determine whether there is an increase in the magnitude and duration of pulmonary pathology and greater impairment in function in burn-injured mice who are also subjected to radiation injury relative to animals given either insult alone. This will be accomplished using an established murine model of dorsal scald (burn) injury in combination with sublethal radiation exposure. If we see differences in response to the combined insult, then we will go on to define the roles of key pro-inflammatory and fibrogenic cytokines which are produced locally and systemically during the early and later post-injury period. During the R33 phase, we will explore both the mechanisms responsible for the aberrant pulmonary response, including the cellular sources of these factors and the signaling cascades which turn on their expression in order to determine the extent to which the alveolar macrophage dictates the outcome by virtue of its cytokine production capacity. Additionally, we will determine if therapeutic interventions designed to decrease pulmonary inflammation improve lung pathology using anti-chemokine receptor and anti-adhesion molecule receptor antibodies, as well as if decreasing permeability of critical barriers in the lung and the intestine is beneficial. Taken together, it is anticipated that the proposed experiments will provide valuable information about the mechanisms responsible for the elevated level of tissue damage after the combined injury of radiation and burn. In addition, subsequent experiments will explore therapeutic interventions designed to diminish pulmonary inflammatory responses after injury.