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联合损伤比单独损伤引起更大急性肺损伤（ALI）的机制。肺是一个重要器官，对远端损伤特别敏感。这部分是由于该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量产生引起的，促炎细胞因子是全身和局部（肺）对损伤（如烧伤和辐射损伤）的反应，在综合损伤后可能会被放大。我们假设，在遭受辐射照射的个体中出现的并发症是由全身炎症介质引发的过度炎症反应引发的。在此，在本应用程序的R21部分，我们将确定在遭受辐射损伤的烧伤小鼠中，与单独给予任何一种损伤的动物相比，肺部病理的程度和持续时间是否增加，功能损害是否更大。这将通过建立背烫伤（烧伤）损伤与亚致死辐射暴露相结合的小鼠模型来完成。如果我们看到对联合损伤的反应差异，那么我们将继续定义在损伤早期和后期局部和全身产生的关键促炎和纤维化细胞因子的作用。在R33期，我们将探索异常肺反应的机制，包括这些因子的细胞来源和信号级联，以确定肺泡巨噬细胞通过其细胞因子生产能力决定结果的程度。此外，我们将确定使用抗趋化因子受体和抗粘附分子受体抗体来减少肺部炎症的治疗干预是否能改善肺部病理，以及降低肺和肠道关键屏障的通透性是否有益。综上所述，我们期望所提出的实验将为辐射和烧伤复合损伤后组织损伤水平升高的机制提供有价值的信息。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.