The Importance of Temperature on Inflammation after TBI

创伤性脑损伤(TBI)是一个重大的健康问题，影响着美国140万人。 尽管人们对脑外伤的病理生理机制知之甚少，但很少有治疗策略。 已经成功地转化到临床环境中。脑外伤引发大脑多重损伤级联反应 包括加重最初损伤的炎症过程。我们的实验室发现- 创伤性温度操作可以显著减弱创伤诱导的炎症过程和 显著改善颅脑损伤后的预后。亚低温可减少炎性细胞的侵袭 并抑制促炎细胞因子白介素1(IL-1)的升高。 此修订应用程序的总体目标是识别符合以下条件的炎性信号事件 以及这是否影响临床相关的功能结果。在AIM 1我们将确定低温对创伤性癫痫(PTE)形成的影响。 发生在多达四分之一的脑损伤患者中。在癫痫的实验模型中，炎症增加 在大脑中，癫痫发作和抗炎治疗会减少癫痫的形成。因此， 我们将评估颅脑损伤后的亚低温治疗是否能调节癫痫发作阈值，以及改善 大脑中有助于癫痫形成的组织病理学和电生理变化。在AIM 2 我们将研究颅脑损伤后的低温治疗是否会降低血脑屏障(BBB)的通透性 以及炎症细胞在大脑中的积累和激活，如单核细胞来源的巨噬细胞， 多形核白细胞、小胶质细胞和星形胶质细胞。一组新的BBB探头将用于 彻底描述低温降低血脑屏障通透性的程度。在目标3中，我们将直接 检测创伤后全身炎症机制和内源性炎症机制之间的因果关系 PTE的发展。我们还将评估提高全身IL-1水平对PTE的影响 全身促炎细胞因子水平是颅脑损伤合并多器官损伤的常见后果 病人群体。该项目得到了一组成熟的调查人员的高度支持，他们提供了一个 在TBI、实验室技术和温度控制方面拥有丰富的专业知识。这项研究将提供 关于在急性和慢性损伤环境中使用治疗性低温的重要信息。 拟议的研究将提供有关脑外伤后癫痫发作发展的新信息，并 确定低温治疗如何改善脑外伤的这种衰弱后果。

Traumatic brain injury (TBI) is a significant health concern affecting 1.4 million people in the United States. Although much is known about the pathophysiological mechanisms underlying TBI, few therapeutic strategies have been successfully translated to the clinical setting. TBI initiates multiple injury cascades in the brain including inflammatory processes that exacerbate the initial injury. Our laboratory has found that post- traumatic temperature manipulations can dramatically attenuate trauma-induced inflammatory processes and significantly improve outcome after TBI. Mild to moderate hypothermia reduces the infiltration of inflammatory cells into the injured brain and attenuates elevations of the pro-inflammatory cytokine, interleukin-1¿ (IL-1¿). The overall objective of this revised application is to identify the inflammatory signaling events that are regulated by hypothermia after TBI and whether this influences clinically relevant functional outcomes. In Aim 1 we will determine the effects of hypothermia on the formation of posttraumatic epilepsy (PTE) after TBI which occurs in as many as 1 in 4 brain-injured patients. In experimental models of epilepsy, inflammation increases in the brain as a consequence of seizures and anti-inflammatory treatments reduce seizure formation. Thus, we will assess whether hypothermia therapy after TBI modulates seizure threshold, as well as improves the histopathological and electrophysiological changes in the brain that contribute to seizure formation. In Aim 2 we will investigate whether hypothermia therapy after TBI attenuates blood-brain barrier (BBB) permeability and the accumulation and activation of inflammatory cells in the brain such as monocyte-derived macrophages, polymorphonuclear leukocytes, microglia, and astrocytes. A new battery of BBB probes will be used to thoroughly characterize the extent to which hypothermia reduces BBB permeability. In Aim 3 we will directly test a causal relationship between systemic and endogenous inflammatory mechanisms initiated after TBI and the development of PTE. We will also assess the effects of elevating systemic levels of IL-1¿ on PTE since systemic levels of pro-inflammatory cytokines are a common consequence of multi-organ trauma in the TBI patient population. This project is highly supported by an established group of investigators who provide a wealth of expertise in TBI, laboratory techniques, and temperature manipulations. This research will provide important information regarding the use of therapeutic hypothermia in both the acute and chronic injury setting. The proposed studies will provide novel information regarding the development of seizures after TBI and determine how hypothermia therapy may improve this debilitating consequence of TBI.