The Importance of Temperature on Inflammation after TBI

创伤性脑损伤（TBI）是影响美国140万人的重大健康问题。 虽然对TBI的病理生理机制了解很多，但很少有治疗策略。 已成功应用于临床。TBI在大脑中引发多个损伤级联反应 包括加重初始损伤的炎症过程。我们的实验室发现， 创伤性温度处理可以显著减弱创伤诱导的炎症过程， 显著改善TBI后的结果。轻度至中度低温可减少炎性细胞浸润， 细胞进入受损的大脑，并减弱促炎细胞因子白细胞介素-1 <$（IL-1 <$）的升高。 这一修订申请的总体目标是确定炎症信号传导事件， TBI后低温调节以及这是否影响临床相关的功能结果。在Aim中 1我们将确定低温对TBI后创伤后癫痫（PTE）形成的影响， 发生在四分之一的脑损伤患者身上。在癫痫的实验模型中， 在大脑中作为癫痫发作和抗炎治疗的结果减少癫痫发作的形成。因此，在本发明中， 我们将评估TBI后的低温治疗是否调节癫痫发作阈值，以及改善癫痫发作阈值。 导致癫痫发作形成的脑组织病理学和电生理学变化。在目标2中 我们将研究TBI后的低温治疗是否会减弱血脑屏障（BBB）的通透性 以及脑中炎性细胞如单核细胞衍生的巨噬细胞的积累和活化， 多形核白细胞、小胶质细胞和星形胶质细胞。将使用一组新的BBB探头， 彻底表征低温降低BBB渗透性的程度。在目标3中，我们直接 测试TBI后引发的全身性和内源性炎症机制之间的因果关系， PTE的发展。我们还将评估全身IL-1水平升高对PTE的影响， 全身促炎细胞因子水平是TBI中多器官创伤的常见结果 患者人群。这个项目得到了一个既定的调查小组的高度支持，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TBI后癫痫发作发展的新信息， 确定低温疗法如何改善TBI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.