The Importance of Temperature on Inflammation after TBI

描述（由申请人提供）：创伤性脑损伤（TBI）是影响美国140万人的重大健康问题。尽管人们对创伤性脑损伤的病理生理机制了解甚多，但很少有治疗策略被成功地应用于临床。TBI在大脑中引发多重损伤级联反应，包括加剧初始损伤的炎症过程。我们的实验室发现，创伤后温度控制可以显著减轻创伤性炎症过程，显著改善创伤性脑损伤后的预后。轻度至中度低温可减少炎症细胞向损伤脑的浸润，并降低促炎细胞因子白介素-12 （IL-12）的升高。本修订申请的总体目标是确定TBI后由低温调节的炎症信号事件，以及这是否影响临床相关的功能结局。在Aim 1中，我们将确定低温对TBI后创伤后癫痫（PTE）形成的影响，这种情况发生在多达1 / 4的脑损伤患者中。在癫痫的实验模型中，由于癫痫发作，大脑中的炎症增加，而抗炎治疗可以减少癫痫发作的形成。因此，我们将评估TBI后的低温治疗是否能调节癫痫阈值，以及改善大脑中导致癫痫发作的组织病理学和电生理变化。在Aim 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，以及大脑中炎症细胞（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）的积累和激活。一组新的血脑屏障探头将用于彻底表征低温降低血脑屏障通透性的程度。在Aim 3中，我们将直接测试TBI后启动的全身性和内源性炎症机制与PTE发展之间的因果关系。我们还将评估IL-12全身性水平升高对PTE的影响，因为全身性促炎细胞因子水平是TBI患者多器官创伤的常见后果。该项目得到了一组研究人员的大力支持，他们在TBI、实验室技术和温度操作方面提供了丰富的专业知识。这项研究将提供重要的信息，关于使用治疗性低温在急性和慢性损伤设置。拟议的研究将提供有关TBI后癫痫发作发展的新信息，并确定低温治疗如何改善TBI的这种衰弱后果。公共卫生相关性：在美国，创伤性脑损伤（TBI）是导致死亡和残疾的主要原因。目前还没有治疗方法可以逆转脑部创伤的行为后果。这项拨款将在临床相关的TBI动物模型中测试创伤后将脑温度降低到33℃是否会减少癫痫的发病率并改善功能结果。

DESCRIPTION (provided by applicant): 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-12 (IL-12). 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-12 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. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is a major cause of death and disability in the United States. There are currently no treatments to reverse the behavioral consequences of brain trauma. This grant will test whether reducing brain temperature to 33¿C after trauma will reduce the incidence of epilepsy and improve functional outcome in a clinically relevant animal model of TBI.