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。虽然对TBI的病理生理机制了解很多，但很少有治疗策略成功地转化为临床环境。TBI在大脑中引发多个损伤级联，包括加重初始损伤的炎症过程。我们的实验室发现，创伤后温度处理可以显着减弱创伤诱导的炎症过程，并显着改善TBI后的结果。轻度至中度低温可减少炎性细胞向受损脑中的浸润，并减弱促炎细胞因子白细胞介素-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传导事件，以及这是否影响临床相关的功能结局。在目标1中，我们将确定低温对TBI后创伤后癫痫（PTE）形成的影响，TBI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，抗炎治疗减少癫痫发作的形成。因此，我们将评估TBI后的低温治疗是否调节癫痫发作阈值，以及改善有助于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症细胞（如单核细胞衍生的巨噬细胞、多形核白细胞、小胶质细胞和星形胶质细胞）的积累和活化。一组新的血脑屏障探针将用于彻底表征低温降低血脑屏障通透性的程度。在目标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。我们还将评估升高全身IL-12水平对PTE的影响，因为全身促炎细胞因子水平是TBI患者群体中多器官创伤的常见后果。该项目得到了一个既定的研究小组的高度支持，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，在急性和慢性损伤设置使用治疗低温。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：创伤性脑损伤（TBI）是美国死亡和残疾的主要原因。目前还没有治疗方法可以逆转脑外伤的行为后果。这项资助将测试创伤后将脑温降至33 ℃是否会降低癫痫的发病率，并改善临床相关的TBI动物模型的功能结果。

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.