Importance of Brain Temperature on the Inflammatory and Microvascular Consequences of Mild TBI

脑震荡或轻度创伤性脑损伤(MTBI)的潜在有害影响是一个主要的公共健康问题。 有问题。虽然大多数mTBI患者在1-2周内恢复，但亚群需要数周时间才能恢复 几个月才能完全康复，一些人报告说，最初的创伤后症状会持续数年。因此，确定 影响脑损伤后脑功能恢复的临床相关因素尚未得到充分研究，但仍需进一步研究 区域。临床研究报告称，剧烈运动和锻炼可导致心脏轻度升高。 和大脑温度。我们现在发现，相对温和的大脑温度仅升高39摄氏度，这一点非常显著 与两种不同的mTBI模型相比，加重神经病理和认知结果 常温mTBI。这些观察表明，大脑温度在这一时间或前后的微小变化 创伤的严重程度可能影响创伤性脑损伤的急性和长期创伤后果。新的初步结果 证明mTBI时体温过高对炎症、微血管和 血液动力学紊乱。这项提议的目标是调查温度和温度之间的因果联系。 敏感的炎症和脑血管反应以及结构和行为变化的出现 这可能是高温mTBI后预后恶化的基础。目标1将描述炎症性 常温或高温条件下对mTBI的反应。将使用流式细胞术来表征 巨噬细胞/小胶质细胞表型和包括细胞因子和趋化因子信号在内的生物标志物分析 与慢性认知结果相关。互补的大鼠和转基因模型包括CCL2和 Caspase 1基因敲除小鼠将阐明炎症细胞渗透在触发细胞毒性炎症中的作用 高温mTBI后。目标2将重点研究常温或低氧后的微血管通透性模式 高温mTBI伴随紧密连接蛋白和内皮细胞黏附分子的变化。这个 巨噬细胞来源的细胞鉴定对脑血管通透性和完整性的影响将与 细胞间黏附分子-1和基质金属蛋白酶-9转基因模型的炎症反应 以及三维图像的可视化和量化。因为创伤后大脑的血液动力学状态 影响mTBI后继发性损伤机制，Aim 3将评估局部脑血流和 血管反应性的放射自显影和双光子激光扫描显微镜。潜在的 这些血流动力学反应的机制将用eNOS和iNOS基因敲除的小鼠进行测试。临床上 相关治疗包括针对小胶质细胞和巨噬细胞/内皮细胞的米诺环素和孕酮 相互作用将在高温mTBI和脑震荡的这些模型中进行测试。总而言之，这些研究将 明确高温mTBI后的温度敏感性炎症和脑血管事件，确定 体温过高与继发性损伤机制的因果关系及临床干预试验 这些药物已经在临床上使用，以减少这种常见类型的脑损伤的破坏性后果。

The potentially detrimental effects of concussion or mild traumatic brain injury (mTBI) are a major public health problem. Although the majority of mTBI patients recover within 1-2 weeks, a subpopulation takes weeks to months for full recovery and some report symptoms lasting years after the initial trauma. Thus, identification of clinically relevant factors that alter the brain's recovery after mTBI is an understudied, but much needed research area. Clinical investigations have reported that strenuous activity and exercise can lead to mild elevations in core and brain temperature. We now show that a relatively mild brain temperature elevation of only 39oC significantly aggravates neuropathological and cognitive outcome in two distinct models of mTBI as compared to normothermic mTBI. These observations suggest that small variations in brain temperature at or around the time of injury may influence the acute and long term traumatic consequences of mTBI. Novel preliminary results demonstrate that hyperthermia at the time of mTBI has profound effects on inflammatory, microvascular and hemodynamic perturbations. The goal of this proposal is to investigate the causal links between temperature- sensitive inflammatory and cerebrovascular responses and the emergence of structural and behavioral changes that may underlie the exacerbation of outcome after hyperthermic mTBI. Aim 1 will characterize the inflammatory responses to mTBI during normothermic or hyperthermic conditions. Flow cytometry will be used to characterize macrophage/microglia phenotypes and biomarker analysis including cytokine and chemokine signaling correlated with chronic cognitive outcomes. Complementary rat and transgenic models including CCL2 and caspase 1 knockout mice will clarify the role of inflammatory cell infiltration on triggering cytotoxic inflammation after hyperthermic mTBI. Aim 2 will focus on the microvascular permeability patterns following normothermic or hyperthermic mTBI in concert with tight junctional protein and endothelial adhesion molecule changes. The cellular identification of macrophage origins on cerebrovascular permeability and integrity will be correlated with inflammatory responses using ICAM-1 and MMP-9 transgenic models with light sheet fluorescence microscopy and 3D image visualization and quantitation. Because the hemodynamic state of the posttraumatic brain can influence secondary injury mechanisms after mTBI, Aim 3 will assess alterations in local cerebral blood flow and vascular reactivity using autoradiography and two-photon laser scanning microscopy. The underlying mechanisms of these hemodynamic responses will be tested using eNOS and iNOS knockout mice. Clinically relevant treatments including minocycline and progesterone targeting microglia and macrophage/endothelial interactions will be tested in these models of hyperthermic mTBI and concussion. Together, these studies will clarify the temperature-sensitive inflammatory and cerebrovascular events after hyperthermic mTBI, determine causal relationships of hyperthermia and secondary injury mechanisms and test clinically relevant interventions that are already in use in the clinic to reduce the devastating consequences of this common type of brain injury.