Inflammatory Mechanisms in Cerebral Ischemia

在实验水平上，低温一直是减少脑缺血损伤的有效手段。尽管这种神经保护的机制被归因于新陈代谢储存的保存和减少兴奋性氨基酸的释放，但这不能解释只有大脑温度略有下降或大脑降温推迟几个小时时的同样强大的保护。最近在卒中领域的研究也表明，炎症过程被激活，并通过释放活性氧基(ROS)、蛋白酶和脂肪酶而加剧损伤，导致脑水肿和局部组织破坏的增加。炎症刺激上调炎症细胞因子，从而激活小胶质细胞并刺激黏附分子的表达。后者参与将白细胞吸引到激活和受损的内皮细胞，然后内皮细胞进入受损组织。我们和其他几个小组发现，抑制中性粒细胞迁移可以减少实验性中风后的缺血性损伤，而亚低温可以减少中性粒细胞对缺血脑区的渗透。我们的目的是进一步探索已知的介导这种炎症反应的机制，并确定亚低温是否会改变这些机制。利用脑缺血和炎症模型，我们将首先检验以下假设：亚低温可以减少脑组织中白细胞亚群的渗透，并抑制小胶质细胞的激活。然后，我们将研究亚低温是否会改变炎症介质的表达，如炎症细胞因子IL-1β(白细胞介素1β)和肿瘤坏死因子-α(肿瘤坏死因子-α)，以及黏附分子。然后，我们将确定亚低温是否减少炎症细胞产生潜在有毒物质，如ROS、诱导型一氧化氮合酶(INOS)和兴奋性氨基酸。为了进一步证实炎症的温度依赖性及其对脑损伤的影响，我们将确定ICAM-1缺陷的小鼠是否受到高温的保护。这项研究的结果应该为低温的保护作用提供洞察力，并可能为中风的治疗提供抗炎靶点。

At the experimental level, hypothermia has consistently been an effective means of reducing cerebral ischemic injury. Although the mechanisms underlying this neuroprotection have been attributed to the preservation of metabolic stores and reducing excitatory amino acid release, this cannot explain the equally robust protection seen with only small decreases in brain temperature, or when brain cooling is delayed by a few hours. Recent work in the area of stroke has also shown that inflammatory processes are activated and exacerbate injury by the release of reactive oxygen species (ROS), proteases, and lipases leading to increases in cerebral edema and local tissue destruction. Inflammatory stimuli upregulate inflammatory cytokines, which activate microglia and stimulate expression of adhesion molecules. These latter proteins are involved in attracting leukocytes to activated and damaged endothelium, which then enter damaged tissue. We, and a few other groups have found that inhibition of neutrophil migration reduces ischemic injury following experimental stroke, and that mild hyopthermia attenuates neutrophil infiltration into ischemic brain regions. We purpose to further explore the mechanisms known to mediate this inflammatory response, and determine whether mild hypothermia alters them. Using models of brain ischemia and inflammation, we will first test the hypothesis that mild hypothermia attenuates cerebral infiltration of leukocyte subpopulations, and suppresses microglial activation. We will then study whether mild hypothermia alters expression of inflammatory mediators such as the inflammatory cytokines IL- 1beta (interleukin-1beta) and TNF-alpha (tumor necrosis factor- alpha), and adhesion molecules. We will then determine whether mild hypothermia attenuates inflammatory cell generation of potentially toxic substances such as ROS, inducible nitric oxide synthase (iNOS), and excitatory amino acids. To further confirm the temperature dependence of inflammation and its effects on brain injury, we will determine whether mice deficient in ICAM-1 are protected against hyperthermia. The results of this study should provide insight into the protective role of hypothermia, and may suggest anti-inflammatory targets for stroke treatment.