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。虽然这种神经保护的机制被归因于代谢储存的保存和减少兴奋性氨基酸的释放，但这不能解释仅在脑温度小幅降低或脑冷却延迟几个小时时看到的同样强大的保护。最近在中风领域的研究还表明，炎症过程被激活，并通过释放活性氧（ROS）、蛋白酶和脂肪酶加剧损伤，导致脑水肿和局部组织破坏增加。 炎性刺激上调炎性细胞因子，其激活小胶质细胞并刺激粘附分子的表达。 后一种蛋白质参与吸引白细胞到活化和受损的内皮，然后进入受损组织。 我们和其他一些研究小组发现，抑制中性粒细胞迁移可减少实验性卒中后的缺血性损伤，轻度低温可减少中性粒细胞浸润到缺血性脑区。我们的目的是进一步探讨已知的机制，介导这种炎症反应，并确定是否轻度低温改变他们。 使用脑缺血和炎症模型，我们将首先测试的假设，即亚低温减弱脑浸润的白细胞亚群，并抑制小胶质细胞活化。 然后，我们将研究轻度低温是否会改变炎症介质的表达，如炎症细胞因子IL-1 β（白细胞介素-1 β）和TNF-α（肿瘤坏死因子-α）和粘附分子。 然后，我们将确定是否轻度低温减弱炎症细胞产生的潜在毒性物质，如活性氧，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缺陷的小鼠是否能免受高温的影响。 这项研究的结果应该提供深入了解低温的保护作用，并可能建议中风治疗的抗炎目标。

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.