Janata Andreas, Magnet Ingrid A M, Uray Thomas, Stezoski Jason P, Janesko-Feldman Keri, Tisherman Samuel A, Kochanek Patrick M, Drabek Tomas
Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Resuscitation. 2014 May;85(5):694-701. doi: 10.1016/j.resuscitation.2014.01.033. Epub 2014 Feb 12.
Cardiac arrest (CA) triggers neuroinflammation that could play a role in a delayed neuronal death. In our previously established rat model of ventricular fibrillation (VF) CA characterized by extensive neuronal death, we tested the hypothesis that individual brain regions have specific neuroinflammatory responses, as reflected by regional brain tissue levels of tumor necrosis factor (TNF)α and other cytokines. In a prospective study, rats were randomized to 6min (CA6), 8min (CA8) or 10min (CA10) of VF CA, or sham group. Cortex, striatum, hippocampus and cerebellum were evaluated for TNFα and interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 and interferon gamma at 3h, 6h or 14 d after CA by ELISA and Luminex. Immunohistochemistry was used to determine the cell source of TNFα. CA resulted in a selective TNFα response with significant regional and temporal differences. At 3h after CA, TNFα-levels increased in all regions depending on the duration of the insult. The most pronounced increase was observed in striatum that showed 20-fold increase in CA10 vs. sham, and 3-fold increase vs. CA6 or CA8 group, respectively (p<0.01). TNFα levels in striatum decreased between 3h and 6h, but increased in other regions between 3h and 14 d. TNFα levels remained twofold higher in CA6 vs. shams across brain regions at 14 d (p<0.01). In contrast to pronounced TNFα response, other cytokines showed only a minimal increase in CA6 and CA8 groups vs. sham in all brain regions with the exception that IL-1β increased twofold in cerebellum and striatum (p<0.01). TNFα colocalized with neurons. In conclusion, CA produced a duration-dependent acute TNFα response, with dramatic increase in the striatum where TNFα colocalized with neurons. Increased TNFα levels persist for at least two weeks. This TNFα surge contrasts the lack of an acute increase in other cytokines in brain after CA. Given that striatum is a selectively vulnerable brain region, our data suggest possible role of neuronal TNFα in striatum after CA and identify therapeutic targets for future experiments. This study was approved by the University of Pittsburgh IACUC 1002340A-3.
心脏骤停（CA）会引发神经炎症，这可能在迟发性神经元死亡中起作用。在我们先前建立的以广泛神经元死亡为特征的室颤（VF）性CA大鼠模型中，我们检验了这样一种假设，即各个脑区具有特定的神经炎症反应，这可通过肿瘤坏死因子（TNF）α和其他细胞因子的脑区组织水平反映出来。在一项前瞻性研究中，将大鼠随机分为VF性CA 6分钟（CA6）组、8分钟（CA8）组或10分钟（CA10）组，或假手术组。在CA后3小时、6小时或14天，通过酶联免疫吸附测定（ELISA）和Luminex技术评估皮质、纹状体、海马体和小脑中的TNFα以及白细胞介素（IL）-1α、IL-1β、IL-2、IL-4、IL-6、IL-10、IL-12和干扰素γ。采用免疫组织化学法确定TNFα的细胞来源。CA导致了选择性TNFα反应，存在显著的区域和时间差异。CA后3小时，所有区域的TNFα水平均升高，升高程度取决于损伤持续时间。纹状体中观察到最明显的升高，在CA10组中与假手术组相比升高了20倍，与CA6组或CA8组相比分别升高了3倍（p<0.01）。纹状体中的TNFα水平在3小时至6小时之间下降，但在其他区域在3小时至14天之间升高。在14天时，CA6组全脑区域的TNFα水平仍比假手术组高两倍（p<0.01）。与明显的TNFα反应不同，其他细胞因子在CA6组和CA8组中与假手术组相比，在所有脑区仅显示出最小程度的升高，不过IL-1β在小脑和纹状体中升高了两倍（p<0.01）。TNFα与神经元共定位。总之，CA产生了一种持续时间依赖性的急性TNFα反应，纹状体中TNFα显著升高且与神经元共定位。TNFα水平升高至少持续两周。这种TNFα激增与CA后脑内其他细胞因子缺乏急性升高形成对比。鉴于纹状体是一个选择性易损脑区，我们的数据表明CA后神经元TNFα在纹状体中可能发挥作用，并为未来实验确定了治疗靶点。本研究经匹兹堡大学机构动物护理与使用委员会（IACUC）批准，批准号为1002340A-3。
