Astrocyte Reactivity Following Blast Exposure Involves Aberrant Histone Acetylation.
Astrocyte Reactivity Following Blast Exposure Involves Aberrant Histone Acetylation.
复制标题
DOI：
10.3389/fnmol.2016.00064
复制
发表时间：
2016
影响因子：
4.8
通讯作者：
VandeVord PJ
中科院分区：
文献类型：
--
作者：
Bailey ZS;Grinter MB;VandeVord PJ
爆炸性神经损伤（BINT）是军队和平民人群中常见的损伤。损伤的特征在于细胞水平的持续炎症，其表现为多种认知和功能障碍。转录的表观遗传调控为基因表达和细胞功能提供了重要的控制机制，这可能是慢性炎症和导致神经退行性变的基础。我们推测组蛋白乙酰化模式的改变可能与爆炸诱导的炎症和神经胶质细胞的慢性激活有关。本研究旨在阐明损伤后组蛋白乙酰化的变化以及这些变化在病理学中的作用。使Sprague道利大鼠在高级冲击波模拟器（ABS）中经受10或17 psi的冲击波超压。假手术动物在没有爆炸暴露的情况下经历相同的程序。在损伤后第2天和第7天，使用新物体识别（NOR）测试测量记忆障碍。在第7天收集组织用于蛋白质印迹和免疫组织化学（IHC）分析。假手术动物在每个时间点显示出完整的记忆。新物体辨别力在损伤后2 ~ 7天显著下降（p < 0.05）。这是记忆力受损的征兆。免疫印迹分析显示，胶质细胞酸性蛋白（GFAP），一种已知的活化星形胶质细胞的标志物，在两个损伤组的冲击波暴露后，在前额叶皮层（PFC）升高。组蛋白提取物的分析显示PFC内任何总组蛋白水平没有变化。然而，组蛋白H2 b、H3和H4的乙酰化水平在两组中均降低（p < 0.05）。共定位免疫荧光用于进一步研究组蛋白乙酰化降低与星形胶质细胞活化之间的任何潜在相关性。这些实验显示暴露于17 psi冲击波而不是10 psi冲击波的星形胶质细胞中H3乙酰化的类似降低。通过聚合酶链反应（PCR）阵列对基因表达的进一步研究显示，参与神经炎症过程的几种细胞因子和细胞因子受体调节异常。我们已经发现异常的组蛋白乙酰化模式与胚细胞诱导的星形胶质细胞增生和认知障碍有关。进一步了解它们在损伤进展中的作用可能会导致新的治疗靶点。
Blast induced neurotrauma (BINT) is a prevalent injury within military and civilian populations. The injury is characterized by persistent inflammation at the cellular level which manifests as a multitude of cognitive and functional impairments. Epigenetic regulation of transcription offers an important control mechanism for gene expression and cellular function which may underlie chronic inflammation and result in neurodegeneration. We hypothesize that altered histone acetylation patterns may be involved in blast induced inflammation and the chronic activation of glial cells. This study aimed to elucidate changes to histone acetylation occurring following injury and the roles these changes may have within the pathology. Sprague Dawley rats were subjected to either a 10 or 17 psi blast overpressure within an Advanced Blast Simulator (ABS). Sham animals underwent the same procedures without blast exposure. Memory impairments were measured using the Novel Object Recognition (NOR) test at 2 and 7 days post-injury. Tissues were collected at 7 days for Western blot and immunohistochemistry (IHC) analysis. Sham animals showed intact memory at each time point. The novel object discrimination decreased significantly between two and 7 days for each injury group (p < 0.05). This is indicative of the onset of memory impairment. Western blot analysis showed glial fibrillary acidic protein (GFAP), a known marker of activated astrocytes, was elevated in the prefrontal cortex (PFC) following blast exposure for both injury groups. Analysis of histone protein extract showed no changes in the level of any total histone proteins within the PFC. However, acetylation levels of histone H2b, H3, and H4 were decreased in both groups (p < 0.05). Co-localization immunofluorescence was used to further investigate any potential correlation between decreased histone acetylation and astrocyte activation. These experiments showed a similar decrease in H3 acetylation in astrocytes exposed to a 17 psi blast but not a 10 psi blast. Further investigation of gene expression by polymerase chain reaction (PCR) array, showed dysregulation of several cytokine and cytokine receptors that are involved in neuroinflammatory processes. We have shown aberrant histone acetylation patterns involved in blast induced astrogliosis and cognitive impairments. Further understanding of their role in the injury progression may lead to novel therapeutic targets.