Repeated Low-Level Blast Overpressure Leads to Endovascular Disruption and Alterations in TDP-43 and Piezo2 in a Rat Model of Blast TBI
Repeated Low-Level Blast Overpressure Leads to Endovascular Disruption and Alterations in TDP-43 and Piezo2 in a Rat Model of Blast TBI
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DOI：
10.3389/fneur.2019.00766
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发表时间：
2019-07-30
影响因子：
3.4
通讯作者：
Sajja, Venkata Siva Sai Sujith
中科院分区：
文献类型：
--
作者：
Heyburn, Lanier;Abutarboush, Rania;Sajja, Venkata Siva Sai Sujith
最近的证据表明，在作战和训练环境中反复遭受低强度爆炸超压暴露与神经认知能力下降、神经炎症和神经退行性过程有关，这引起了人们对反复暴露于爆炸对服役人员大脑的累积有害影响的担忧。重复暴露于低水平的原发性爆炸可能会导致类似于轻度创伤性脑损伤 (TBI) 的症状（亚临床），并伴有进行性血管和细胞变化，这可能导致神经退行性变。在细胞水平上，与爆炸暴露相关的机械力可能会引起大脑细胞扰动，导致继发性损伤。为了检查重复爆炸对大脑的累积影响，使用先进的爆炸模拟器（ABS）来密切模拟“自由场”爆炸。大鼠每天接受 1-4 次爆炸（每天一次，间隔 24 小时），峰值事故压力为 13、16 或 19 psi，正向持续时间为 4-5 毫秒，横向或纵向均可。在爆炸暴露后测量血脑屏障 (BBB) 标记物（血管内皮生长因子 (VEGF)、occludin 和 claudin-5）、反式反应 DNA 结合蛋白 (TDP-43) 和机械敏感通道 Piezo2。反复冲击波暴露后 VEGF、occludin 和 claudin-5 表达的变化表明 BBB 发生了变化，而 BBB 已被证明在 TBI 后被破坏。 TDP-43 在大脑中受到非常严格的调节，在临床诊断的 TBI 患者中发现 TDP-43 的表达发生改变。 TDP-43 水平受到爆炸暴露次数和强度的不同影响，在 2 次暴露后下降，但在不同强度的更多次暴露后增加。最后，Piezo2 已被证明在爆炸暴露后失调，并且在多次中等程度的爆炸后观察到 Piezo2 增加，表明爆炸可能会导致大脑对机械刺激的敏感性发生变化，并可能导致细胞损伤。这些发现表明，反复暴露于爆炸的累积效应可导致大脑的病理生理变化，证明爆炸损伤与神经退行性疾病之间可能存在联系，这是了解如何预防暴露于爆炸的士兵中这些疾病的重要第一步。
Recent evidence linking repeated low-level blast overpressure exposure in operational and training environments with neurocognitive decline, neuroinflammation, and neurodegenerative processes has prompted concern over the cumulative deleterious effects of repeated blast exposure on the brains of service members. Repetitive exposure to low-level primary blast may cause symptoms (subclinical) similar to those seen in mild traumatic brain injury (TBI), with progressive vascular and cellular changes, which could contribute to neurodegeneration. At the cellular level, the mechanical force associated with blast exposure can cause cellular perturbations in the brain, leading to secondary injury. To examine the cumulative effects of repetitive blast on the brain, an advanced blast simulator (ABS) was used to closely mimic "free-field" blast. Rats were exposed to 1-4 daily blasts (one blast per day, separated by 24 h) at 13, 16, or 19 psi peak incident pressures with a positive duration of 4-5 ms, either in a transverse or longitudinal orientation. Blood-brain barrier (BBB) markers (vascular endothelial growth factor (VEGF), occludin, and claudin-5), transactive response DNA binding protein (TDP-43), and the mechanosensitive channel Piezo2 were measured following blast exposure. Changes in expression of VEGF, occludin, and claudin-5 after repeated blast exposure indicate alterations in the BBB, which has been shown to be disrupted following TBI. TDP-43 is very tightly regulated in the brain and altered expression of TDP-43 is found in clinically-diagnosed TBI patients. TDP-43 levels were differentially affected by the number and magnitude of blast exposures, decreasing after 2 exposures, but increasing following a greater number of exposures at various intensities. Lastly, Piezo2 has been shown to be dysregulated following blast exposure and was here observed to increase after multiple blasts of moderate magnitude, indicating that blast may cause a change in sensitivity to mechanical stimuli in the brain and may contribute to cellular injury. These findings reveal that cumulative effects of repeated exposures to blast can lead to pathophysiological changes in the brain, demonstrating a possible link between blast injury and neurodegenerative disease, which is an important first step in understanding how to prevent these diseases in soldiers exposed to blast.