Improvised explosive devices (IEDs) represent the leading causes for casualties among civilians and soldiers in the present war (including counter-terrorism). Traumatic brain injury (TBI) caused by IEDs results in different degrees of impairment of cognition and behavior, but the exact brain pathophysiological mechanism following exposure to blast has not been clearly investigated. Here, we sought to establish a rat model of closed-head blast injury using compressed gas to deliver a single blast only to the brain without systemic injuries. The cognitive functions of these bTBI models were assessed by Morris Water Maze test (MWM test). The HE staining, flow cytometry, ELISA and Western Blotting were used to measure the effects of shock wave on general histology, regulatory T (Treg) cells percentage, inflammatory reactions, the expression and phosphorylation level of tau, respectively. In addition, the brain water content and 24 -h mortality were also assessed. As the distance from the blast source increased, the input pressure did not change, the overpressure decreased, and the mortality decreased. Receiver operating characteristic (ROC) curves for predicting 24 -h mortality using peak overpressure fits with the following areas under ROC curves: 0.833. In 2 weeks after blast injury, cognitive tests revealed significantly decreased performance at 20 cm distance from the blast (about 136.44 kPa) as demonstrated by increased escape latency in the acquisition phase, and decreased crossing numbers in the probe phase of MWM test. Interestingly, a single blast exposure (at 20 cm) lead to significantly increased tau phosphorylation at the Thr205 epitope but not at the Ser404 and Ser262 epitopes at 12 h, 24 h, 3d, and 7d after blast injury. Blast decreased the percentage of CD4+T cells, CD8+T cells, Treg cells and lymphocytes at different time points after blast injury, and blast increased the percentage of neutrophils at 12 h after blast injury and significantly increased IL-6 production at 12 h, 24 h and 3d after blast injury. In addition, blast lead to an increase of brain edema at 24 h and 3d after blast injury. However, no obvious alterations in brain gross pathology were found acutely in the blast-exposed rats. In conclusion, we established a rat model of simple craniocerebral blast injury characterized by impairment of cognitive function, Thr205 phosphorylation of tau, decreased Treg cells and increased inflammatory reactions and brain edema. We expect this model may help clarify the underlying mechanism after blast injury and possibly serve as a useful animal model in the development of novel therapeutic and diagnostic approaches.

中文翻译：

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一种由压缩气体引起的爆炸诱发的创伤性脑损伤的新模型在大鼠中产生了持续的认知缺陷：涉及 Thr205 表位的 tau 磷酸化。

简易爆炸装置 (IED) 是当前战争（包括反恐）中平民和士兵伤亡的主要原因。由简易爆炸装置引起的创伤性脑损伤 (TBI) 导致不同程度的认知和行为受损，但暴露于爆炸后的确切脑病理生理机制尚未得到明确研究。在这里，我们试图建立一个使用压缩气体仅向大脑传递一次爆炸而没有全身性损伤的闭合性头部爆炸损伤的大鼠模型。这些 bTBI 模型的认知功能通过莫里斯水迷宫测试（MWM 测试）进行评估。HE染色、流式细胞术、ELISA和Western Blotting用于测量冲击波对一般组织学、调节性T（Treg）细胞百分比、炎症反应、tau 的表达和磷酸化水平。此外，还评估了脑含水量和 24 小时死亡率。随着距爆源距离的增加，输入压力不变，超压降低，死亡率降低。使用峰值超压预测 24 小时死亡率的接受者操作特征 (ROC) 曲线与 ROC 曲线下的以下面积拟合：0.833。在爆炸损伤后 2 周内，认知测试显示在距爆炸 20 cm 距离（约 136.44 kPa）处的性能显着下降，这表现为获取阶段的逃逸潜伏期增加，以及 MWM 测试的探测阶段的交叉数减少。有趣的是，在爆炸损伤后 12 小时、24 小时、3 天和 7 天，单次爆炸暴露（20 厘米）导致 Thr205 表位的 tau 磷酸化显着增加，但不是 Ser404 和 Ser262 表位的 tau 磷酸化。Blast 降低了爆炸伤后不同时间点的 CD4+T 细胞、CD8+T 细胞、Treg 细胞和淋巴细胞的百分比，爆炸伤后 12 h 时 Blast 增加了中性粒细胞的百分比，并在 12 h 显着增加了 IL-6 的产生, 24 h 和 3d 爆炸伤后。此外，爆炸导致爆炸伤后 24 h 和 3 d 脑水肿加重。然而，在暴露于爆炸的大鼠中没有发现明显的脑大体病理学改变。总之，我们建立了以认知功能障碍、tau 的 Thr205 磷酸化、Treg 细胞减少，炎症反应和脑水肿增加。我们预计该模型可能有助于阐明爆炸损伤后的潜在机制，并可能作为开发新治疗和诊断方法的有用动物模型。