1 Department of Pathology & Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri.
2 Bedford VA Medical Center, Bedford, Massachusetts.
J Neurotrauma. 2019 May 15;36(10):1591-1605. doi: 10.1089/neu.2018.6114. Epub 2019 Jan 14.
Service members during military actions or combat training are frequently exposed to primary blasts by weaponry. Most studies have investigated moderate or severe brain injuries from blasts generating overpressures >100 kPa, whereas understanding the pathophysiology of low-intensity blast (LIB)-induced mild traumatic brain injury (mTBI) leading to neurological deficits remains elusive. Our recent studies, using an open-field LIB-induced mTBI mouse model with a peak overpressure at 46.6 kPa, demonstrated behavioral impairments and brain nanoscale damages, notably mitochondrial and axonal ultrastructural changes. In this study, we used tandem mass tagged (TMT) quantitative proteomics and bioinformatics analysis to seek insights into the molecular mechanisms underlying ultrastructural pathology. Changes in global- and phospho-proteomes were determined at 3 and 24 h and at 7 and 30 days post injury (DPI), in order to investigate the biochemical and molecular correlates of mitochondrial dysfunction. Results showed striking dynamic changes in a total of 2216 proteins and 459 phosphorylated proteins at vary time points after blast. Disruption of key canonical pathways included evidence of mitochondrial dysfunction, oxidative stress, axonal/cytoskeletal/synaptic dysregulation, and neurodegeneration. Bioinformatic analysis identified blast-induced trends in networks related to cellular growth/development/movement/assembly and cell-to-cell signaling interactions. With observations of proteomic changes, we found LIB-induced oxidative stress associated with mitochondrial dysfunction mainly at 7 and 30 DPI. These dysfunctions included impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated respiration-relevant enzyme activities. Insights on the early pathogenesis of primary LIB-induced brain damage provide a template for further characterization of its chronic effects, identification of potential biomarkers, and targets for intervention.
在军事行动或战斗训练中，军人经常会受到武器的初级爆炸冲击。大多数研究都调查了超过 100kPa 的超压产生的中度或重度脑损伤，而对于导致神经功能缺损的低强度爆炸（LIB）引起的轻度创伤性脑损伤（mTBI）的病理生理学的理解仍难以捉摸。我们最近的研究使用峰值超压为 46.6kPa 的开放式 LIB 诱导 mTBI 小鼠模型，证明了行为障碍和大脑纳米级损伤，特别是线粒体和轴突超微结构的变化。在这项研究中，我们使用串联质量标签（TMT）定量蛋白质组学和生物信息学分析来寻求对超微结构病理学的分子机制的深入了解。在损伤后 3 小时和 24 小时以及 7 天和 30 天（DPI），确定了全局和磷酸化蛋白质组的变化，以研究线粒体功能障碍的生化和分子相关性。结果显示，在爆炸后不同时间点，共有 2216 种蛋白质和 459 种磷酸化蛋白质发生了显著的动态变化。关键的典型途径的破坏包括线粒体功能障碍、氧化应激、轴突/细胞骨架/突触失调和神经退行性变的证据。生物信息学分析确定了与细胞生长/发育/运动/组装和细胞间信号转导相互作用相关的网络中与爆炸相关的趋势。随着蛋白质组变化的观察，我们发现 LIB 诱导的氧化应激与线粒体功能障碍有关，主要发生在 7 天和 30 天 DPI。这些功能障碍包括分裂-融合动力学受损、自噬减少、氧化磷酸化减少以及呼吸相关酶活性的代偿。原发性 LIB 引起的脑损伤的早期发病机制的见解为进一步描述其慢性影响、鉴定潜在的生物标志物和干预靶点提供了模板。
