Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Center for Brain Science, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Department of Neurosurgery, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Neuroscience. 2022 Nov 1;503:45-57. doi: 10.1016/j.neuroscience.2022.08.023. Epub 2022 Sep 8.
Traumatic brain injury (TBI) is the leading cause of death in young adults and the main cause of mortality and disability across all ages worldwide. We previously analyzed the expression profile data of TBI models obtained from the Gene Expression Omnibus (GEO) database and found that the seripina3n mRNA was markedly upregulated in the acute phase of TBI in four mRNA expression profile data sets, indicating that serpina3n may be involved in the pathophysiological process of TBI. Therefore, we further investigated the biological role and molecular mechanism of serpina3n in traumatic brain injury in this study. As a result, the endogenous level of sepina3n was markedly elevated in the cortex around the contusion sit in mice at day 1 and day 3 after TBI. Inhibiting the expression of serpina3n caused aggravation of neutrophil elastase (NE) expression, BBB disruption, and neurological deficit. With the inactivation of NE, even if serpina3n was silenced, the disruption of the BBB was not further aggravated. In vitro experiments further proved that recombinant serpina3n dose-dependently inhibited the activity of recombinant NE. Based on the above, this study demonstrated that the endogenous level of sepina3n was significantly elevated in the cortex around the contusion sit after TBI in mice, which reduced the secondary blood-brain barrier disruption by inhibiting the activity of neutrophil elastase.
创伤性脑损伤（TBI）是导致年轻人死亡的主要原因，也是全球各年龄段人群死亡和残疾的主要原因。我们之前分析了从基因表达综合数据库（GEO）数据库获得的 TBI 模型的表达谱数据，发现 seripina3n mRNA 在四个 mRNA 表达谱数据集中，TBI 的急性期明显上调，表明 serpina3n 可能参与 TBI 的病理生理过程。因此，我们在这项研究中进一步研究了 serpina3n 在创伤性脑损伤中的生物学作用和分子机制。结果表明，TBI 后第 1 天和第 3 天，小鼠挫伤部位周围皮质中的内源性 sepina3n 水平明显升高。抑制 serpina3n 的表达导致中性粒细胞弹性蛋白酶（NE）表达、血脑屏障破坏和神经功能缺损加重。随着 NE 的失活，即使沉默 serpina3n，血脑屏障的破坏也不会进一步加重。体外实验进一步证明重组 serpina3n 可剂量依赖性抑制重组 NE 的活性。综上所述，本研究表明，TBI 后小鼠挫伤部位周围皮质中的内源性 sepina3n 水平显著升高，通过抑制中性粒细胞弹性蛋白酶的活性，减少继发性血脑屏障破坏。
