中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2020, Vol. 15 ›› Issue (11): 2073-2081.doi: 10.4103/1673-5374.282258

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

人蛋白S治疗小鼠急性创伤性脑损伤

  

  • 出版日期:2020-11-15 发布日期:2020-08-23
  • 基金资助:

    该项工作得到罗彻斯特大学机构基金（2011NSG-Huang），美国国立卫生研究院的部分资助,以及来自贝勒斯科特与怀特医疗中心Hellen Vosberg McCrillus Plummer和Robert Robert Lee Plummer，Jr捐助的资金

Acute effects of human protein S administration after traumatic brain injury in mice

Xiaowei Wang1 , Jing Tong2, Xiaodi Han3, Xiaoming Qi4, Jun Zhang5, Erxi Wu4, 6, Jason H. Huang 4, 6   

  1. 1 Center for Translational Neuromedicine, University of Rochester, Rochester, NY, USA
    2 Department of Neurosurgery, 4 th Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
    3 Department of Neurosurgery, Tiantan Hospital, Beijing, China
    4 Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, USA
    5 Department of Neurosurgery, PLA General Hospital, Beijing, China
    6 College of Medicine, Texas A&M Health Science Center, Temple, TX, USA
  • Online:2020-11-15 Published:2020-08-23
  • Contact: Jason H. Huang, MD,Jason.Huang@BSWHealth.org.
  • Supported by:
    This work was supported in part by a University of Rochester Institutional Grant (2011NSG-Huang; to JHH), National Institute of Health (NIH-R01-NS-067435; to JHH), and the Hellen Vosberg McCrillus Plummer and Robert Edward Lee Plummer, Jr, Endowment fund from Baylor Scott & White Medical Center (to JHH).

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摘要：

目前尚未发现针对急性创伤性脑损伤的有效药物治疗方法，其障碍在于脑损伤后的继发性损伤发病机制较为复杂。为明确天然多功能蛋白蛋白S对急性创伤性脑损伤的干预效果，于控制性脑皮质撞击创伤性脑损伤小鼠模型建立后10-15min，按1mg/kg剂量静脉内单次注射蛋白S或溶媒磷酸盐缓冲盐水。与未治疗组相比，在损伤后24h，蛋白S治疗组小鼠显示出明显的脑水肿改善和良好的运动协调性，并减轻了进行性脑组织损伤。免疫组织化学和针对caspase-3，Bcl-2的免疫印迹以及TUNEL检测分析表明，蛋白S治疗组小鼠脑组织中细胞凋亡受到明显抑制。CD11b的免疫组织化学染色结果显示，在蛋白S治疗组中白细胞浸润有限。此外，经蛋白S处理还提高了损伤区脑组织aquaporin-4的表达水平，这可能是其减轻水肿功能的潜在机制。这些结果表明，创伤性脑损伤后立即进行静脉蛋白S治疗，可减轻脑损伤急性期炎症和细胞凋亡，并降低继发性损伤程度，从而改善预后。实验经美国罗彻斯特大学医学中心动物资源大学委员会（UCAR）于2013年11月12日批准了动物使用协议（AUPs）（批准号UCAR-2008-102R）。

orcid: 0000-0002-4426-0168 (Jason H. Huang)

关键词:

创伤性脑损伤, 蛋白S, TBI治疗, 继发性脑损伤, 炎症, 细胞凋亡, 水肿, 急性期

Abstract: Despite years of effort, no effective acute phase treatment has been discovered for traumatic brain injury. One impediment to successful drug development is entangled secondary injury pathways. Here we show that protein S, a natural multifunctional protein that regulates coagulation, inflammation, and apoptosis, is able to reduce the extent of multiple secondary injuries in traumatic brain injury, and therefore improve prognosis. Mice subjected to controlled cortical impact were treated acutely (10–15 minutes post-injury) with a single dose of either protein S (1 mg/kg) or vehicle phosphate buffered saline via intravenous in- jection. At 24 hours post-injury, compared to the non-treated group, the protein S treated group showed substantial improvement of edema and fine motor coordination, as well as mitigation of progressive tissue loss. Immunohistochemistry and western blot targeting caspase-3, B-cell lymphoma 2 (Bcl-2) along with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that apoptosis was suppressed in treated animals. Immunohistochemistry targeting CD11b showed limited leukocyte infil- tration in the protein S-treated group. Moreover, protein S treatment increased the ipsilesional expression of aquaporin-4, which may be the underlying mechanism of its function in reducing edema. These results indicate that immediate intravenous protein S treatment after controlled cortical impact is beneficial to traumatic brain injury prognosis. Animal Use Protocols (AUPs) were approved by the University Commit- tee on Animal Resources (UCAR) of University of Rochester Medical Center (approval No. UCAR-2008- 102R) on November 12, 2013.

Key words: apoptosis, aquaporin-4, controlled cortical impact, edema, inflammation, protein S, TBI therapy, traumatic brain injury