中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (3): 523-530.doi: 10.4103/1673-5374.293152

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

阿托伐他汀联合小剂量地塞米松治疗慢性硬膜下血肿引起的血管内皮细胞功能障碍

  

  • 出版日期:2021-03-15 发布日期:2020-12-17
  • 基金资助:

    国家自然科学基金（81671380，81720108015，81930031，81771221，81901525）；中国天津医科大学临床研究项目（2017kylc007）；中国天津市自然科学基金（17JCZDJC35900）；中国天津市科技计划项目（19YFZCSY00650）

Atorvastatin combined with low-dose dexamethasone for vascular endothelial cell dysfunction induced by chronic subdural hematoma

Yue-Shan Fan1, 2, 3, #, Bo Wang1, 2, 3, #, Dong Wang1, 2, 3, Xin Xu4, Chuang Gao1, 2, Ying Li1, 2, Shu Zhang1, 2, Gui-Li Yang1, 2, Xiao Liu1, 2, Rong-Cai Jiang1, 2, *, Jian-Ning Zhang1, 2, *   

  1. 1 Department of Neurosurgery, General Hospital of Tianjin Medical University, Tianjin, China;  2 Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin, China;  3 Graduate School, Tianjin Medical University, Tianjin, China;  4 Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China
  • Online:2021-03-15 Published:2020-12-17
  • Contact: Jian-Ning Zhang, MD, jianningzhang@hotmail.com; Rong-Cai Jiang, MD, jiang116216@163.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 81671380 (to DW), 81720108015 (to JNZ), 81930031 (to JNZ), 81771221 (to YL), and 81901525 (to SZ); the Clinical Study of Tianjin Medical University of China, No. 2017kylc007 (to RCJ); the Natural Science Foundation of Tianjin of China, No. 17JCZDJC35900 (to DW); the Tianjin Science and Technology Plan Program of China, No.19YFZCSY00650 (to RCJ). 

PDF

45

摘要：

阿托伐他汀已被证明是治疗慢性硬膜下血肿的一种安全有效的非手术治疗选择。地塞米松具有抗炎及免疫调节作用，且小剂量地塞米松也已在治疗强制性脊柱炎、获得性社区肺炎等多种疾病中被证明是安全有效的。那么阿托伐他汀和小剂量地塞米松治疗慢性硬膜下血肿的效果如何？试验采集中国天津医科大学总医院慢性硬膜下血肿患者的血肿样本，并以1:1的比例在内皮细胞培养基中稀释，在培养基中单独加入阿托伐他汀或单独加入地塞米松或两者联合应用进行干预。(1) 试验通过跳跃探针离子电导显微镜(HPICM)和通透性实验检测发现，筛选出改善内皮细胞的通透性的最佳剂量为阿托伐他汀0.1 μM和地塞米松0.1 μM，阿托伐他汀和地塞米松单独和联合处理均能明显改善损伤内皮细胞恢复情况。(2) 进一步进行动物实验：将小鼠皮下注射稀释的血肿液，然后采用单独阿托伐他汀（0.1μM）或单独地塞米松或两者联合皮下注射进行干预；(3) 采用HPICM、Western-bolt和PCR检测人脑微血管内皮细胞状态和细胞紧密连接蛋白水平发现，阿托伐他汀和地塞米松单独和联合处理均可减少血肿液造成的小鼠皮下血管渗漏，两者联合应用的疗效明显优于单独应用，人脑微血管内皮细胞Krüppel样因子KLF-2蛋白显著升高，而且各治疗组的血管通透标记物紧密连接蛋白VE-cadherin表达均高于血肿损伤组；(4)实验结果发现，慢性硬膜下血肿患者的血肿液可能会损害血管内皮细胞。然而，用阿托伐他汀和小剂量地塞米松治疗可以通过增加血肿损伤后紧密连接蛋白的表达来挽救内皮细胞的功能障碍。与单一阿托伐他汀治疗相比，阿托伐他汀和小剂量地塞米松联合干预的治疗效果更好，而KLF-2升高可能在慢性硬膜下血肿的治疗过程中起重要作用。

https://orcid.org/0000-0002-7290-0994 (Jian-Ning Zhang); 

0000-0002-9119-0115 (Rong-Cai Jiang)

关键词: 脑, 脑外伤, 细胞, 中枢神经系统, 炎症, 可塑性, 蛋白质, 修复

Abstract: Atorvastatin has been shown to be a safe and effective non-surgical treatment option for patients with chronic subdural hematoma. However, treatment with atorvastatin is not effective in some patients, who must undergo further surgical treatment. Dexamethasone has anti-inflammatory and immunomodulatory effects, and low dosages are safe and effective for the treatment of many diseases, such as ankylosing spondylitis and community-acquired pneumonia. However, the effects of atorvastatin and low-dose dexamethasone for the treatment of chronic subdural hematoma remain poorly understood. Hematoma samples of patients with chronic subdural hematoma admitted to the General Hospital of Tianjin Medical University of China were collected and diluted in endothelial cell medium at 1:1 as the hematoma group. Atorvastatin, dexamethasone, or their combination was added to the culture medium. The main results were as follows: hopping probe ion conductance microscopy and permeability detection revealed that the best dosages to improve endothelial cell permeability were 0.1 μM atorvastatin and 0.1 μM dexamethasone. Atorvastatin, dexamethasone, or their combination could markedly improve the recovery of injured endothelial cells. Mice subcutaneously injected with diluted hematoma solution and then treated with atorvastatin, dexamethasone, or their combination exhibited varying levels of rescue of endothelial cell function. Hopping probe ion conductance microscopy, western blot assay, and polymerase chain reaction to evaluate the status of human cerebral endothelial cell status and expression level of tight junction protein indicated that atorvastatin, dexamethasone, or their combination could reduce subcutaneous vascular leakage caused by hematoma fluid. Moreover, the curative effect of the combined treatment was significantly better than that of either single treatment. Expression of Krüppel-like factor 2 protein in human cerebral endothelial cells was significantly increased, as was expression of the tight junction protein and vascular permeability marker vascular endothelial cadherin in each treatment group compared with the hematoma stimulation group. Hematoma fluid in patients with chronic subdural hematoma may damage vascular endothelial cells. However, atorvastatin combined with low-dose dexamethasone could rescue endothelial cell dysfunction by increasing the expression of tight junction proteins after hematoma injury. The effect of combining atorvastatin with low-dose dexamethasone was better than that of atorvastatin alone. Increased expression of Krüppel-like factor 2 may play an important role in the treatment of chronic subdural hematoma. The animal protocols were approved by the Animal Care and Use Committee of Tianjin Medical University of China on July 31, 2016 (approval No. IRB2016-YX-036). The study regarding human hematoma samples was approved by the Ethics Committee of Tianjin Medical University of China on July 31, 2018 (approval No. IRB2018-088-01).

Key words: brain, brain trauma, cells, central nervous system, inflammation, plasticity, protein, repair