Pathological hemodynamic changes and leukocyte transmigration disrupt the blood-spinal cord barrier after spinal cord injury.
Pathological hemodynamic changes and leukocyte transmigration disrupt the blood-spinal cord barrier after spinal cord injury.
复制标题
DOI：
10.1186/s12974-023-02787-w
复制
发表时间：
2023-05-20
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
血-脊髓屏障（Blood-spinal cord barrier，BSCB）的破坏是脊髓损伤（spinal cord injury，SCI）后的一个重要事件，它使血液中的有害物质进入神经组织，加重继发性损伤。然而，有限的机械冲击通常会导致SCI中大规模的BSCB破坏。在SCI急性期，BSCB的破坏是如何沿着脊髓传播的尚不清楚。因此，缺乏适当的临床治疗策略。在野生型和LysM-YFP转基因小鼠中建立SCI挫伤小鼠模型。进行体内双光子成像和补充研究，包括免疫染色、毛细管蛋白质印迹和全组织清除，以监测BSCB破坏并验证相关损伤机制。临床应用的目标温度管理（TTM），以降低核心体温的衰减BSCB中断的功效进行了测试。在几分钟内，在挫伤震中检测到屏障泄漏，然后逐渐蔓延到更远的地区。主要紧密连接蛋白的膜表达在损伤后4小时保持不变。伤后15 min，多节段脊髓小血管间的细胞旁紧密连接出现大量连接间隙。在静脉系统中观察到之前未注意到的病理性血流动力学变化，这可能通过对BSCB施加异常物理力而促进间隙形成和屏障渗漏。白细胞在SCI后30分钟内迅速开始穿过BSCB，积极促进间隙形成和屏障渗漏。诱导白细胞迁移产生间隙形成和屏障渗漏。此外，病理性血流动力学变化或白细胞迁移的药理学缓解减少了间隙形成和屏障渗漏。TTM对SCI早期BSCB的保护作用很小，仅部分减轻白细胞浸润。我们的数据表明，在SCI的早期BSCB中断是一个继发性的变化，这是由广泛的间隙形成的紧密连接。病理性血流动力学改变和白细胞迁移有助于间隙的形成，这可能会促进我们对BSCB破坏的理解，并为潜在的治疗策略提供新的线索。最终，TTM不足以保护早期SCI的BSCB。在线版本包含补充材料，可通过10.1186/s12974-023-02787-w获得。
Blood–spinal cord barrier (BSCB) disruption is a key event after spinal cord injury (SCI), which permits unfavorable blood-derived substances to enter the neural tissue and exacerbates secondary injury. However, limited mechanical impact is usually followed by a large-scale BSCB disruption in SCI. How the BSCB disruption is propagated along the spinal cord in the acute period of SCI remains unclear. Thus, strategies for appropriate clinical treatment are lacking. A SCI contusion mouse model was established in wild-type and LysM-YFP transgenic mice. In vivo two-photon imaging and complementary studies, including immunostaining, capillary western blotting, and whole-tissue clearing, were performed to monitor BSCB disruption and verify relevant injury mechanisms. Clinically applied target temperature management (TTM) to reduce the core body temperature was tested for the efficacy of attenuating BSCB disruption. Barrier leakage was detected in the contusion epicenter within several minutes and then gradually spread to more distant regions. Membrane expression of the main tight junction proteins remained unaltered at four hours post-injury. Many junctional gaps emerged in paracellular tight junctions at the small vessels from multiple spinal cord segments at 15 min post-injury. A previously unnoticed pathological hemodynamic change was observed in the venous system, which likely facilitated gap formation and barrier leakage by exerting abnormal physical force on the BSCB. Leukocytes were quickly initiated to transverse through the BSCB within 30 min post-SCI, actively facilitating gap formation and barrier leakage. Inducing leukocyte transmigration generated gap formation and barrier leakage. Furthermore, pharmacological alleviation of pathological hemodynamic changes or leukocyte transmigration reduced gap formation and barrier leakage. TTM had very little protective effects on the BSCB in the early period of SCI other than partially alleviating leukocyte infiltration. Our data show that BSCB disruption in the early period of SCI is a secondary change, which is indicated by widespread gap formation in tight junctions. Pathological hemodynamic changes and leukocyte transmigration contribute to gap formation, which could advance our understanding of BSCB disruption and provide new clues for potential treatment strategies. Ultimately, TTM is inadequate to protect the BSCB in early SCI. The online version contains supplementary material available at 10.1186/s12974-023-02787-w.
登录
查看更多内容
影响因子：
4.2
作者：
Dietrich, W. Dalton;Atkins, Coleen M.;Bramlett, Helen M.
通讯作者：
Bramlett, Helen M.
影响因子：
9.3
作者：
Chio, Jonathon Chon Teng;Wang, Jian;Fehlings, Michael G.
通讯作者：
Fehlings, Michael G.
影响因子：
2.9
作者：
Armao, D;Kornfeld, M;Rosenberg, GA
通讯作者：
Rosenberg, GA
影响因子：
15.9
作者：
BORREGAARD, N;KJELDSEN, L;JOHNSEN, AH
通讯作者：
JOHNSEN, AH
影响因子：
33.6
作者：
Chiu JJ;Chien S
通讯作者：
Chien S