Wei Xing, Zhou Yaqing, Song Jinning, Zhao Junjie, Huang Tingqin, Zhang Ming, Zhao Yonglin
Department of Gynaecology and Obstetrics, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
Department of Oncology, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, People's Republic of China.
Inflammation. 2023 Feb;46(1):129-145. doi: 10.1007/s10753-022-01716-y. Epub 2022 Jul 20.
Hyperglycemia aggravates brain damage after diffuse axonal injury (DAI), but the underlying mechanisms are not fully defined. In this study, we aimed to investigate a possible role for hyperglycemia in the disruption of blood-brain barrier (BBB) integrity in a rat model of DAI and the underlying mechanisms. Accordingly, 50% glucose was intraperitoneally injected after DAI to establish the hyperglycemia model. Hyperglycemia treatment aggravated neurological impairment and axonal injury, increased cell apoptosis and glial activation, and promoted the release of inflammatory factors, including TNF-α, IL-1β, and IL-6. It also exacerbated BBB disruption and decreased the expression of tight junction-associated proteins, including ZO-1, claudin-5, and occludin-1, whereas the PPARγ agonist rosiglitazone (RSG) had the opposite effects. An in vitro BBB model was established by a monolayer of human microvascular endothelial cells (HBMECs). Hyperglycemia induction worsened the loss of BBB integrity induced by oxygen and glucose deprivation (OGD) by increasing the release of inflammatory factors and decreasing the expression of tight junction-associated proteins. Hyperglycemia further reduced the expression of PPARγ and caveolin-1, which significantly decreased after DAI and OGD. Hyperglycemia also further increased the expression of toll-like receptor 4 (TLR4), which significantly increased after OGD. Subsequently, the PPARγ agonist RSG increased caveolin-1 expression and decreased TLR4 expression and inflammatory factor levels. In contrast, caveolin-1 siRNA abrogated the protective effects of RSG in the in vitro BBB model of hyperglycemia by increasing TLR4 and Myd88 expression and the levels of inflammatory factors, including TNF-α, IL-1β, and IL-6. Collectively, we demonstrated that hyperglycemia was involved in mediating secondary injury after DAI by disrupting BBB integrity by inducing inflammation through the PPARγ/caveolin-1/TLR4 pathway.
高血糖会加重弥漫性轴索损伤（DAI）后的脑损伤，但其潜在机制尚未完全明确。在本研究中，我们旨在探讨高血糖在DAI大鼠模型中血脑屏障（BBB）完整性破坏中的可能作用及其潜在机制。因此，在DAI后腹腔注射50%葡萄糖以建立高血糖模型。高血糖治疗加重了神经功能障碍和轴索损伤，增加了细胞凋亡和胶质细胞活化，并促进了包括TNF-α、IL-1β和IL-6在内的炎症因子释放。它还加剧了BBB破坏，并降低了紧密连接相关蛋白（包括ZO-1、claudin-5和occludin-1）的表达，而PPARγ激动剂罗格列酮（RSG）则具有相反的作用。通过人微血管内皮细胞（HBMECs）单层建立体外BBB模型。高血糖诱导通过增加炎症因子释放和降低紧密连接相关蛋白表达，加重了氧糖剥夺（OGD）诱导的BBB完整性丧失。高血糖进一步降低了PPARγ和小窝蛋白-1的表达，这在DAI和OGD后显著降低。高血糖还进一步增加了Toll样受体4（TLR4）的表达，这在OGD后显著增加。随后，PPARγ激动剂RSG增加了小窝蛋白-1表达，降低了TLR4表达和炎症因子水平。相比之下，小窝蛋白-1 siRNA通过增加TLR4和髓样分化因子88（Myd88）表达以及包括TNF-α、IL-1β和IL-6在内的炎症因子水平，消除了RSG在高血糖体外BBB模型中的保护作用。总体而言，我们证明高血糖通过PPARγ/小窝蛋白-1/TLR4途径诱导炎症，破坏BBB完整性，从而参与介导DAI后的继发性损伤。
