Liao Jianwen, Zhang Mingchao, Shi Zichuan, Lu Hao, Wang Lichen, Fan Weijia, Tong Xiaoguang, Yan Hua
Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin Neurosurgical Institute, Tianjin, China.
Clinical College of Neurology, Neurosurgery, and Neurorehabilitation, Tianjin Medical University, Tianjin, China.
J Neurotrauma. 2023 Feb;40(3-4):383-394. doi: 10.1089/neu.2022.0150. Epub 2022 Oct 26.
Brain edema is the most common and fatal complication after traumatic brain injury (TBI). Meningeal lymphatic vessels (MLVs) are the conduits that transport cerebrospinal fluid (CSF) and macromolecules to deep extracranial cervical lymph nodes (dCLNs). After TBI, the drainage function of MLVs can become impaired. However, the scenario in which the improvement of the function of MLVs can promote brain edema absorption after TBI has not been reported. Therefore, the purpose of this study was to investigate the effects of ketoprofen, 9-cis retinoic acid (RA) and vascular endothelial cell growth factor-C (VEGF-C), which promote the proliferation of peripheral lymphatic vessels, on the cerebellar medullary cistern injection of TBI rats, as well as their mechanism of action on brain edema after TBI. In the experiment, we found that ketoprofen, 9-cisRA, and VEGF-C can improve the function of MLVs, promote the extracranial drainage of CSF and the absorption of brain edema, weaken the neuroinflammatory response, reduce reactive oxygen species (ROS) production, maintain the structural integrity of MLVs, and improve neurological function. In addition, ketoprofen, 9-cisRA, and VEGF-C upregulated the lymphatic-specific proteins VEGF receptor (VEGFR)3, PROX1, forkhead box protein C2 (FOXC2), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1). These results indicate that ketoprofen, 9-cisRA, and VEGF-C may maintain the integrity of the meningeal lymphatic wall and promote lymphatic proliferation by upregulating the expression of lymphatic vessel-specific proteins, improve meningeal lymphatic function after TBI, promote CSF drainage and brain edema absorption, reduce the immune response of the nervous system, and reduce ROS formation, thereby improving prognoses. These findings may provide new ideas for the treatment of brain edema after TBI.
脑水肿是创伤性脑损伤（TBI）后最常见且致命的并发症。脑膜淋巴管（MLVs）是将脑脊液（CSF）和大分子转运至颅外深部颈淋巴结（dCLNs）的管道。TBI后，MLVs的引流功能可能受损。然而，MLVs功能改善可促进TBI后脑水肿吸收的情况尚未见报道。因此，本研究旨在探讨促进外周淋巴管增殖的酮洛芬、9-顺式视黄酸（RA）和血管内皮生长因子-C（VEGF-C）对TBI大鼠小脑延髓池注射后的影响及其对TBI后脑水肿的作用机制。在实验中，我们发现酮洛芬、9-顺式RA和VEGF-C可改善MLVs的功能，促进CSF的颅外引流和脑水肿的吸收，减弱神经炎症反应，减少活性氧（ROS）生成，维持MLVs的结构完整性，并改善神经功能。此外，酮洛芬、9-顺式RA和VEGF-C上调了淋巴管特异性蛋白血管内皮生长因子受体（VEGFR）3、PROX1、叉头框蛋白C2（FOXC2）和淋巴管内皮透明质酸受体1（LYVE1）。这些结果表明，酮洛芬、9-顺式RA和VEGF-C可能通过上调淋巴管特异性蛋白的表达来维持脑膜淋巴管壁的完整性并促进淋巴管增殖，改善TBI后的脑膜淋巴功能，促进CSF引流和脑水肿吸收，降低神经系统的免疫反应，减少ROS形成，从而改善预后。这些发现可能为TBI后脑水肿的治疗提供新思路。
