抗纤维蛋白溶解药物对创伤性脑损伤后全身和脑炎症的影响。
Effects of antifibrinolytics on systemic and cerebral inflammation after traumatic brain injury.
机构信息
From the Department of Surgery, University of Cincinnati, Cincinnati, Ohio.
出版信息
J Trauma Acute Care Surg. 2022 Jul 1;93(1):30-37. doi: 10.1097/TA.0000000000003607. Epub 2022 Mar 22.
BACKGROUND
Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury-related mortality. The effect of these medications on post-traumatic brain injury (TBI) inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI.
METHODS
An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mg/kg of TXA, 400 mg/kg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIU/kg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation.
RESULTS
One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS.
CONCLUSION
Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI.
背景
使用抗纤维蛋白溶解药物，包括氨甲环酸（TXA），可降低颅脑损伤相关死亡率。这些药物对创伤性脑损伤（TBI）炎症反应的影响尚不清楚。本研究的目的是研究现有的抗纤维蛋白溶解药物对 TBI 后全身和大脑炎症的作用。
方法
采用已建立的小鼠落体模型诱导中度 TBI。在 TBI 后 10 分钟，TXA 给予 1、10 或 100mg/kg、氨甲环酸（Amicar，Hospira，Lake Forest，IL）给予 400mg/kg、抑肽酶给予 100kIU/kg 或给予等体积生理盐水（NS）。在 1、6 或 24 小时处死小鼠。分析血清和脑组织中的神经元特异性烯醇化酶和炎症细胞因子。在 30 天时评估海马组织学以检测磷酸化 tau 的积累。
结果
TBI 后 1 小时，给予 TXA 的小鼠大脑组织中肿瘤坏死因子-α（TNF-α）和白细胞介素（IL）-6 的浓度降低，24 小时时 TNF-α、IL-6 和单核细胞趋化蛋白 1 的浓度也降低，但 TXA-TBI 组在 1 至 24 小时内血清 TNF-α 和巨噬细胞炎性蛋白 1α（MIP-1α）浓度明显升高。TBI-TXA 组与 TBI-NS 组相比，磷酸化 tau 的浓度呈剂量依赖性降低。相反，Amicar 给药在 TBI 后 1 小时增加了 IL-6 的大脑细胞因子水平，与 TBI-NS 相比，24 小时时 TNF-α、MIP-1α 和单核细胞趋化蛋白 1 的血清水平升高。抑肽酶给药在 1 至 24 小时内增加了血清 TNF-α、IL-6 和 MIP-1α，与 TBI-NS 相比，大脑细胞因子没有差异。
结论
氨甲环酸给药可在剂量依赖性方式下提供急性神经炎症保护。Amicar 给药可能会因增加大脑和全身炎症反应而对 TBI 造成损害。抑肽酶给药可能会增加全身炎症，而对神经炎症没有明显贡献。虽然没有抗纤维蛋白溶解药物能改善全身炎症，但这些数据表明，TXA 可能在 TBI 后提供最有益的炎症调节。
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