Nikolian Vahagn C, Dekker Simone E, Bambakidis Ted, Higgins Gerald A, Dennahy Isabel S, Georgoff Patrick E, Williams Aaron M, Andjelkovic Anuska V, Alam Hasan B
Department of Surgery, University of Michigan, Ann Arbor, MI.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI.
Crit Care Med. 2018 Jan;46(1):e59-e66. doi: 10.1097/CCM.0000000000002800.
Combined traumatic brain injury and hemorrhagic shock are highly lethal. Following injuries, the integrity of the blood-brain barrier can be impaired, contributing to secondary brain insults. The status of the blood-brain barrier represents a potential factor impacting long-term neurologic outcomes in combined injuries. Treatment strategies involving plasma-based resuscitation and valproic acid therapy have shown efficacy in this setting. We hypothesize that a component of this beneficial effect is related to blood-brain barrier preservation.
Following controlled traumatic brain injury, hemorrhagic shock, various resuscitation and treatment strategies were evaluated for their association with blood-brain barrier integrity. Analysis of gene expression profiles was performed using Porcine Gene ST 1.1 microarray. Pathway analysis was completed using network analysis tools (Gene Ontology, Ingenuity Pathway Analysis, and Parametric Gene Set Enrichment Analysis).
Female Yorkshire swine were subjected to controlled traumatic brain injury and 2 hours of hemorrhagic shock (40% blood volume, mean arterial pressure 30-35 mmHg).
Subjects were resuscitated with 1) normal saline, 2) fresh frozen plasma, 3) hetastarch, 4) fresh frozen plasma + valproic acid, or 5) hetastarch + valproic acid (n = 5 per group). After 6 hours of observation, brains were harvested for evaluation.
Immunofluoroscopic evaluation of the traumatic brain injury site revealed significantly increased expression of tight-junction associated proteins (zona occludin-1, claudin-5) following combination therapy (fresh frozen plasma + valproic acid and hetastarch + valproic acid). The extracellular matrix protein laminin was found to have significantly improved expression with combination therapies. Pathway analysis indicated that valproic acid significantly modulated pathways involved in endothelial barrier function and cell signaling.
Resuscitation with fresh frozen plasma results in improved expression of proteins essential for blood-brain barrier integrity. The addition of valproic acid provides significant improvement to these protein expression profiles. This is likely secondary to activation of key pathways related to endothelial functions.
创伤性脑损伤合并失血性休克具有很高的致死率。受伤后，血脑屏障的完整性可能受损，从而导致继发性脑损伤。血脑屏障的状态是影响合并伤长期神经功能预后的一个潜在因素。涉及基于血浆的复苏和丙戊酸治疗的策略已在这种情况下显示出疗效。我们假设这种有益作用的一个组成部分与血脑屏障的保存有关。
在控制性创伤性脑损伤、失血性休克后，评估各种复苏和治疗策略与血脑屏障完整性的相关性。使用猪基因ST 1.1微阵列进行基因表达谱分析。使用网络分析工具（基因本体论、 Ingenuity通路分析和参数化基因集富集分析）完成通路分析。
雌性约克夏猪接受控制性创伤性脑损伤和2小时失血性休克（血容量的40%，平均动脉压30 - 35 mmHg）。
用1）生理盐水、2）新鲜冷冻血浆、3）羟乙基淀粉、4）新鲜冷冻血浆+丙戊酸或5）羟乙基淀粉+丙戊酸对受试者进行复苏（每组n = 5）。观察6小时后，取出大脑进行评估。
对创伤性脑损伤部位的免疫荧光镜评估显示，联合治疗（新鲜冷冻血浆+丙戊酸和羟乙基淀粉+丙戊酸）后紧密连接相关蛋白（闭合蛋白-1、claudin-5）的表达显著增加。发现联合治疗可显著改善细胞外基质蛋白层粘连蛋白的表达。通路分析表明，丙戊酸显著调节参与内皮屏障功能和细胞信号传导的通路。
用新鲜冷冻血浆进行复苏可改善血脑屏障完整性所必需的蛋白质的表达。添加丙戊酸可显著改善这些蛋白质表达谱。这可能继发于与内皮功能相关的关键通路的激活。
