在穿透性弹道样脑损伤的啮齿动物模型中，急性和亚急性微小RNA失调与细胞因子反应相关。
Acute and subacute microRNA dysregulation is associated with cytokine responses in the rodent model of penetrating ballistic-like brain injury.
作者信息
Johnson David, Cartagena Casandra M, Tortella Frank C, Dave Jitendra R, Schmid Kara E, Boutté Angela M
机构信息
From the Department of Pathology and Area Laboratory Services (D.J.), Landstuhl Regional Medical Center, Landstuhl, Germany; Brain Trauma Neuroprotection and Neurorestoration Branch, Center for Military Psychiatry and Neuroscience (C.M.C., F.C.T., J.R.D., A.M.B.), Walter Reed Army Institute of Research, Silver Spring; and Neurotrauma and Psychological Health Project Management Office (K.E.S.), U.S. Army Medical Materiel Development Activity (USAMMDA), Fort Detrick, Maryland.
出版信息
J Trauma Acute Care Surg. 2017 Jul;83(1 Suppl 1):S145-S149. doi: 10.1097/TA.0000000000001475.
BACKGROUND
MicroRNAs (miRNAs) are small stable RNAs that regulate translational degradation or repression of genes involved in brain trauma-mediated inflammation. More recently, miRNAs have emerged as potential novel TBI biomarkers. The aim of this study was to determine if a select set of miRNAs (miR-21, Let-7i, miR-124a, miR-146a, miR-107) that were previously associated with TBI models and clinical studies would be dysregulated and correlated to inflammatory cytokine abundance in the rat penetrating ballistic-like brain injury (PBBI) model.
METHODS
Adult male Sprague-Dawley rats received a unilateral frontal 10% PBBI, which produces a temporary cavity. Sham animals received a craniotomy only. Ipsilateral brain tissue and serum were collected 4 hours to 7 days post-injury. Quantitation of miR-21, Let-7i, miR-124a, miR-146a, or miR-107 levels was conducted using Taqman PCR assays normalized to the endogenous reference, U6 snRNA. Brain tissue derived from matching cohorts was used to determine 1L-1beta and IL-6 levels by enzyme-linked immunosorbent assay.
RESULTS
Brain tissue Let-7i and miR-21 increased at 4 hours and 1 day, whereas miR-124a and miR-107 were enhanced only 1 day post-injury. MiR-146a displayed a biphasic response and increased 1 day and 7 days, whereas elevation of miR-21 was sustained 1 day to 7 days after PBBI. Pathway analysis indicated that miRNAs were linked to inflammatory proteins, IL-6 and IL-1beta. Confirmation by enzyme-linked immunosorbent assay indicated that both cytokines were increased and peaked at 1 day, but fell at 3 days through 7 days after PBBI, indicating an inverse relationship with miRNA abundance. Serum Let-7i, alone, was differentially abundant 7 days after PBBI.
CONCLUSION
Brain tissue-derived miRNAs linked to increased cytokine levels demonstrates a plausible therapeutic target of TBI-induced inflammation. Suppression of serum derived Let-7i may have utility as a biomarker of subacute injury progression or therapeutic responses.
背景
微小RNA（miRNA）是一类小的稳定RNA，可调节参与脑外伤介导炎症的基因的翻译降解或抑制。最近，miRNA已成为潜在的新型创伤性脑损伤（TBI）生物标志物。本研究的目的是确定一组先前与TBI模型和临床研究相关的特定miRNA（miR-21、Let-7i、miR-124a、miR-146a、miR-107）在大鼠穿透性弹道样脑损伤（PBBI）模型中是否失调，并与炎性细胞因子丰度相关。
方法
成年雄性Sprague-Dawley大鼠接受单侧额叶10%PBBI，形成一个临时腔隙。假手术动物仅接受开颅手术。在损伤后4小时至7天收集同侧脑组织和血清。使用以内源性参照U6 snRNA标准化的Taqman PCR测定法对miR-21、Let-7i、miR-124a、miR-146a或miR-107水平进行定量。来自匹配队列的脑组织用于通过酶联免疫吸附测定法测定IL-1β和IL-6水平。
结果
脑组织中Let-7i和miR-21在4小时和1天时增加，而miR-124a和miR-107仅在损伤后1天增强。MiR-146a表现出双相反应，在1天和7天时增加，而miR-21在PBBI后1天至7天持续升高。通路分析表明，miRNA与炎性蛋白IL-6和IL-1β相关。酶联免疫吸附测定法证实，两种细胞因子均增加并在1天时达到峰值，但在PBBI后3天至7天下降，表明与miRNA丰度呈负相关。仅血清Let-7i在PBBI后7天差异丰富。
结论
与细胞因子水平升高相关的脑组织来源的miRNA证明是TBI诱导炎症的一个合理治疗靶点。血清来源的Let-7i的抑制可能作为亚急性损伤进展或治疗反应的生物标志物。
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