Szmydynger-Chodobska Joanna, Shan Rongzi, Thomasian Nicole, Chodobski Adam
Neurotrauma and Brain Barriers Research Laboratory, Department of Emergency Medicine, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
PLoS One. 2016 Dec 28;11(12):e0167677. doi: 10.1371/journal.pone.0167677. eCollection 2016.
The pathophysiological mechanisms underlying mild traumatic brain injury (mTBI) are not well understood, but likely involve neuroinflammation. Here the controlled cortical impact model of mTBI in rats was used to test this hypothesis. Mild TBI caused a rapid (within 6 h post-mTBI) upregulation of synthesis of TNF-α and IL-1β in the cerebral cortex and hippocampus, followed by an increase in production of neutrophil (CXCL1-3) and monocyte (CCL2) chemoattractants. While astrocytes were not a significant source of CXC chemokines, they highly expressed CCL2. An increase in production of CXC chemokines coincided with the influx of neutrophils into the injured brain. At 6 h post-mTBI, we observed a robust influx of CCL2-expressing neutrophils across pial microvessels into the subarachnoid space (SAS) near the injury site. Mild TBI was not accompanied by any significant influx of neutrophils into the brain parenchyma until 24 h after injury. This was associated with an early induction of expression of intercellular adhesion molecule 1 on the endothelium of the ipsilateral pial, but not intraparenchymal, microvessels. At 6 h post-mTBI, we also observed a robust influx of neutrophils into the ipsilateral cistern of velum interpositum (CVI), a slit-shaped cerebrospinal fluid space located above the 3rd ventricle with highly vascularized pia mater. From SAS and CVI, neutrophils appeared to move along the perivascular spaces to enter the brain parenchyma. The monocyte influx was not observed until 24 h post-mTBI, and these inflammatory cells predominantly entered the ipsilateral SAS and CVI, with a limited invasion of brain parenchyma. These observations indicate that the endothelium of pial microvessels responds to injury differently than that of intraparenchymal microvessels, which may be associated with the lack of astrocytic ensheathment of cerebrovascular endothelium in pial microvessels. These findings also suggest that neuroinflammation represents the potential therapeutic target in mTBI.
轻度创伤性脑损伤（mTBI）的病理生理机制尚未完全明确，但可能与神经炎症有关。在此，我们采用大鼠mTBI的控制性皮质撞击模型来验证这一假说。轻度创伤性脑损伤导致大脑皮层和海马体中肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）的合成迅速上调（在mTBI后6小时内），随后中性粒细胞（CXCL1 - 3）和单核细胞（CCL2）趋化因子的产生增加。虽然星形胶质细胞不是CXC趋化因子的重要来源，但它们高表达CCL2。CXC趋化因子产生的增加与中性粒细胞流入受损大脑同时发生。在mTBI后6小时，我们观察到表达CCL2的中性粒细胞大量穿过软脑膜微血管流入损伤部位附近的蛛网膜下腔（SAS）。轻度创伤性脑损伤在损伤后24小时之前，并没有伴随任何明显的中性粒细胞流入脑实质。这与同侧软脑膜而非脑实质微血管内皮细胞上细胞间黏附分子1表达的早期诱导有关。在mTBI后6小时，我们还观察到大量中性粒细胞流入同侧中间帆池（CVI），这是一个位于第三脑室上方的裂隙状脑脊液间隙，其软脑膜血管高度丰富。中性粒细胞似乎从SAS和CVI沿着血管周围间隙进入脑实质。直到mTBI后24小时才观察到单核细胞流入，并且这些炎性细胞主要进入同侧SAS和CVI，对脑实质侵犯有限。这些观察结果表明，软脑膜微血管内皮对损伤的反应与脑实质微血管不同，这可能与软脑膜微血管中脑血管内皮缺乏星形胶质细胞包绕有关。这些发现还表明，神经炎症是mTBI潜在的治疗靶点。
