Liu Han, He Junchi, Wu Yue, Du Yang, Jiang Yinghua, Chen Chengzhi, Yu Zhanyang, Zhong Jianjun, Wang Zhigang, Cheng Chongjie, Sun Xiaochuan, Huang Zhijian
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Neurosurgery, Qilu Hospital of Shandong University (Qingdao Campus), Qingdao, China.
Front Neurosci. 2021 Feb 18;15:627110. doi: 10.3389/fnins.2021.627110. eCollection 2021.
Following brain trauma, blood-brain barrier (BBB) disruption and inflammatory response are critical pathological steps contributing to secondary injury, leading to high mortality and morbidity. Both pathologies are closely associated with endothelial remodeling. In the present study, we concentrated on annexin A1 (ANXA1) as a novel regulator of endothelial function after traumatic brain injury.
After establishing controlled cortical impact (CCI) model in male mice, human recombinant ANXA1 (rANXA1) was administered intravenously, followed by assessments of BBB integrity, brain edema, inflammatory response, and neurological deficits.
Animals treated with rANXA1 (1 μg/kg) at 1 h after CCI exhibited optimal BBB protection including alleviated BBB disruption and brain edema, as well as endothelial junction proteins loss. The infiltrated neutrophils and inflammatory cytokines were suppressed by rANXA1, consistent with decreased adhesive and transmigrating molecules from isolated microvessels. Moreover, rANXA1 attenuated the neurological deficits induced by CCI. We further found that the Ras homolog gene family member A (RhoA) inhibition has similar effect as rANXA1 in ameliorating brain injuries after CCI, whereas rANXA1 suppressed CCI-induced RhoA activation.
Our findings suggest that the endothelial remodeling by exogenous rANXA1 corrects BBB disruption and inflammatory response through RhoA inhibition, hence improving functional outcomes in CCI mice.
脑外伤后，血脑屏障（BBB）破坏和炎症反应是导致继发性损伤的关键病理步骤，可导致高死亡率和高发病率。这两种病理过程均与内皮重塑密切相关。在本研究中，我们聚焦于膜联蛋白A1（ANXA1），将其作为创伤性脑损伤后内皮功能的一种新型调节因子。
在雄性小鼠中建立控制性皮质撞击（CCI）模型后，静脉注射人重组ANXA1（rANXA1），随后评估血脑屏障完整性、脑水肿、炎症反应和神经功能缺损。
在CCI后1小时接受rANXA1（1μg/kg）治疗的动物表现出最佳的血脑屏障保护作用，包括减轻血脑屏障破坏和脑水肿，以及减少内皮连接蛋白的丢失。rANXA1抑制了浸润的中性粒细胞和炎性细胞因子，这与从分离的微血管中减少的黏附分子和迁移分子一致。此外，rANXA1减轻了CCI诱导的神经功能缺损。我们进一步发现，Ras同源基因家族成员A（RhoA）抑制在改善CCI后脑损伤方面具有与rANXA1相似的作用，而rANXA1抑制了CCI诱导的RhoA激活。
我们的研究结果表明，外源性rANXA1引起的内皮重塑通过抑制RhoA纠正血脑屏障破坏和炎症反应，从而改善CCI小鼠的功能结局。
