MFGE8/整合素β3通路减轻大鼠蛛网膜下腔出血后早期脑损伤中的细胞凋亡和炎症反应。
MFGE8/Integrin β3 pathway alleviates apoptosis and inflammation in early brain injury after subarachnoid hemorrhage in rats.
作者信息
Liu Fei, Chen Yujie, Hu Qin, Li Bo, Tang Junjia, He Yue, Guo Zongduo, Feng Hua, Tang Jiping, Zhang John H
机构信息
Department of Neurosurgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China; Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China; Department of Anesthesiology, Loma Linda University, CA, USA; Department of Neurosurgery, Loma Linda University, CA, USA; Department of Physiology, Loma Linda University, CA, USA.
出版信息
Exp Neurol. 2015 Oct;272:120-7. doi: 10.1016/j.expneurol.2015.04.016. Epub 2015 May 1.
BACKGROUND
Milk fat globule-epidermal growth factor-factor 8(MFGE8)/Integrin β3 pathway was reported to be involved in reducing oxidative stress and early brain injury after subarachnoid hemorrhage (SAH). In the present study, the potential effects of MFGE8 and its receptor Integrin β3 in the inhibition of apoptosis and neuroinflammation in early brain injury after SAH were investigated.
METHODS
Ninety-five (95) male Sprague-Dawley rats were used. The SAH model was induced by endovascular perforation. Recombinant human MFGE8 (rhMFGE8), MFGE8 small interfering RNA (siRNA) and Integrin β3 siRNA were injected intracerebroventricularly. SAH grade, neurologic scores, Western blots and immunofluorescence were employed to study the mechanisms of MFGE8 and its receptor Integrin β3, as well as neurological outcome.
RESULTS
SAH induced significant neuronal apoptosis and inflammation and exhibited neurological dysfunction in rats. Knockdown endogenous MFGE8 with siRNA significantly increased the protein levels of cleaved caspase 3 and IL-1β, accompanied with more neurological deficits. rhMFGE8 significantly reduced neural cell death in cortex, decreased cleaved caspase 3 and IL-1β expressions, and improved neurological functions 24h after SAH. The anti-apoptosis and anti-inflammation effects of rhMFGE8 were abolished by Integrin β3 siRNA.
CONCLUSION
MFGE8 could alleviate neurologic damage in early brain injury after SAH via anti-inflammation and anti-apoptosis effects. MFGE8 may serve as a promising therapeutic target for future management of SAH patients.
背景
据报道，乳脂肪球表皮生长因子8（MFGE8）/整合素β3通路参与减轻蛛网膜下腔出血（SAH）后的氧化应激和早期脑损伤。在本研究中，探讨了MFGE8及其受体整合素β3在抑制SAH后早期脑损伤中细胞凋亡和神经炎症方面的潜在作用。
方法
使用95只雄性Sprague-Dawley大鼠。通过血管内穿刺诱导SAH模型。将重组人MFGE8（rhMFGE8）、MFGE8小干扰RNA（siRNA）和整合素β3 siRNA脑室内注射。采用SAH分级、神经功能评分、蛋白质免疫印迹法和免疫荧光法研究MFGE8及其受体整合素β3的作用机制以及神经功能结局。
结果
SAH诱导大鼠出现明显的神经元凋亡和炎症，并表现出神经功能障碍。用siRNA敲低内源性MFGE8可显著增加裂解的半胱天冬酶3和白细胞介素-1β的蛋白水平，并伴有更多的神经功能缺损。rhMFGE8可显著减少皮质神经细胞死亡，降低裂解的半胱天冬酶3和白细胞介素-1β的表达，并改善SAH后24小时的神经功能。整合素β3 siRNA消除了rhMFGE8的抗凋亡和抗炎作用。
结论
MFGE8可通过抗炎和抗凋亡作用减轻SAH后早期脑损伤中的神经损伤。MFGE8可能成为未来SAH患者治疗的一个有前景的治疗靶点。
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