Patra Aparna, Chen Xiaodi, Sadowska Grazyna B, Zhang Jiyong, Lim Yow-Pin, Padbury James F, Banks William A, Stonestreet Barbara S
Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States.
Pediatrics, Women & Infants Hospital of Rhode Island, The Alpert Medical School of Brown University, Providence, RI 02905, United States.
Neuroscience. 2017 Mar 27;346:113-125. doi: 10.1016/j.neuroscience.2016.12.051. Epub 2017 Jan 9.
Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood-brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia-reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in Escherichia coli (E. coli) BL-21 cells was produced, purified, and radiolabeled with I. BBB permeability was quantified using the blood-to-brain transfer constant (K) with I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P<0.001). Blood-to-brain transport of I-IL-1β was lower (P<0.04) across brain regions in the anti-IL-1β mAb-treated than placebo-treated ischemic fetuses. Plasma I-IL-1β counts were higher (P<0.001) in the anti-IL-1β mAb- than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1β mAb reduce IL-1β transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy.
缺氧缺血性损伤易导致围产期脑损伤。促炎细胞因子在这种损伤的发展过程中起重要作用。白细胞介素-1β（IL-1β）是炎症反应的关键介质，脑内IL-1β水平升高与脑损伤后不良神经发育结局相关。血脑屏障（BBB）功能受损是胎儿缺氧缺血性脑损伤的重要组成部分。此外，缺血再灌注会增加细胞因子通过绵羊胎儿BBB的转运。减少促炎细胞因子进入脑内可能是减轻缺血相关脑损伤的一种新方法。我们假设，输注中和性IL-1β单克隆抗体（mAb）可减少胎儿缺血后IL-1β通过BBB的转运。在颈动脉闭塞30分钟后24小时对胎羊进行研究。在缺血后15分钟和4小时，给胎儿静脉注射安慰剂或抗IL-1β mAb。在大肠杆菌（E. coli）BL-21细胞中表达的源自IL-1β pGEX-2T载体的绵羊IL-1β蛋白被制备、纯化并用I进行放射性标记。使用I放射性标记的IL-1β的血脑转移常数（K）对BBB通透性进行定量。在mAb治疗组的脑中观察到抗IL-1β mAb增加（P<0.001）。与安慰剂治疗的缺血胎儿相比，抗IL-1β mAb治疗的缺血胎儿脑内各区域I-IL-1β的血脑转运较低（P<0.04）。与安慰剂治疗的缺血胎儿相比，抗IL-1β mAb治疗的缺血胎儿血浆I-IL-1β计数更高（P<0.001）。全身输注抗IL-1β mAb可减少绵羊胎儿缺血后IL-1β通过BBB的转运。我们的研究结果表明，与全身促炎细胞因子增加和神经发育障碍相关的情况可能受益于抗细胞因子治疗策略。
