Increased systemic and tissue levels of interleukin (IL)-1β are associated with greater risk of impaired neurodevelopment after birth. In this study, we tested the hypothesis that systemic IL-1 receptor antagonist (Ra) administration would attenuate brain inflammation and injury in near-term fetal sheep exposed to lipopolysaccharide (LPS). Chronically instrumented near-term fetal sheep at 0.85 of gestation were randomly assigned to saline infusion (control, n = 9), repeated LPS infusions (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng, n = 8) or repeated LPS plus IL-1Ra infusions (13 mg/kg infused over 4 h) started 1 h after each LPS infusion (n = 9). Sheep were euthanized 4 days after starting infusions for histology. LPS infusions increased circulating cytokines and were associated with electroencephalogram (EEG) suppression with transiently reduced mean arterial blood pressure, and increased carotid artery perfusion and fetal heart rate (P < 0.05 vs. control for all). In the periventricular and intragyral white matter, LPS-exposure increased IL-1β immunoreactivity, numbers of caspase 3+ cells and microglia, reduced astrocyte and olig-2+ oligodendrocyte survival but did not change numbers of mature CC1+ oligodendrocytes, myelin expression or numbers of neurons in the cortex and subcortical regions. IL-1Ra infusions reduced circulating cytokines and improved recovery of EEG activity and carotid artery perfusion. Histologically, IL-1Ra reduced microgliosis, IL-1β expression and caspase-3+ cells, and improved olig-2+ oligodendrocyte survival. IL-1Ra improved EEG activity and markedly attenuated systemic inflammation, microgliosis and oligodendrocyte loss following LPS exposure in near-term fetal sheep. Further studies examining the long-term effects on brain maturation are now needed.

中文翻译：

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近期胎羊进行性全身性脂多糖暴露后，IL-1 阻断可减轻白质炎症和少突胶质细胞丢失

白细胞介素 (IL)-1β 的全身和组织水平升高与出生后神经发育受损的风险增加有关。在这项研究中，我们检验了以下假设：全身性 IL-1 受体拮抗剂 (Ra) 给药会减轻暴露于脂多糖 (LPS) 的近期胎羊的脑部炎症和损伤。将 0.85 孕期的长期仪器化的近期胎羊随机分配到盐水输注组（对照，n = 9），重复 LPS 输注组（0 小时 = 300 纳克，24 小时 = 600 纳克，48 小时 = 1200 纳克，n = 8 ）或在每次 LPS 输注后 1 小时开始重复 LPS 加 IL-1Ra 输注（13 mg/kg 输注超过 4 小时）（n = 9）。在开始输注进行组织学检查后 4 天对绵羊实施安乐死。LPS 输注增加了循环细胞因子，并与脑电图 (EEG) 抑制相关，同时平均动脉血压短暂降低，颈动脉灌注和胎儿心率增加（P < 0.05 与所有对照组相比）。在脑室周围和脑内白质中，LPS 暴露增加了 IL-1β 免疫反应性、caspase 3+ 细胞和小胶质细胞的数量，降低了星形胶质细胞和 olig-2+ 少突胶质细胞的存活率，但不改变成熟 CC1+ 少突胶质细胞的数量、髓鞘表达或皮层和皮层下区域的神经元。IL-1Ra 输注减少了循环细胞因子并改善了脑电图活动和颈动脉灌注的恢复。组织学上，IL-1Ra 减少了小胶质细胞增生、IL-1β 表达和 caspase-3+ 细胞，并提高了 olig-2+ 少突胶质细胞的存活率。IL-1Ra 改善 EEG 活动并显着减轻近期胎羊暴露 LPS 后的全身炎症、小胶质细胞增生和少突胶质细胞丢失。现在需要进一步研究检查对大脑成熟的长期影响。