Galinsky Robert, Dhillon Simerdeep K, Dean Justin M, Davidson Joanne O, Lear Christopher A, Wassink Guido, Nott Fraser, Kelly Sharmony B, Fraser Mhoyra, Yuill Caroline, Bennet Laura, Gunn Alistair Jan
Department of Physiology, Faculty of Medical and Health Sciences, University of Auckland, Private bag 92019, Auckland, 1023, New Zealand.
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
J Neuroinflammation. 2020 Mar 23;17(1):92. doi: 10.1186/s12974-020-01769-6.
Increased circulating levels of tumor necrosis factor (TNF) are associated with greater risk of impaired neurodevelopment after preterm birth. In this study, we tested the hypothesis that systemic TNF inhibition, using the soluble TNF receptor Etanercept, would attenuate neuroinflammation in preterm fetal sheep exposed to lipopolysaccharide (LPS).
Chronically instrumented preterm fetal sheep at 0.7 of gestation were randomly assigned to receive saline (control; n = 7), LPS infusion (100 ng/kg i.v. over 24 h then 250 ng/kg/24 h for 96 h plus 1 μg LPS boluses at 48, 72, and 96 h, to induce inflammation; n = 8) or LPS plus two i.v. infusions of Etanercept (2 doses, 5 mg/kg infused over 30 min, 48 h apart) started immediately before LPS-exposure (n = 8). Sheep were killed 10 days after starting infusions, for histology.
LPS boluses were associated with increased circulating TNF, interleukin (IL)-6 and IL-10, electroencephalogram (EEG) suppression, hypotension, tachycardia, and increased carotid artery perfusion (P < 0.05 vs. control). In the periventricular and intragyral white matter, LPS exposure increased gliosis, TNF-positive cells, total oligodendrocytes, and cell proliferation (P < 0.05 vs control), but did not affect myelin expression or numbers of neurons in the cortex and subcortical regions. Etanercept delayed the rise in circulating IL-6, prolonged the increase in IL-10 (P < 0.05 vs. LPS), and attenuated EEG suppression, hypotension, and tachycardia after LPS boluses. Histologically, Etanercept normalized LPS-induced gliosis, and increase in TNF-positive cells, proliferation, and total oligodendrocytes.
TNF inhibition markedly attenuated white matter gliosis but did not affect mature oligodendrocytes after prolonged systemic inflammation in preterm fetal sheep. Further studies of long-term brain maturation are now needed.
肿瘤坏死因子（TNF）循环水平升高与早产后脑发育受损风险增加相关。在本研究中，我们检验了如下假设：使用可溶性TNF受体依那西普进行全身性TNF抑制，可减轻暴露于脂多糖（LPS）的早产胎羊的神经炎症。
将妊娠0.7期的慢性植入仪器的早产胎羊随机分为三组，分别接受生理盐水（对照组；n = 7）、LPS输注（100 ng/kg静脉注射，持续24小时，然后250 ng/kg/24小时，持续96小时，并在48、72和96小时给予1 μg LPS推注，以诱导炎症；n = 8）或LPS加两次静脉输注依那西普（2剂，5 mg/kg在30分钟内输注，间隔48小时），在LPS暴露前立即开始输注（n = 8）。输注开始10天后处死绵羊，进行组织学检查。
LPS推注与循环TNF、白细胞介素（IL）-6和IL-10升高、脑电图（EEG）抑制、低血压、心动过速以及颈动脉灌注增加相关（与对照组相比，P < 0.05）。在脑室周围和脑回内白质中，LPS暴露增加了胶质增生、TNF阳性细胞、少突胶质细胞总数和细胞增殖（与对照组相比，P < 0.05），但不影响皮质和皮质下区域的髓鞘表达或神经元数量。依那西普延迟了循环IL-6的升高，延长了IL-10的增加时间（与LPS组相比，P < 0.05），并减轻了LPS推注后的EEG抑制、低血压和心动过速。组织学上，依那西普使LPS诱导的胶质增生、TNF阳性细胞增加、增殖和少突胶质细胞总数恢复正常。
在早产胎羊长期全身性炎症后，TNF抑制显著减轻了白质胶质增生，但不影响成熟少突胶质细胞。现在需要进一步研究长期脑成熟情况。
