Background Mechanical ventilation of preterm neonates is associated with neuroinflammation and an increased risk of adverse neurological outcomes. Human amnion epithelial cells (hAECs) have anti-inflammatory and regenerative properties. We aimed to determine if intravenous administration of hAECs to preterm lambs would reduce neuroinflammation and injury at 2 days of age. Methods Preterm lambs were delivered by cesarean section at 128−130 days’ gestation (term is ~147 days) and either ventilated for 48 h or humanely killed at birth. Lambs received 3 mL surfactant (Curosurf) via endotracheal tube prior to delivery (either with or without 90 × 10 6 hAECs) and 3 mL intravenous phosphate-buffered saline (with or without 90 × 10 6 hAECs, consistent with intratracheal treatment) after birth. Results Ventilation increased microglial activation, total oligodendrocyte cell number, cell proliferation and blood−brain barrier permeability ( P < 0.05, PBS + ventilation and hAEC + ventilation vs. control), but did not affect numbers of immature and mature oligodendrocytes. Ventilation reduced astrocyte and neuron survival ( P < 0.05, PBS + ventilation and hAEC + ventilation vs. control). hAEC administration did not alter markers of neuroinflammation or injury within the white or gray matter. Conclusions Mechanical ventilation for 48 h upregulated markers of neuroinflammation and injury in preterm lambs. Administration of hAECs did not affect markers of neuroinflammation or injury. Impact Mechanical ventilation of preterm lambs for 48 h, in a manner consistent with contemporary neonatal intensive care, causes neuroinflammation, neuronal loss and pathological changes in oligodendrocyte and astrocyte survival consistent with evolving neonatal brain injury. Intravenous administration of hAECs immediately after birth did not affect neonatal cardiorespiratory function and markers of neuroinflammation or injury. Reassuringly, our findings in a translational large animal model demonstrate that intravenous hAEC administration to the preterm neonate is safe. Considering that hAECs are being used in phase 1 trials for the treatment of BPD in preterm infants, with future trials planned for neonatal neuroprotection, we believe these observations are highly relevant.

中文翻译：

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通风早产羔羊的羊膜上皮细胞不会改变 48 小时的脑炎症和损伤

背景 早产新生儿的机械通气与神经炎症和不良神经学结果的风险增加有关。人羊膜上皮细胞 (hAEC) 具有抗炎和再生特性。我们旨在确定对早产羔羊静脉注射 hAEC 是否会减少 2 日龄时的神经炎症和损伤。方法 早产羔羊在妊娠 128-130 天（足月约 147 天）时通过剖宫产分娩，并在出生时通风 48 小时或人道处死。羔羊在分娩前通过气管插管接受 3 mL 表面活性剂 (Curosurf)（有或没有 90 × 10 6 hAEC）和 3 mL 静脉注射磷酸盐缓冲盐水（有或没有 90 × 10 6 hAEC，与气管内治疗一致） . 结果 通风增加了小胶质细胞的活化，少突胶质细胞总数、细胞增殖和血脑屏障通透性（P < 0.05，PBS + 通气和 hAEC + 通气 vs. 对照），但不影响未成熟和成熟少突胶质细胞的数量。通气降低星形胶质细胞和神经元存活率（P < 0.05，PBS + 通气和 hAEC + 通气 vs. 对照）。hAEC 给药不会改变白质或灰质内神经炎症或损伤的标志物。结论 机械通气 48 小时上调了早产羔羊神经炎症和损伤的标志物。hAEC 的施用不影响神经炎症或损伤的标志物。影响 早产羔羊机械通气 48 小时，以符合当代新生儿重症监护的方式，导致神经炎症，少突胶质细胞和星形胶质细胞存活的神经元丢失和病理变化与不断发展的新生儿脑损伤一致。出生后立即静脉注射 hAEC 不会影响新生儿的心肺功能和神经炎症或损伤的标志物。令人欣慰的是，我们在转化大动物模型中的发现表明，对早产儿静脉注射 hAEC 是安全的。考虑到 hAEC 正在用于治疗早产儿 BPD 的 1 期试验中，未来计划进行新生儿神经保护试验，我们认为这些观察结果非常相关。令人欣慰的是，我们在转化大动物模型中的发现表明，对早产儿静脉注射 hAEC 是安全的。考虑到 hAEC 正在用于治疗早产儿 BPD 的 1 期试验中，未来计划进行新生儿神经保护试验，我们认为这些观察结果非常相关。令人欣慰的是，我们在转化大动物模型中的发现表明，对早产儿静脉注射 hAEC 是安全的。考虑到 hAEC 正在用于治疗早产儿 BPD 的 1 期试验中，未来计划进行新生儿神经保护试验，我们认为这些观察结果非常相关。