Aridas James D S, McDonald Courtney A, Paton Madison C B, Yawno Tamara, Sutherland Amy E, Nitsos Ilias, Pham Yen, Ditchfield Michael, Fahey Michael C, Wong Flora, Malhotra Atul, Castillo-Melendez Margie, Bhakoo Kishore, Wallace Euan M, Jenkin Graham, Miller Suzanne L
The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia.
J Physiol. 2016 Mar 1;594(5):1421-35. doi: 10.1113/JP271104. Epub 2015 Dec 14.
Perinatal asphyxia is a significant cause of death or long-term neurodevelopmental impairment. Hypothermia, currently the only effective treatment, leads to modest improvements, but new therapeutic strategies are required. Umbilical cord blood (UCB) mononuclear cells have potent anti-inflammatory properties and may reduce neuropathology. This study examined whether autologous UCB mononuclear cells were neuroprotective when administered to newborn lambs at 12 h after birth asphyxia. At caesarean section, birth asphyxia was induced by clamping the umbilical cord until mean arterial blood pressure decreased to 18-20 mmHg. Asphyxia (n = 20) or control (n = 11) lambs were resuscitated and maintained, with magnetic resonance spectroscropy (MRS) performed at 12 and 72 h, and were then killed at 72 h. Cord blood was collected once the cord was clamped, and mononuclear cells were isolated and labelled fluorescently and administered to control (n = 3) or asphyxia (n = 8) lambs. Asphyxia induced a significant increase in cellular apoptosis (caspase-3 immunopositive) within all brain regions examined, including cortex, hippocampus, thalamus, striatum and subcortical white matter (P < 0.01 vs. control). Additionally, asphyxia induced significant and widespread astrogliosis and increased inflammatory cells (activated microglia and macrophages). The administration of UCB mononuclear cells (asphyxia+UCB) significantly decreased neuronal apoptosis, astrogliosis and inflammation (P < 0.05 vs. asphyxia alone). Asphyxia+UCB lambs also demonstrated decreased brain metabolites lactate:choline (P = 0.01) and lactate:N-acetylaspartate (P < 0.01) from 12 to 72 h, detected using MRS. Autologous UCB mononuclear cell treatment restores normal brain metabolism following perinatal asphyxia, and reduces brain inflammation, astrogliosis and neuronal apoptosis, supporting its use as a neuroprotective therapy following asphyxia.
围产期窒息是导致死亡或长期神经发育障碍的重要原因。低温是目前唯一有效的治疗方法，虽能带来一定程度的改善，但仍需要新的治疗策略。脐带血（UCB）单个核细胞具有强大的抗炎特性，可能减轻神经病理学损伤。本研究探讨了在新生羔羊出生后窒息12小时给予自体UCB单个核细胞是否具有神经保护作用。剖宫产时，通过钳夹脐带直至平均动脉血压降至18 - 20 mmHg来诱导出生窒息。将窒息组（n = 20）或对照组（n = 11）羔羊复苏并维持生命，在12小时和72小时进行磁共振波谱（MRS）检查，然后在72小时处死。脐带钳夹后采集脐带血，分离单个核细胞并进行荧光标记，然后给予对照组（n = 3）或窒息组（n = 8）羔羊。窒息导致所有检测脑区（包括皮层、海马、丘脑、纹状体和皮质下白质）的细胞凋亡（半胱天冬酶-3免疫阳性）显著增加（与对照组相比，P < 0.01）。此外，窒息还导致显著且广泛的星形胶质细胞增生以及炎症细胞（活化的小胶质细胞和巨噬细胞）增多。给予UCB单个核细胞（窒息 + UCB组）可显著降低神经元凋亡、星形胶质细胞增生和炎症（与单纯窒息组相比，P < 0.05）。使用MRS检测发现，窒息 + UCB组羔羊在12小时至72小时期间脑代谢物乳酸:胆碱（P = 0.01）和乳酸:N - 乙酰天门冬氨酸（P < 0.01）也有所降低。自体UCB单个核细胞治疗可在围产期窒息后恢复正常脑代谢，并减轻脑炎症、星形胶质细胞增生和神经元凋亡，支持其作为窒息后的神经保护疗法。
