Bonestroo Hilde J C, Heijnen Cobi J, Groenendaal Floris, van Bel Frank, Nijboer Cora H
Laboratory of Neuroimmunology and Developmental Origins of Disease (NIDOD), University Medical Center Utrecht, Utrecht, The Netherlands.
Dev Neurosci. 2015;37(1):78-94. doi: 10.1159/000368770. Epub 2015 Jan 23.
Antenatal inflammation is associated with increased severity of hypoxic-ischemic (HI) encephalopathy and adverse outcome in human neonates and experimental rodents. We investigated the effect of lipopolysaccharide (LPS) on the timing of HI-induced cerebral tissue loss and gray matter injury, white matter injury and integrity, and the cerebral inflammatory response. On postnatal day 9, mice underwent HI by unilateral carotid artery occlusion followed by systemic hypoxia which resulted in early neuronal damage (MAP2 loss) at 3 h that did not increase up to day 15. LPS injection 14 h before HI (LPS+HI) significantly and gradually aggravated MAP2 loss from 3 h up to day 15, resulting in an acellular cystic lesion. LPS+HI increased white matter damage, reduced myelination in the corpus callosum and increased white matter fiber coherency in the cingulum. The number of oligodendrocytes throughout the lineage (Olig2-positive) was increased whereas more mature myelinating (CNPase-positive) oligodendrocytes were strongly decreased after LPS+HI. LPS+HI induced an increased and prolonged expression of cerebral cytokines/chemokines compared to HI. Additionally, LPS+HI increased macrophage/microglia activation and influx of neutrophils in the brain compared to HI. This study demonstrates the sensitizing effect of LPS on neonatal HI brain injury for an extended time-frame up to 15 days postinsult. LPS before HI induced a gradual increase in gray and white matter deficits, including reduced numbers of more mature myelinating oligodendrocytes and a decrease in white matter integrity. Moreover, LPS+HI prolonged and intensified the cerebral inflammatory response, including cellular infiltration. In conclusion, as the timing of damage and/or involved pathways are changed when HI is preceded by inflammation, experimental therapies might require modifications in the time window, dosage or combinations of therapies for efficacious neuroprotection.
产前炎症与人类新生儿和实验性啮齿动物缺氧缺血性（HI）脑病的严重程度增加及不良预后相关。我们研究了脂多糖（LPS）对HI诱导的脑组织丢失时间、灰质损伤、白质损伤及完整性以及脑炎症反应的影响。在出生后第9天，小鼠通过单侧颈动脉闭塞并随后进行全身缺氧来诱导HI，这导致在3小时时出现早期神经元损伤（微管相关蛋白2（MAP2）丢失），至第15天损伤未增加。在HI前14小时注射LPS（LPS+HI）显著且逐渐加重了从3小时至第15天的MAP2丢失，导致无细胞囊性病变。LPS+HI增加了白质损伤，减少了胼胝体中的髓鞘形成，并增加了扣带束中的白质纤维连贯性。整个谱系（少突胶质细胞转录因子2（Olig2）阳性）的少突胶质细胞数量增加，而LPS+HI后更成熟的髓鞘形成（2',3'-环核苷酸3'-磷酸二酯酶（CNPase）阳性）少突胶质细胞则显著减少。与HI相比，LPS+HI诱导脑细胞因子/趋化因子的表达增加且持续时间延长。此外，与HI相比，LPS+HI增加了巨噬细胞/小胶质细胞的激活以及脑中中性粒细胞的流入。本研究证明了LPS在长达损伤后15天的延长时间范围内对新生儿HI脑损伤的致敏作用。HI前的LPS诱导灰质和白质缺陷逐渐增加，包括更成熟的髓鞘形成少突胶质细胞数量减少以及白质完整性降低。此外，LPS+HI延长并加剧了脑炎症反应，包括细胞浸润。总之，由于炎症先于HI时损伤的时间和/或涉及的途径发生了变化，实验性治疗可能需要在时间窗、剂量或治疗组合方面进行调整以实现有效的神经保护。
