Complex pattern of interaction between in utero hypoxia-ischemia and intra-amniotic inflammation disrupts brain development and motor function.
Complex pattern of interaction between in utero hypoxia-ischemia and intra-amniotic inflammation disrupts brain development and motor function.
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DOI：
10.1186/1742-2094-11-131
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发表时间：
2014-08-01
影响因子：
9.3
通讯作者：
Robinson S
中科院分区：
文献类型：
--
作者：
Jantzie LL;Corbett CJ;Berglass J;Firl DJ;Flores J;Mannix R;Robinson S
早产儿通常会遭受缺氧缺血 (HI) 和感染性围产期炎症损伤的困扰，从而导致脑瘫、认知迟缓、行为问题和癫痫。使用妊娠晚期 HI 和脂多糖 (LPS) 诱导的炎症相结合的新型大鼠模型，我们检验了我们的假设，即 HI 和 LPS 引起的炎症对出生后第一个月的神经胶质增生、白质发育和运动障碍有不同的影响。怀孕大鼠在胚胎第 18 天接受剖腹手术并进行短暂全身性 HI (TSHI) 和/或羊膜内 LPS 注射。沙姆斯只接受了剖腹手术和麻醉。幼崽足月出生。进行免疫组织化学和体视学估计来评估区域神经胶质负荷，并进行蛋白质印迹来检测蛋白质表达。使用定量PCR对促红细胞生成素配体和受体水平进行定量。数字步态分析检测到步态缺陷。通过单向方差分析和事后 Bonferonni 校正进行统计分析。与假手术相比，出生后第 2 天 TSHI + LPS 菌毛中的小胶质细胞和星形胶质细胞免疫标记升高（均 P < 0.03）。出生后第 15 天，与假手术组相比，TSHI + LPS 幼仔中的髓磷脂碱性蛋白表达降低了 31%（P < 0.05）。到出生后第 28 天，仅 TSHI 幼崽的白质损伤从急性损伤模式转变为慢性损伤模式。出生后 28 天的 TSHI 幼崽中，髓磷脂碱性蛋白表达 (P < 0.01) 和磷酸神经丝/神经丝比率（轴突功能障碍的标志物）均降低 (P < 0.001)。暴露于 TSHI 和 LPS 的大脑之间，促红细胞生成素配体与受体的比例不同。步态分析显示，所有组（TSHI、LPS 和 TSHI + LPS）均存在共济失调，在步幅、爪子位置、步态一致性和协调性方面存在缺陷（所有 P < 0.001）。产前 TSHI 和 TSHI + LPS 会导致不同模式的髓鞘形成、轴突完整性和步态缺陷损伤。双重损伤会导致神经胶质反应和细胞炎症的急性改变，而单独使用 TSHI 会导致更明显的慢性白质和轴突损伤。两种损伤都会导致严重的步态缺陷。进一步的研究将有助于对早产儿损伤机制进行分层，并指导有前景的治疗干预措施的使用。
Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month. Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction. Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001). Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.
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DOI：
10.1136/archdischild-2013-304374
发表时间：
2014-05-01
影响因子：
4.4
作者：
Fox, Lisa M.;Choo, Pauline;Cheong, Jeanie L. Y.
通讯作者：
Cheong, Jeanie L. Y.
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影响因子：
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Haynes, Robin L.;Billiards, Saraid S.;Kinney, Hannah C.
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影响因子：
3.4
作者：
Eklind, S;Mallard, C;Hagberg, H
通讯作者：
Hagberg, H
影响因子：
7.8
作者：
Barichello, Tatiana;Simoes, Lutiana R.;Quevedo, Joao
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Quevedo, Joao