BACKGROUND Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is associated with significant neurological deficits in infants, including white matter damage. Previous work using an animal model of IUGR has demonstrated that IUGR rats exhibit neurobehavioral deficits and developmental delays in oligodendrocyte maturation and myelination, but the mechanisms which cause this delay are unknown. Inflammation may be an important etiological factor in IUGR and has been recognized as playing a fundamental role in the pathogenesis of myelin disorders, including cerebral palsy. METHODS To create the model, the uterine arteries of pregnant rats were ligated at embryonic day 15. Rats delivered spontaneously. Cytokine and chemokine expression was evaluated at one prenatal and three postnatal time points, and myelin protein expression and oligodendrocyte cell numbers were evaluated by several methods at postnatal day 14. IL-4 was identified as a potential inhibitor of myelination, and rat pups were injected with IL-4 function blocking antibody from postnatal days 1-5 and myelination was assessed. RESULTS Here, we show a novel mechanism of white matter injury. IUGR induces an exaggerated Th2 response in the developing rat brain, including upregulation of several Th2 cytokines. Of these, IL-4 is significantly increased during the period corresponding to robust developmental myelination. We show that neutralizing IL-4 antibody therapy given in the newborn period ameliorates inflammation and restores myelin protein expression and oligodendrocyte cell number in the IUGR brain to control levels, demonstrating a novel role for Th2 responses and IL-4 in IUGR and white matter injury. In addition, IL-4 directly affects oligodendrocytes in vitro decreasing differentiation. CONCLUSIONS In this study, we have identified inflammation as a factor in the decrease in myelin seen in an animal model of IUGR. IL-4, an inflammatory protein often thought to be protective in the adult, is specifically increased, and treatment of these animals to prevent this increase ameliorates white matter damage. Our results suggest that the immune system plays a role in IUGR that is different in the perinatal period than in the adult and preventing this exaggerated Th2 response may be a potential therapeutic target.

中文翻译：

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通过中和 IL-4 抗体减少 Th2 炎症可挽救 IUGR 大鼠脑中的髓鞘形成。

背景宫内生长受限（IUGR）是妊娠常见的并发症，与婴儿的显着神经功能缺损有关，包括白质损伤。先前使用 IUGR 动物模型的工作表明，IUGR 大鼠在少突胶质细胞成熟和髓鞘形成方面表现出神经行为缺陷和发育延迟，但导致这种延迟的机制尚不清楚。炎症可能是 IUGR 的一个重要病因，并且已被公认为在髓鞘疾病（包括脑瘫）的发病机制中起重要作用。方法为建立模型，在胚胎第15天结扎妊娠大鼠的子宫动脉。大鼠自然分娩。在一个产前和三个产后时间点评估细胞因子和趋化因子的表达，在出生后第 14 天通过多种方法评估髓鞘蛋白表达和少突胶质细胞数量。 IL-4 被鉴定为髓鞘形成的潜在抑制剂，并从出生后第 1-5 天和髓鞘形成给幼鼠注射 IL-4 功能阻断抗体被评估。结果在这里，我们展示了一种新的白质损伤机制。IUGR 在发育中的大鼠大脑中诱导过度的 Th2 反应，包括几种 Th2 细胞因子的上调。其中，IL-4 在对应于强劲发育髓鞘形成的时期内显着增加。我们表明，在新生儿期给予的中和 IL-4 抗体治疗可减轻炎症，并将 IUGR 大脑中的髓鞘蛋白表达和少突胶质细胞数量恢复到控制水平，证明了 Th2 反应和 IL-4 在 IUGR 和白质损伤中的新作用。此外，IL-4 直接影响体外减少分化的少突胶质细胞。结论 在这项研究中，我们已经确定炎症是 IUGR 动物模型中髓鞘减少的一个因素。IL-4 是一种通常被认为对成人具有保护作用的炎症蛋白，它特别增加，对这些动物进行治疗以防止这种增加可以改善白质损伤。我们的结果表明免疫系统在围产期与成人不同的 IUGR 中发挥作用，防止这种过度的 Th2 反应可能是一个潜在的治疗目标。我们已经确定炎症是 IUGR 动物模型中髓鞘减少的一个因素。IL-4 是一种通常被认为对成人具有保护作用的炎症蛋白，它特别增加，对这些动物进行治疗以防止这种增加可以改善白质损伤。我们的结果表明免疫系统在围产期与成人不同的 IUGR 中发挥作用，防止这种过度的 Th2 反应可能是一个潜在的治疗目标。我们已经确定炎症是 IUGR 动物模型中髓鞘减少的一个因素。IL-4 是一种通常被认为对成人具有保护作用的炎症蛋白，它特别增加，对这些动物进行治疗以防止这种增加可以改善白质损伤。我们的结果表明免疫系统在围产期与成人不同的 IUGR 中发挥作用，防止这种过度的 Th2 反应可能是一个潜在的治疗目标。