Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy.
Therapeutic Hypothermia Inhibits the Classical Complement Pathway in a Rat Model of Neonatal Hypoxic-Ischemic Encephalopathy.
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DOI：
10.3389/fnins.2021.616734
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发表时间：
2021
影响因子：
4.3
通讯作者：
Lattanzio FA
中科院分区：
文献类型：
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作者：
Shah TA;Pallera HK;Kaszowski CL;Bass WT;Lattanzio FA
补体激活在缺氧缺血性脑病(HIE)的发病机制中起重要作用，HIE是全球新生儿死亡和残疾的重要原因。治疗性低温(HT)是治疗HIE的唯一有效治疗方法，只能适度改善预后。补体调节已被认为是一种治疗高血压的辅助手段，但由于补体系统在发育中的大脑的神经炎症、内稳态和神经发生中的广泛作用而具有挑战性。我们试图通过测量羟色胺治疗对新生儿HIE神经元和胶质细胞补体效应器表达的影响，特别是小胶质细胞和C1q之间的相互作用，来确定潜在的治疗靶点。采用Vannucci模型建立足月等龄大鼠缺氧缺血性脑病模型。在P10-12龄时，将幼崽随机分为三个不同的处理组：假手术组(对照组)、常温组(NT)和低温组(HT)。采用酶联免疫吸附试验、原位末端标记法和免疫荧光标记法检测局部和全身补体表达及神经细胞凋亡情况，并进行组间比较。羟色胺治疗可降低全身性C1q和小胶质细胞的表达，降低全身性C5a水平，减少C3和C9的小胶质细胞和神经元沉积。羟色胺对细胞因子的影响随促炎症和抗炎效应分子表达的减少而变化。羟色胺治疗与细胞上C1q结合减少有关。我们的数据显示了新生儿HIE免疫反应的极端复杂性。我们建议调节下游效应器C3a和C5a作为羟色胺的治疗辅助手段，以加强发育中大脑的神经保护。
Complement activation is instrumental in the pathogenesis of Hypoxic-ischemic encephalopathy (HIE), a significant cause of neonatal mortality and disability worldwide. Therapeutic hypothermia (HT), the only available treatment for HIE, only modestly improves outcomes. Complement modulation as a therapeutic adjunct to HT has been considered, but is challenging due to the wide-ranging role of the complement system in neuroinflammation, homeostasis and neurogenesis in the developing brain. We sought to identify potential therapeutic targets by measuring the impact of treatment with HT on complement effector expression in neurons and glia in neonatal HIE, with particular emphasis on the interactions between microglia and C1q. The Vannucci model was used to induce HIE in term-equivalent rat pups. At P10-12, pups were randomly assigned to three different treatment groups: Sham (control), normothermia (NT), and hypothermia (HT) treatment. Local and systemic complement expression and neuronal apoptosis were measured by ELISA, TUNEL and immunofluorescence labeling, and differences compared between groups. Treatment with HT is associated with decreased systemic and microglial expression of C1q, decreased systemic C5a levels, and decreased microglial and neuronal deposition of C3 and C9. The effect of HT on cytokines was variable with decreased expression of pro and anti-inflammatory effectors. HT treatment was associated with decreased C1q binding on cells undergoing apoptosis. Our data demonstrate the extreme complexity of the immune response in neonatal HIE. We propose modulation of downstream effectors C3a and C5a as a therapeutic adjunct to HT to enhance neuroprotection in the developing brain.
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影响因子：
9.3
作者：
Fisch, Urs;Bregere, Catherine;Guzman, Raphael
通讯作者：
Guzman, Raphael
影响因子：
8.2
作者：
Liu, Fudong;McCullough, Louise D.
通讯作者：
McCullough, Louise D.
影响因子：
5.3
作者：
Brennan, Faith H.;Gordon, Richard;Ruitenberg, Marc J.
通讯作者：
Ruitenberg, Marc J.
影响因子：
9.3
作者：
Brennan FH;Anderson AJ;Taylor SM;Woodruff TM;Ruitenberg MJ
通讯作者：
Ruitenberg MJ
缺血和再灌注 - 从翻译机构。
影响因子：
82.9
作者：
通讯作者：
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