Department of Pediatrics, Loma Linda University, CA, USA.
Department of Pediatrics, Loma Linda University, CA, USA Department of Biological Sciences, California State University, Fullerton, CA, USA.
ASN Neuro. 2014 Nov 24;6(6). doi: 10.1177/1759091414558418. Print 2014.
While hypothermia (HT) is the standard-of-care for neonates with hypoxic ischemic injury (HII), the mechanisms underlying its neuroprotective effect are poorly understood. We examined ischemic core/penumbra and cytokine/chemokine evolution in a 10-day-old rat pup model of HII. Pups were treated for 24 hr after HII with HT (32℃; n = 18) or normothermia (NT, 35℃; n = 15). Outcomes included magnetic resonance imaging (MRI), neurobehavioral testing, and brain cytokine/chemokine profiling (0, 24, 48, and 72 hr post-HII). Lesion volumes (24 hr) were reduced in HT pups (total 74%, p < .05; penumbra 68%, p < .05; core 85%, p = .19). Lesion volumes rebounded at 72 hr (48 hr post-HT) with no significant differences between NT and HT pups. HT reduced interleukin-1β (IL-1β) at all time points (p < .05); monocyte chemoattractant protein-1 (MCP-1) trended toward being decreased in HT pups (p = .09). The stem cell signaling molecule, stromal cell-derived factor-1 (SDF-1) was not altered by HT. Our data demonstrate that HT reduces total and penumbral lesion volumes (at 24 and 48 hr), potentially by decreasing IL-1β without affecting SDF-1. Disassociation between the increasing trend in HII volumes from 48 to 72 hr post-HII when IL-1β levels remained low suggests that after rewarming, mechanisms unrelated to IL-1β expression are likely to contribute to this delayed increase in injury. Additional studies should be considered to determine what these mechanisms might be and also to explore whether extending the duration or degree of HT might ameliorate this delayed increase in injury.
虽然低温（HT）是缺氧缺血性损伤（HII）新生儿的标准治疗方法，但低温的神经保护作用机制仍不清楚。我们研究了 10 天大的 HII 大鼠幼仔模型的缺血核心/半影区和细胞因子/趋化因子的演变。HII 后 24 小时内，幼仔接受 HT（32℃；n=18）或正常体温（NT，35℃；n=15）治疗。结果包括磁共振成像（MRI）、神经行为测试和脑细胞因子/趋化因子谱分析（HII 后 0、24、48 和 72 小时）。HT 幼仔的病变体积（24 小时）减少（总病变体积减少 74%，p<0.05；半影区减少 68%，p<0.05；核心区减少 85%，p=0.19）。72 小时（HT 后 48 小时）病变体积反弹，NT 和 HT 幼仔之间无显著差异。HT 降低了所有时间点的白细胞介素-1β（IL-1β）（p<0.05）；单核细胞趋化蛋白-1（MCP-1）在 HT 幼仔中呈下降趋势（p=0.09）。HT 未改变干细胞信号分子基质细胞衍生因子-1（SDF-1）。我们的数据表明，HT 减少了总病变体积和半影区病变体积（在 24 和 48 小时），可能是通过降低 IL-1β 而不影响 SDF-1 来实现的。HII 体积在 HT 后 48 至 72 小时之间呈上升趋势，而 IL-1β 水平保持较低，这表明复温后，与 IL-1β 表达无关的机制可能导致损伤的延迟增加。应考虑进行更多研究以确定这些机制是什么，并探讨延长 HT 的持续时间或程度是否可能减轻这种延迟性损伤增加。
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