Rocha-Ferreira E, Phillips E, Francesch-Domenech E, Thei L, Peebles D M, Raivich G, Hristova M
Perinatal Brain Protection and Repair Group, EGA Institute for Women's Health, University College London, WC1E 6HX London, UK.
Perinatal Brain Protection and Repair Group, EGA Institute for Women's Health, University College London, WC1E 6HX London, UK.
Neuroscience. 2015 Dec 17;311:292-307. doi: 10.1016/j.neuroscience.2015.10.035. Epub 2015 Oct 26.
Genetic background is known to influence the outcome in mouse models of human disease, and previous experimental studies have shown strain variability in the neonatal mouse model of hypoxia-ischemia. To further map out this variability, we compared five commonly used mouse strains: C57BL/6, 129SVJ, BALB/c, CD1 and FVB in a pure hypoxic-ischemic setup and following pre-sensitization with lipopolysaccharide (LPS). Postnatal day 7 pups were subjected to unilateral carotid artery occlusion followed by continuous 30 min 8% oxygen exposure at 36 °C. Twelve hours prior, a third of the pups received a single intraperitoneal LPS (0.6 μg/g) or a saline (vehicle) administration, respectively; a further third underwent hypoxia-ischemia alone without preceding injection. Both C57BL/6 and 129SVJ strains showed minimal response to 30min hypoxia-ischemia alone, BALB/c demonstrated a moderate response, and both CD1 and FVB revealed the highest brain damage. LPS pre-sensitization led to substantial increase in overall brain infarction, microglial and astrocyte response and cell death in four of the five strains, with exception of BALB/c that only showed a significant effect with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Saline administration prior to hypoxia-ischemia resulted in an increase in inflammatory-associated markers, particularly in the astroglial activation of C57BL/6 mice, and in combined microglial activation and neuronal cell loss in FVB mice. Finally, two of the four strongly affected strains--C57BL/6 and CD1--revealed pronounced contralateral astrogliosis with a neuroanatomical localization similar to that observed on the occluded hemisphere. Overall, the current findings demonstrate strain differences in response to hypoxia-ischemia alone, to stress associated with vehicle injection, and to LPS-mediated pre-sensitization, which partially explains the high variability seen in the neonatal mouse models of hypoxia-ischemia. These results can be useful in future studies of fetal/neonatal response to inflammation and reduced oxygen-blood supply.
已知遗传背景会影响人类疾病小鼠模型的结果，先前的实验研究表明，在缺氧缺血新生小鼠模型中存在品系变异性。为了进一步明确这种变异性，我们在单纯缺氧缺血条件下以及用脂多糖（LPS）预致敏后，比较了五种常用的小鼠品系：C57BL/6、129SVJ、BALB/c、CD1和FVB。出生后第7天的幼崽接受单侧颈动脉结扎，随后在36℃下持续30分钟暴露于8%的氧气中。在缺氧缺血前12小时，分别有三分之一的幼崽接受单次腹腔注射LPS（0.6μg/g）或生理盐水（溶剂对照）；另有三分之一仅接受缺氧缺血，未进行预先注射。单独30分钟的缺氧缺血，C57BL/6和129SVJ品系反应最小，BALB/c表现出中度反应，而CD1和FVB均显示出最高的脑损伤。LPS预致敏导致五个品系中的四个品系总体脑梗死、小胶质细胞和星形胶质细胞反应以及细胞死亡大幅增加，但BALB/c除外，该品系仅在末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）时显示出显著影响。缺氧缺血前给予生理盐水导致炎症相关标志物增加，特别是C57BL/6小鼠的星形胶质细胞活化，以及FVB小鼠的小胶质细胞活化和神经元细胞丢失。最后，四个受影响严重的品系中的两个——C57BL/6和CD1——显示出明显的对侧星形胶质细胞增生，其神经解剖定位与闭塞半球观察到的相似。总体而言，当前研究结果表明，各品系在对单独缺氧缺血、溶剂对照注射相关应激以及LPS介导的预致敏反应方面存在差异，这部分解释了缺氧缺血新生小鼠模型中出现的高变异性情况。这些结果对于未来胎儿/新生儿对炎症和氧供减少反应的研究可能有用。
