Department of Obstetrics and Gynecology, University of Kansas School of Medicine, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA.
Am J Obstet Gynecol. 2011 Mar;204(3):254.e16-28. doi: 10.1016/j.ajog.2010.11.032. Epub 2011 Jan 26.
The purpose of this study was to investigate the impact of chronic hypoxia on the nitric oxide synthase isoenzymes in specific brain structures.
Time-mated pregnant guinea pigs were exposed to 10.5% molecular oxygen for 14 days (animals with chronic fetal hypoxia; HPX) or room air (control animals; NMX); L-N6-(1-iminoethyl)-lysine (L-NIL; an inducible nitric oxide synthase inhibitor, 1 mg/kg/d) was administered to HPX group for 14 days (L-NIL + HPX). Fetal brains were harvested at term. Multilabeled immunofluorescence was used to generate a brain injury map. Laser capture microdissection and quantitative polymerase chain reaction were applied; cell injury markers, apoptosis activation, neuron loss, total nitric oxide, and the levels of individual nitric oxide synthase isoenzymes were quantified.
Chronic hypoxia causes selective fetal brain injury rather than global. Injury is associated with differentially affected nitric oxide synthases in both neurons and glial cells, with inducible macrophage-type nitric oxide synthase up-regulated at all injury sites. L-NIL attenuated the injury, despite continued hypoxia.
These studies demonstrate that chronic hypoxia selectively injures the fetal brain in part by the differential regulation of nitric oxide synthase isoenzymes in an anatomic- and cell-specific manner.
本研究旨在探讨慢性缺氧对特定脑结构中一氧化氮合酶同工酶的影响。
将时间匹配的怀孕豚鼠暴露于 10.5%的分子氧中 14 天（具有慢性胎儿缺氧的动物；HPX）或室内空气（对照动物；NMX）；L-N6-（1-亚氨基乙基）-赖氨酸（L-NIL；诱导型一氧化氮合酶抑制剂，1mg/kg/d）在 HPX 组中给药 14 天（L-NIL+HPX）。在足月时收获胎脑。采用多标记免疫荧光技术生成脑损伤图谱。应用激光捕获显微切割和定量聚合酶链反应；量化细胞损伤标志物、细胞凋亡激活、神经元丢失、总一氧化氮和个体一氧化氮合酶同工酶的水平。
慢性缺氧引起选择性的胎儿脑损伤，而不是全身性的。损伤与神经元和神经胶质细胞中不同的一氧化氮合酶同工酶相关，诱导型巨噬细胞型一氧化氮合酶在所有损伤部位均上调。尽管持续缺氧，L-NIL 减轻了损伤。
这些研究表明，慢性缺氧通过在解剖和细胞特异性方式下差异调节一氧化氮合酶同工酶，部分选择性地损伤胎儿大脑。
