Frøen J Frederik, Amerio Giulia, Stray-Pedersen Babill, Saugstad Ola Didrik
Department of Pediatric Research, The National Hospital, University of Oslo, Norway.
Biol Neonate. 2002;82(3):188-96. doi: 10.1159/000063610.
Hypoxia-ischemia is a major cause of perinatal brain damage, but evidence shows that brain injury also is associated with intrauterine infections and maternal smoking. The mechanisms are not known, and we therefore explored the effects of experimental inflammation or nicotine on perinatal brain metabolism and injury during severe hypoxemia. Twenty-eight 1-week-old piglets were anesthetized and instrumented with microdialysis probes in the striatum and brainstem. We studied three pretreatment groups: (1) 20 microg/kg i.v. nicotine (n = 9); (2) 1 microg/kg i.v. endotoxin from Escherichia coli (n = 11), or (3) control (n = 8). The piglets were subsequently exposed to 30 min of hypoxemia (6% O(2)). In order to minimize any ischemic component and increase survival, this was abrupted for 1 min if blood pressure fell to 30 mm Hg. During hypoxemia, both the pretreatment with endotoxin and nicotine induced higher levels of extracellular lactate and peak lactate/pyruvate ratio compared with controls (54.7 +/- 9.6 (p < 0.01) and 65.2 +/- 13.1 (p < 0.02) vs. 15.9 +/- 7.4, respectively), reflecting a deterioration of the metabolic status in these groups. The two pretreated groups reached significantly higher peak levels of extracellular glycerol (30.9 +/- 4.1 vs. 77.9 +/- 12.7 and 89.4 +/- 14.2 micromol/l, respectively, p = 0.01), indicating a higher level of cellular membrane disintegration or leakage. In addition, 3 endotoxin piglets and 4 nicotine piglets died during reoxygenation, while all controls survived (p = 0.13 and p < 0.04, respectively). Mortality was associated with a rise in extracellular glutamate at the end of hypoxemia/start reoxygenation (p = 0.02). These findings contribute in explaining how nicotine and inflammatory response to bacterial toxins could act as cofactors for hypoxic-ischemic neurologic injury in the immature brain.
缺氧缺血是围产期脑损伤的主要原因，但有证据表明脑损伤也与宫内感染和母亲吸烟有关。其机制尚不清楚，因此我们探讨了实验性炎症或尼古丁对严重低氧血症期间围产期脑代谢和损伤的影响。28只1周龄仔猪麻醉后在纹状体和脑干植入微透析探针。我们研究了三个预处理组：(1)静脉注射20微克/千克尼古丁（n = 9）；(2)静脉注射1微克/千克大肠杆菌内毒素（n = 11），或(3)对照组（n = 8）。随后仔猪暴露于30分钟的低氧血症（6%氧气）中。为了尽量减少任何缺血成分并提高存活率，如果血压降至30毫米汞柱，则中断1分钟。在低氧血症期间，与对照组相比，内毒素和尼古丁预处理均导致细胞外乳酸水平升高以及乳酸/丙酮酸峰值比率升高（分别为54.7±9.6（p < 0.01）和65.2±13.1（p < 0.02），而对照组为15.9±7.4），反映出这些组代谢状态的恶化。两个预处理组细胞外甘油的峰值水平显著更高（分别为30.9±4.1与77.9±12.7和89.4±14.2微摩尔/升，p = 0.01），表明细胞膜解体或渗漏程度更高。此外，3只内毒素组仔猪和4只尼古丁组仔猪在复氧期间死亡，而所有对照组仔猪均存活（分别为p = 0.13和p < 0.04）。死亡率与低氧血症末期/开始复氧时细胞外谷氨酸水平升高有关（p = 0.02）。这些发现有助于解释尼古丁和对细菌毒素的炎症反应如何作为未成熟脑缺氧缺血性神经损伤的辅助因素。
