Stevens Jonathan P, Churchill Thomas, Fokkelman Karien, Haase Erika, Idikio Halliday, Korbutt Gregory, Bigam David L, Cheung Po-Yin
Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
Eur J Pharmacol. 2008 Feb 12;580(3):385-93. doi: 10.1016/j.ejphar.2007.11.019. Epub 2007 Nov 23.
We designed a randomized controlled study to identify and compare the liver tissue responses in systemic hypoxia and resuscitation with 21% and 100% oxygen using an animal model of neonatal hypoxia and reoxygenation. Twenty-seven piglets (1-3 days old, weight 1.5-2.0 kg) were acutely instrumented and mechanically ventilated. The animals underwent 2 h of normocapnic alveolar hypoxia (10-15% oxygen) then reoxygenation with 21% or 100% oxygen for 1 h, then 1 h with 21% oxygen. Controls were sham-operated without hypoxia-reoxygenation. After 2 h of reoxygenation liver tissue samples were immediately processed for histological and biochemical analyses of markers of oxidative stress and tissue injury. Two hours of hypoxia caused a significant reduction in mean arterial pressure with cardiogenic shock and metabolic acidemia, with similar recovery upon resuscitation with 21% and 100% oxygen. After 2 h of reoxygenation, the hepatic GSSG:total glutathione ratio and matrix metalloproteninase-9 activity, which correlated with the portal venous oxygenation at 15 min of reoxygenation, were greater in the 100% group and hepatic lactate level was higher in the 21% group than the controls (all P<0.05). Both hypoxic-reoxygenated groups had similarly elevated hepatic Bcl-2 levels. Apart from more non-distinct mitochondria identified in the 100% group, hepatic tissue adenylate energy charge and plasma transaminases levels did not differ among groups. We concluded that in this acute model of neonatal hypoxia and reoxygenation, resuscitation using 21% oxygen avoids the excess oxidative stress and elevated matrix metalloproteninase-9 activity in the liver when 100% oxygen was used. The study supports the conservative use of oxygen in optimizing post-hypoxic hepatic recovery.
我们设计了一项随机对照研究，以使用新生儿缺氧和复氧动物模型，识别和比较全身缺氧及分别用21%和100%氧气复苏时的肝组织反应。27头仔猪（1 - 3日龄，体重1.5 - 2.0千克）被急性插管并进行机械通气。动物先经历2小时的正常碳酸血症性肺泡缺氧（10 - 15%氧气），然后分别用21%或100%氧气复氧1小时，接着再用21%氧气1小时。对照组进行假手术，不经历缺氧 - 复氧过程。复氧2小时后，立即对肝组织样本进行处理，以对氧化应激和组织损伤标志物进行组织学和生化分析。两小时的缺氧导致平均动脉压显著降低，伴有心源性休克和代谢性酸血症，用21%和100%氧气复苏后的恢复情况相似。复氧2小时后，100%氧气组的肝谷胱甘肽二硫化物与总谷胱甘肽比值及基质金属蛋白酶 - 9活性更高，且与复氧15分钟时的门静脉氧合相关，21%氧气组的肝乳酸水平高于对照组（均P<0.05）。两个缺氧 - 复氧组的肝Bcl - 2水平均同样升高。除了在100%氧气组中发现更多不清晰的线粒体之外，各组之间肝组织腺苷酸能荷和血浆转氨酶水平并无差异。我们得出结论，在这个新生儿缺氧和复氧的急性模型中，使用21%氧气复苏可避免使用100%氧气时肝脏中过度的氧化应激和基质金属蛋白酶 - 9活性升高。该研究支持在优化缺氧后肝脏恢复过程中保守使用氧气。
