Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung.
Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung.
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DOI：
10.1016/j.freeradbiomed.2013.03.003
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发表时间：
2013-08
影响因子：
7.4
通讯作者：
Schumacker, Paul T.
中科院分区：
文献类型：
--
作者：
Berkelhamer, Sara K.;Kim, Gina A.;Radder, Josiah E.;Wedgwood, Stephen;Czech, Lyubov;Steinhorn, Robin H.;Schumacker, Paul T.
关键词：
新生小鼠暴露于高吸入氧会引起肺泡和血管发育受损的独特表型，尽管与成人相比，长期暴露于新生儿的致死率较低。由于高氧的影响是由过量的活性氧 (ROS) 产生介导的，我们假设与成年小鼠相比，新生小鼠可能表现出抗氧化防御表达增强或 ROS 产生减弱。我们测量了出生后小鼠肺发育过程中不同时间点肺切片和肺泡上皮细胞对急性高氧的亚细胞氧化反应。使用 roGFP（一种针对细胞质或线粒体基质的比例蛋白质硫醇氧化还原传感器）评估氧化应激。与新生儿对氧诱导死亡的抵抗力相反，与成年小鼠相比，年轻小鼠的肺切片细胞表现出过度的线粒体基质氧化应激，而细胞质中不存在氧化应激反应。暴露于高氧环境 48 小时的新生小鼠肺切片中的细胞死亡也高于成年小鼠。与这些发现一致的是，新生儿肺部抗氧化酶的表达低于成人，并且在体内暴露的 24 小时内不存在抗氧化水平和活性的诱导。然而，在幼年肺中，活性氧生成酶 NADPH 氧化酶 1 (NOX1) 的表达随着高氧暴露而增加，但成年肺中的表达却没有增加。总的来说，这些结果表明，成年动物的更大致死率可能更可能归因于炎症等过程，而不是抗氧化防御的差异。因此，新生儿和成人氧化性肺损伤的治疗应考虑并解决氧化应激反应的发育差异。
Exposure of newborn mice to high inspired oxygen elicits a distinct phenotype of compromised alveolar and vascular development, although lethality during long-term exposure is lower in newborns compared to adults. As the effects of hyperoxia are mediated by excessive reactive oxygen species (ROS) generation, we hypothesized that newborn mice may exhibit enhanced expression of antioxidant defenses or attenuated ROS generation compared with adults. We measured subcellular oxidant responses to acute hyperoxia in lung slices and alveolar epithelial cells at varying time points during postnatal murine lung development. Oxidant stress was assessed using roGFP, a ratiometric protein thiol redox sensor, targeted to the cytosol or the mitochondrial matrix. In contrast to newborn resistance to oxygen-induced mortality, cells of lung slices from younger mice demonstrated exaggerated mitochondrial matrix oxidant stress compared to adults, whereas oxidant stress responses in the cytosol were absent. Cell death in lung slices from newborn mice exposed to 48 hours of hyperoxia was also greater than for adults. Consistent with these findings, expression of antioxidant enzymes in newborn lungs was lower than in adults, and induction of antioxidant levels and activity during 24 hours of in vivo exposure was absent. However, expression of the reactive oxygen species generating enzyme, NADPH oxidase 1 (NOX1), was increased with hyperoxic exposure in the young but not adult lung. Collectively, these results suggest that the greater lethality in adult animals may be more likely attributed to processes such as inflammation than to differences antioxidant defenses. Therapies for neonatal and adult oxidative lung injury should therefore consider and address developmental differences in oxidative stress responses.
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DOI：
10.1164/rccm.200902-0242oc
发表时间：
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影响因子：
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