Cai Charles, Aranda Jacob V, Valencia Gloria B, Xu Jiliu, Beharry Kay D
Department of Pediatrics, Division of Neonatal-Perinatal Medicine, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
Department of Ophthalmology, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
React Oxyg Species (Apex). 2017 May;3(9):218-236. Epub 2017 May 1.
Critically ill preterm neonates requiring oxygen therapy often experience frequent apneas with intermittent hypoxia (IH). IH-induced oxidative stress causes lipid peroxidation, which targets the liver and contributes to toxic drug reactions. We tested the hypothesis that incremental IH episodes induce oxidative damage in the neonatal liver and alter the expression of genes that regulate drug metabolism. Newborn rats were exposed to increasing IH episodes (12% O) during hyperoxia (50% O), or placed in room air (RA) until postnatal day 21 (P21) for recovery from IH (IHR). RA littermates served as controls, and pups exposed to 50% O served as hyperoxia controls. Hepatic histopathology, biomarkers of oxidative stress and oxidative DNA damage, antioxidants, and expression of genes that regulate drug metabolism were assessed. Oxidative stress and DNA damage, evidenced by 8-isoprostaglandin F (8-isoPGF) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG), respectively, increased as a function of IH episodes, and was associated with decreased superoxide dismutase (SOD) and increased catalase activities. Pathological changes including cellular swelling, steatosis, necrosis, and focal sinusoid congestion were seen in IH, but not in IHR. Similarly, IH was associated with upregulation of several genes involved in DNA repair, which were downregulated during IHR. Of the genes involved in drug metabolism, aldehyde dehydrogenases (involved in lipid peroxidation) and cytochrome P450 (CYP) genes of the 2C family (involved in oxidative stress) were robustly upregulated both in IH and in IHR. Hepatic oxidative stress and lipid peroxidation occurring in response to chronic IH have implications for preterm infants, and may explain, in part, the pharmacokinetic variations and drug toxicities in this vulnerable population.
需要氧疗的危重新生儿早产儿常频繁出现伴有间歇性低氧（IH）的呼吸暂停。IH诱导的氧化应激会导致脂质过氧化，其作用于肝脏并导致药物毒性反应。我们验证了这样一个假说，即递增的IH发作会诱导新生肝脏的氧化损伤，并改变调节药物代谢的基因表达。将新生大鼠在高氧（50%氧气）期间暴露于递增的IH发作（12%氧气）中，或置于室内空气（RA）中直至出生后第21天（P21）以从IH中恢复（IHR）。RA同窝幼崽作为对照，暴露于50%氧气的幼崽作为高氧对照。评估肝脏组织病理学、氧化应激和氧化DNA损伤的生物标志物、抗氧化剂以及调节药物代谢的基因表达。分别由8-异前列腺素F（8-isoPGF）和8-羟基-2'-脱氧鸟苷（8-OH-dG）证明的氧化应激和DNA损伤随IH发作次数增加而增加，并与超氧化物歧化酶（SOD）降低和过氧化氢酶活性增加相关。在IH组可见包括细胞肿胀、脂肪变性、坏死和局灶性窦状隙充血在内的病理变化，而IHR组未见。同样，IH与参与DNA修复的几个基因上调相关，这些基因在IHR期间下调。在参与药物代谢的基因中，醛脱氢酶（参与脂质过氧化）和2C家族的细胞色素P450（CYP）基因（参与氧化应激）在IH组和IHR组均显著上调。慢性IH引起的肝脏氧化应激和脂质过氧化对早产儿有影响，并且可能部分解释了这一脆弱人群的药代动力学变化和药物毒性。
