Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent
Mouse lung development and NOX1 induction during hyperoxia are developmentally regulated and mitochondrial ROS dependent
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DOI：
10.1152/ajplung.00176.2014
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发表时间：
2015-08-15
影响因子：
4.9
通讯作者：
Berkelhamer, Sara K.
中科院分区：
文献类型：
--
作者：
Datta, Ankur;Kim, Gina A.;Berkelhamer, Sara K.
动物模型表明，在新生儿期暴露于超生理氧损害肺和肺血管发育，导致表型与支气管肺发育不良（BPD）相当。我们先前在小鼠模型中的工作确定了出生后抗氧化酶能力的成熟以及高氧下线粒体氧化应激的发育调节。我们推测，高氧的后果也可能是发育调节和线粒体活性氧（ROS）依赖。为了确定暴露的年龄是否影响高氧的效果，新生小鼠在出生后第0天（出生后早期）或第4天（出生后晚期）被放置在75%的氧气中72小时。与常氧对照组相比，出生后早期暴露于高氧的小鼠表现出肺泡化和分隔减少，阻力肺动脉肌化增加和右心室肥大（RVH）。在产后早期高氧期间，使用线粒体特异性抗氧化剂（2-（2，2，6，6-四甲基哌啶-1-氧代-4-基氨基）-2-氧代乙基）氯化三苯基磷（mitoTEMPO）进行治疗，可以防止肺泡化受损和RVH。此外，早期，但不是晚期，出生后高氧导致诱导的NOX 1的表达是线粒体活性氧依赖。由于早期暴露（而非晚期暴露）导致肺和心血管发育受损，我们得出结论，高氧的后果是发育调节的，并随年龄增长而减少。mitoTEMPO治疗的小鼠中的疾病减轻暗示线粒体ROS在新生儿高氧肺损伤的病理生理学中，具有通过NOX 1诱导放大ROS信号传导的潜力。此外，它表明了有针对性的抗氧化治疗在预防或治疗BPD中的潜在作用。
Animal models demonstrate that exposure to supraphysiological oxygen during the neonatal period compromises both lung and pulmonary vascular development, resulting in a phenotype comparable to bronchopulmonary dysplasia (BPD). Our prior work in murine models identified postnatal maturation of antioxidant enzyme capacities as well as developmental regulation of mitochondrial oxidative stress in hyperoxia. We hypothesize that consequences of hyperoxia may also be developmentally regulated and mitochondrial reactive oxygen species (ROS) dependent. To determine whether age of exposure impacts the effect of hyperoxia, neonatal mice were placed in 75% oxygen for 72 h at either postnatal day 0 (early postnatal) or day 4 (late postnatal). Mice exposed to early, but not late, postnatal hyperoxia demonstrated decreased alveolarization and septation, increased muscularization of resistance pulmonary arteries, and right ventricular hypertrophy (RVH) compared with normoxic controls. Treatment with a mitochondria-specific antioxidant, (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (mitoTEMPO), during early postnatal hyperoxia protected against compromised alveolarization and RVH. In addition, early, but not late, postnatal hyperoxia resulted in induction of NOX1 expression that was mitochondrial ROS dependent. Because early, but not late, exposure resulted in compromised lung and cardiovascular development, we conclude that the consequences of hyperoxia are developmentally regulated and decrease with age. Attenuated disease in mitoTEMPO-treated mice implicates mitochondrial ROS in the pathophysiology of neonatal hyperoxic lung injury, with potential for amplification of ROS signaling through NOX1 induction. Furthermore, it suggests a potential role for targeted antioxidant therapy in the prevention or treatment of BPD.