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首页> 外文期刊>American Journal of Physiology >Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats
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Contribution of xanthine oxidase-derived superoxide to chronic hypoxic pulmonary hypertension in neonatal rats

机译：黄嘌呤氧化酶来源的超氧化物对新生大鼠慢性低氧性肺动脉高压的贡献

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First published December 14, 2007; doi:10.1152/ajplung.00166.2007.-Xanthine oxidase (XO)-derived reactive oxygen species (ROS) formation contributes to experimental chronic hypoxic pulmonary hypertension in adults, but its role in neonatal pulmonary hypertension has received little attention. In rats chronically exposed to hypoxia (13% O2) for 14 days from birth, we examined the effects of ROS scavengers (U74389G 10 mg-kg~(-1) day~(-1) or Tempol 100 mg-kg-day~(-1) ip) or a XO inhibitor, Allopurinol (50 mg-kg~(-1) -day~(-1) ip). Both ROS scavengers limited oxidative stress in the lung and attenuated hypoxia-induced vascular remodeling, confirming a critical role for ROS in this model. However, both interventions also significantly inhibited somatic growth and normal cellular proliferation in distal air spaces. Hypoxia-exposed pups had evidence of increased serum and lung XO activity, increased vascular XO-derived superoxide production, and vascular nitrotyrosine formation. These changes were all prevented by treatment with Allopurinol, which also attenuated hypoxia-induced vascular remodeling and partially reversed inhibited endothelium-depen-dent arterial relaxation, without affecting normal growth and proliferation. Collectively, our findings suggest that XO-derived superoxide induces endothelial dysfunction, thus impairing pulmonary arterial relaxation, and contributes to vascular remodeling in hypoxia-exposed neonatal rats. Due to the potential for adverse effects on normal growth, targeting XO may represent a superior "antioxidant" strategy to ROS scavengers for neonates with pulmonary hypertension.
机译：首次发布于2007年12月14日; doi：10.1152 / ajplung.00166.2007.-黄嘌呤氧化酶（XO）衍生的活性氧（ROS）的形成有助于成人实验性慢性低氧性肺动脉高压，但其在新生儿肺动脉高压中的作用却很少受到关注。在出生后慢性暴露于缺氧（13％O2）14天的大鼠中，我们检查了ROS清除剂（U74389G 10 mg-kg〜（-1）天〜（-1）或Tempol 100 mg-kg-天〜 （-1）ip）或XO抑制剂别嘌醇（50 mg-kg〜（-1）-day〜（-1）ip）。两种ROS清除剂均限制了肺中的氧化应激，并减弱了缺氧引起的血管重塑，证实了ROS在该模型中的关键作用。但是，这两种干预措施也显着抑制了远端气隙中的体细胞生长和正常细胞增殖。缺氧暴露的幼崽具有增加的血清和肺XO活性，增加的源自血管XO的超氧化物生成以及血管硝基酪氨酸形成的证据。这些变化均通过别嘌呤醇治疗得以预防，别嘌呤醇还减弱了缺氧引起的血管重塑，部分逆转了内皮依赖性动脉舒张抑制作用，而又不影响正常的生长和增殖。总的来说，我们的发现表明XO衍生的超氧化物诱导内皮功能障碍，从而损害肺动脉舒张，并有助于低氧暴露新生大鼠的血管重塑。由于对正常生长可能产生不利影响，针对患有肺动脉高压的新生儿，靶向XO可能代表优于ROS清除剂的“抗氧化剂”策略。

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