Farrow Kathryn N, Lakshminrusimha Satyan, Reda William J, Wedgwood Stephen, Czech Lyubov, Gugino Sylvia F, Davis Jonathan M, Russell James A, Steinhorn Robin H
Dept. of Pediatrics, Northwestern Univ. Feinberg School of Medicine, 303 E. Chicago Ave., Ward 12-196, Chicago, IL 60611, USA.
Am J Physiol Lung Cell Mol Physiol. 2008 Dec;295(6):L979-87. doi: 10.1152/ajplung.90238.2008. Epub 2008 Sep 12.
Endothelial nitric oxide (NO) synthase (eNOS) expression and activity are decreased in fetal lambs with persistent pulmonary hypertension (PPHN). We sought to determine the impact of mechanical ventilation with O(2) with or without inhaled NO (iNO) or recombinant human SOD (rhSOD) on eNOS in the ductal ligation model of PPHN. PPHN lambs and age-matched controls were ventilated with 100% O(2) for 24 h alone or combined with 20 ppm iNO continuously or a single dose of rhSOD (5 mg/kg) given intratracheally at delivery. In 1-day spontaneously breathing lambs, eNOS expression in resistance pulmonary arteries increased relative to fetal levels. eNOS expression increased in control lambs ventilated with 100% O(2), but not in PPHN lambs. Addition of iNO or rhSOD increased eNOS expression and decreased generation of reactive oxygen species (ROS) in PPHN lambs relative to those ventilated with 100% O(2) alone. However, only rhSOD restored eNOS function, increased tetrahydrobiopterin (BH(4)), a critical cofactor for eNOS function, and restored GTP cyclohydrolase I expression in isolated vessels and lungs from PPHN lambs. These data suggest that ventilation of PPHN lambs with 100% O(2) increases ROS production, blunts postnatal increases in eNOS expression, and decreases available BH(4) in PPHN lambs. Although the addition of iNO or rhSOD diminished ROS production and increased eNOS expression, only rhSOD improved eNOS function and levels of available BH(4). Thus therapies designed to decrease oxidative stress and restore eNOS coupling, such as rhSOD, may prove useful in the treatment of PPHN in newborn infants.
在患有持续性肺动脉高压（PPHN）的胎羊中，内皮型一氧化氮（NO）合酶（eNOS）的表达和活性降低。我们试图确定在PPHN的导管结扎模型中，使用含或不含吸入性NO（iNO）或重组人超氧化物歧化酶（rhSOD）的氧气进行机械通气对eNOS的影响。PPHN羔羊和年龄匹配的对照组单独用100%氧气通气24小时，或持续联合20 ppm的iNO，或在分娩时经气管内给予单剂量的rhSOD（5 mg/kg）。在出生1天自主呼吸的羔羊中，肺阻力动脉中的eNOS表达相对于胎儿水平增加。在使用100%氧气通气的对照羔羊中eNOS表达增加，但在PPHN羔羊中未增加。与仅用100%氧气通气的PPHN羔羊相比，添加iNO或rhSOD可增加PPHN羔羊的eNOS表达并减少活性氧（ROS）的生成。然而，只有rhSOD恢复了eNOS功能，增加了四氢生物蝶呤（BH(4)）（eNOS功能的关键辅助因子），并恢复了PPHN羔羊分离血管和肺中的GTP环化水解酶I表达。这些数据表明，用100%氧气对PPHN羔羊进行通气会增加ROS的产生，抑制出生后eNOS表达的增加，并降低PPHN羔羊中可用的BH(4)水平。虽然添加iNO或rhSOD可减少ROS产生并增加eNOS表达，但只有rhSOD改善了eNOS功能和可用BH(4)的水平。因此，旨在降低氧化应激和恢复eNOS偶联的疗法，如rhSOD，可能被证明对治疗新生儿PPHN有用。
