L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats.
L-citrulline attenuates arrested alveolar growth and pulmonary hypertension in oxygen-induced lung injury in newborn rats.
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DOI：
10.1203/pdr.0b013e3181f90278
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发表时间：
2010-12
影响因子：
3.6
通讯作者：
Thébaud B
中科院分区：
文献类型：
--
作者：
Vadivel A;Aschner JL;Rey-Parra GJ;Magarik J;Zeng H;Summar M;Eaton F;Thébaud B
支气管肺发育不良（BPD）的特征是肺泡发育受阻，并发肺动脉高压（PH）。一氧化氮（NO）促进肺泡生长。吸入NO（iNO）改善实验模型和一些早产儿中的BPD表型。精氨酸琥珀酸合成酶（ASS）和精氨酸琥珀酸裂解酶（ASL）将L-瓜氨酸转化为L-精氨酸; L-瓜氨酸在L-精氨酸合成NO的过程中再生。这些NO前体的血浆水平在PH中较低。我们假设L-瓜氨酸可预防新生大鼠实验性O2诱导的BPD。从出生到出生后第14天（P14），将幼鼠分配到室内空气（RA）、RA+ L-瓜氨酸、95%高氧（BPD模型）和95%O2+ L-瓜氨酸。暴露于高氧的幼鼠有更少和扩大的空气空间和毛细血管密度降低，模仿人类BPD。这与P7时血浆L-精氨酸和L-瓜氨酸浓度降低有关。L-瓜氨酸治疗显著增加血浆L-精氨酸和L-瓜氨酸浓度，并增加高氧下ASL蛋白表达。L-瓜氨酸保护了暴露于O2的幼仔的肺泡和血管生长，并降低了肺动脉中壁厚度和右心室肥大。L-瓜氨酸治疗可逆转暴露于O2的幼鼠肺组织脱氢酶活性增加。补充L-瓜氨酸可预防新生大鼠高氧诱导的肺损伤和PH。L-瓜氨酸可能是iNO预防BPD的一种新的治疗替代品。
Bronchopulmonary dysplasia (BPD) is characterized by arrested alveolar development and complicated by pulmonary hypertension (PH). Nitric oxide (NO) promotes alveolar growth. Inhaled NO (iNO) ameliorates the BPD phenotype in experimental models and in some premature infants. Arginosuccinate synthetase (ASS) and arginosuccinate lyase (ASL) convert L-citrulline to L-arginine; L-citrulline is regenerated during NO synthesis from L-arginine. Plasma levels of these NO precursors are low in PH. We hypothesized that L-citrulline prevents experimental O2-induced BPD in newborn rats. Rat pups were assigned from birth through postnatal day 14 (P14) to room air (RA), RA+L-citrulline, 95% hyperoxia (BPD model), and 95%O2+L-citrulline. Rat pups exposed to hyperoxia had fewer and enlarged air spaces and decreased capillary density, mimicking human BPD. This was associated with decreased plasma L-arginine and L-citrulline concentrations on P7. L-Citrulline treatment significantly increased plasma L-arginine and L-citrulline concentrations and increased ASL protein expression in hyperoxia. L-Citrulline preserved alveolar and vascular growth in O2-exposed pups and decreased pulmonary arterial medial wall thickness and right ventricular hypertrophy. Increased lung arginase activity in O2-exposed pups was reversed by L-citrulline treatment. L-Citrulline supplementation prevents hyperoxia-induced lung injury and PH in newborn rats. L-citrulline may represent a novel therapeutic alternative to iNO for prevention of BPD.