Department of Pediatrics, Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, Ohio 44106-6009, USA.
Neonatology. 2012;101(2):106-15. doi: 10.1159/000329540. Epub 2011 Sep 23.
Prolonged exposure of immature lungs to hyperoxia contributes to neonatal lung injury and airway hyperreactivity. We have previously demonstrated that neonatal exposure of rat pups to ≥95% O2 impairs airway relaxation due to disruption of nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling.
We now hypothesize that these impaired relaxation responses are secondary to hyperoxia-induced upregulation of arginase, which competes with NO synthase for L-arginine.
Rat pups were exposed to moderate neonatal hyperoxia (50% O2) or room air for 7 days from birth. In additional hyperoxic and room air groups, exogenous L-arginine (300 mg/kg/day i.p.) or arginase inhibitor (Nω-hydroxy-nor-arginine, 30 mg/kg/day i.p.) were administered daily. After 7 days, animals were anesthetized and sacrificed either for preparation of lung parenchymal strips or lung perfusion.
In response to electrical field stimulation (EFS), bethanechol-preconstricted lung parenchymal strips from hyperoxic pups exhibited significantly reduced relaxation compared to room air controls. Supplementation of L-arginine or arginase blockade restored hyperoxia-induced impairment of relaxation. Expression of arginase I in airway epithelium was increased in response to hyperoxia but reduced by arginase blockade. Arginase activity was also significantly increased in hyperoxic lungs as compared to room air controls and reduced following arginase blockade. EFS-induced production of NO was decreased in hyperoxia-exposed airway smooth muscle and restored by arginase blockade.
These data suggest that NO-cGMP signaling is disrupted in neonatal rat pups exposed to even moderate hyperoxia due to increased arginase activity and consequent decreased bioavailability of the substrate L-arginine. We speculate that supplementation of arginine and/or inhibition of arginase may be a useful therapeutic tool to prevent or treat neonatal lung injury.
未成熟的肺部长时间暴露在高氧环境中会导致新生儿肺损伤和气道高反应性。我们之前已经证明，新生大鼠暴露于≥95%的氧气中会损害气道松弛，这是由于一氧化氮（NO）-环鸟苷酸（cGMP）信号的破坏。
我们现在假设，这些松弛反应的受损是由于高氧诱导的精氨酸酶上调引起的，精氨酸酶与 NO 合酶竞争 L-精氨酸。
从出生后第 7 天开始，新生大鼠暴露于中等程度的新生儿高氧（50%的 O2）或室内空气环境中。在额外的高氧和室内空气组中，每天腹腔内给予外源性 L-精氨酸（300mg/kg/天）或精氨酸酶抑制剂（Nω-羟基-N-硝基-精氨酸，30mg/kg/天）。7 天后，动物麻醉并安乐死，用于制备肺实质条或肺灌注。
在电刺激（EFS）下，与室内空气对照组相比，高氧组的肺实质条在 Bethanechol 预收缩后表现出明显的松弛减少。补充 L-精氨酸或精氨酸酶抑制可恢复高氧诱导的松弛受损。气道上皮中的精氨酸酶 I 表达在高氧刺激下增加，但被精氨酸酶抑制所减少。高氧肺中的精氨酸酶活性也明显高于室内空气对照组，且在精氨酸酶抑制后降低。EFS 诱导的气道平滑肌中 NO 的产生减少，且在精氨酸酶抑制后恢复。
这些数据表明，即使是中等程度的高氧暴露也会破坏新生大鼠的 NO-cGMP 信号，这是由于精氨酸酶活性增加和随后的底物 L-精氨酸生物利用度降低所致。我们推测，补充精氨酸和/或抑制精氨酸酶可能是预防或治疗新生儿肺损伤的有用治疗工具。
