Potter C F, Kuo N T, Farver C F, McMahon J T, Chang C H, Agani F H, Haxhiu M A, Martin R J
Department of Pediatrics, University Hospitals of Cleveland, Case Western Reserve University, Ohio 44106, USA.
Pediatr Res. 1999 Jan;45(1):8-13. doi: 10.1203/00006450-199901000-00003.
Although hyperoxic exposure is an important contributor to the development of bronchopulmonary dysplasia and nitric oxide (NO) has been implicated in the pulmonary response to oxygen, the role of NO in mediating chronic neonatal lung injury is unclear. Therefore, rat pups were exposed to normoxia or hyperoxia (>95% O2) from d 21 to 29. After the rats were killed, their lungs were removed for analysis of nitric oxide synthase (NOS) expression, NO activity as measured by 3',5'-cyclic guanosine monophosphate (cGMP) assay, and lung pathology. Hyperoxia caused 5-fold and 2-fold increases in inducible (i) NOS and endothelial (e) NOS levels, respectively. NO activity was assessed by measuring cGMP levels after normoxic or hyperoxic exposure in the presence and absence of NOS blockade with either aminoguanidine (AG) or Nomega-nitro-L-arginine (L-NNA). cGMP levels were elevated in hyperoxic versus normoxic rats (287+/-15 versus 106+/-9 pmol/mg protein, respectively, p < 0.001), and this increase in cGMP was attenuated after NOS blockade with either AG or L-NNA. Hyperoxic exposure significantly increased lung/body weight ratios and induced histologic changes of interstitial and alveolar edema; however, these hyperoxia-induced histologic changes were not altered by NOS blockade with AG or L-NNA. We conclude that hyperoxic exposure of rat pups up-regulated both iNOS and eNOS and increased NO activity as measured by cGMP levels derived from both iNOS and eNOS. Blockade of NOS reduced cGMP levels in the hyperoxic rat pups; however, it did not seem to reverse the pathologic consequences of hyperoxic exposure.
尽管高氧暴露是支气管肺发育不良发生的一个重要因素，并且一氧化氮（NO）与肺部对氧的反应有关，但NO在介导慢性新生儿肺损伤中的作用尚不清楚。因此，将新生大鼠从出生第21天至29天暴露于常氧或高氧（>95% O2）环境中。处死大鼠后，取出肺组织分析一氧化氮合酶（NOS）表达、通过3',5'-环磷酸鸟苷（cGMP）测定法检测的NO活性以及肺病理学。高氧分别使诱导型（i）NOS和内皮型（e）NOS水平增加了5倍和2倍。在存在或不存在用氨基胍（AG）或Nω-硝基-L-精氨酸（L-NNA）阻断NOS的情况下，通过测量常氧或高氧暴露后的cGMP水平来评估NO活性。高氧大鼠的cGMP水平高于常氧大鼠（分别为287±15与106±9 pmol/mg蛋白质，p<0.001），在用AG或L-NNA阻断NOS后，cGMP的这种增加减弱。高氧暴露显著增加了肺/体重比，并诱导了间质和肺泡水肿的组织学变化；然而，用AG或L-NNA阻断NOS并没有改变这些高氧诱导的组织学变化。我们得出结论，新生大鼠高氧暴露上调了iNOS和eNOS，并增加了通过源自iNOS和eNOS的cGMP水平测量的NO活性。阻断NOS降低了高氧新生大鼠的cGMP水平；然而，它似乎并没有逆转高氧暴露的病理后果。
