Ekekezie I I, Thibeault D W, Rezaeikhaligh M H, Mabry S M, Norberg M, Reddy G K, Youssef J, Truog W E
Pediatrics, Children's Mercy Hospital, University of Missouri at Kansas City School of Medicine, Kansas City, MO 64108, USA.
Biol Neonate. 2000 Oct;78(3):198-206. doi: 10.1159/000014271.
Nitric oxide (NO), a pro-oxidant gas, is used with hyperoxia (O(2)) to treat neonatal pulmonary hypertension and recently bronchopulmonary dysplasia, but great concerns remain regarding NO's potential toxicity. Based on reports that exposure to oxidant gases results in pulmonary extracellular matrix injury associated with elevated lavage fluid levels of extracellular matrix components, we hypothesized that inhaled NO with or without hyperoxia will have the same effect. We measured alveolar septal width, lung collagen content, lavage fluid hydroxyproline, hyaluronan and laminin levels in neonatal piglets after 5 days' exposure to room air (RA), RA + 50 ppm NO (RA + NO), O(2) (FiO(2) > 0.96) or O(2) + NO. Matrix metalloproteinase (MMP) activity and MMP-2 mRNA were also measured. In recovery experiments, we measured lung collagen content in piglets exposed to RA + NO or O(2) + NO and then allowed to recover for 3 days. The results show that lung collagen increased 4-fold in the RA + NO piglets, the O(2) and O(2) + NO groups had only a 2-fold elevation relative to RA controls. Unlike the RA + NO piglets, the O(2) and O(2) + NO groups had more than 20-fold elevation in lung lavage fluid hydroxyproline compared to the RA group. O(2) and O(2) + NO also had increased lung MMP activity, extravascular water, and lavage fluid proteins. MMP-2 mRNA levels were unchanged. After 3 days' recovery in room air, the RA + NO groups' lung collagen had declined from 4-fold to 2-fold above the RA group values. The O(2) + NO group did not decline. Alveolar septal width increased significantly only in the O(2) and O(2) + NO groups. We conclude that 5 days' exposure to NO does not result in pulmonary matrix degradation but instead significantly increases lung collagen content. This effect appears potentially reversible. In contrast, hyperoxia exposure with or without NO results in pulmonary matrix degradation and increased lung collagen content. The observation that NO increased lung collagen content represents a new finding and suggests NO could potentially induce pulmonary fibrosis.
一氧化氮（NO）是一种促氧化气体，与高氧（O₂）联合用于治疗新生儿肺动脉高压，最近也用于治疗支气管肺发育不良，但人们对NO的潜在毒性仍极为关注。基于有报道称，接触氧化气体可导致肺细胞外基质损伤，同时灌洗液中细胞外基质成分水平升高，我们推测吸入NO（无论是否伴有高氧）会产生相同的效果。我们测定了新生仔猪在暴露于室内空气（RA）、RA + 50 ppm NO（RA + NO）、O₂（FiO₂>0.96）或O₂ + NO 5天后的肺泡间隔宽度、肺胶原蛋白含量、灌洗液羟脯氨酸、透明质酸和层粘连蛋白水平。还测定了基质金属蛋白酶（MMP）活性和MMP - 2 mRNA水平。在恢复实验中，我们测定了暴露于RA + NO或O₂ + NO然后恢复3天的仔猪的肺胶原蛋白含量。结果显示，RA + NO组仔猪的肺胶原蛋白增加了4倍，O₂组和O₂ + NO组相对于RA对照组仅升高了2倍。与RA + NO组仔猪不同，O₂组和O₂ + NO组的肺灌洗液羟脯氨酸相对于RA组升高了20倍以上。O₂组和O₂ + NO组的肺MMP活性、血管外水分和灌洗液蛋白也增加。MMP - 2 mRNA水平未发生变化。在室内空气中恢复3天后，RA + NO组的肺胶原蛋白从高于RA组值的4倍降至2倍。O₂ + NO组未下降。仅O₂组和O₂ + NO组的肺泡间隔宽度显著增加。我们得出结论，暴露于NO 5天不会导致肺基质降解，反而会显著增加肺胶原蛋白含量。这种效应似乎具有潜在的可逆性。相比之下，无论是否有NO，高氧暴露都会导致肺基质降解并增加肺胶原蛋白含量。NO增加肺胶原蛋白含量这一观察结果代表了一项新发现，并表明NO可能潜在地诱导肺纤维化。
