Bronchopulmonary dysplasia (BPD) is characterized by alveolar simplification, airway hyperreactivity, and pulmonary hypertension. In our BPD model, we have investigated the metabolism of the bronchodilator and pulmonary vasodilator GSNO (S-nitrosoglutathione). We have shown the GSNO catabolic enzyme encoded by adh5 (alcohol dehydrogenase-5), GSNO reductase, is epigenetically upregulated in hyperoxia. Here, we investigated the distribution of GSNO reductase expression in human BPD and created an animal model that recapitulates the human data. Blinded comparisons of GSNO reductase protein expression were performed in human lung tissues from infants and children with and without BPD. BPD phenotypes were evaluated in global (adh5^−/−) and conditional smooth muscle (smooth muscle/adh5^−/−) adh5 knockout mice. GSNO reductase was prominently expressed in the airways and vessels of human BPD subjects. Compared with controls, expression was greater in BPD smooth muscle, particularly in vascular smooth muscle (2.4-fold; P = 0.003). The BPD mouse model of neonatal hyperoxia caused significant alveolar simplification, airway hyperreactivity, and right ventricular and vessel hypertrophy. Global adh5^−/− mice were protected from all three aspects of BPD, whereas smooth muscle/adh5^−/− mice were only protected from pulmonary hypertensive changes. These data suggest adh5 is required for the development of BPD. Expression in the pulmonary vasculature is relevant to the pathophysiology of BPD-associated pulmonary hypertension. GSNO-mimetic agents or GSNO reductase inhibitors, both of which are currently in clinical trials for other conditions, could be considered for further study in BPD.

支气管肺发育不良 (BPD) 的特征是肺泡简化、气道高反应性和肺动脉高压。在我们的 BPD 模型中，我们研究了支气管扩张剂和肺血管扩张剂 GSNO（S-亚硝基谷胱甘肽）的代谢。我们已经展示了由adh5（酒精脱氢酶-5）编码的 GSNO 分解代谢酶，即 GSNO 还原酶，在高氧条件下表观遗传上调。在这里，我们研究了人类 BPD 中 GSNO 还原酶表达的分布，并创建了一个概括人类数据的动物模型。在患有和不患有 BPD 的婴儿和儿童的人肺组织中对 GSNO 还原酶蛋白表达进行了盲法比较。BPD 表型在全球 ( adh5 ^-/-）和条件平滑肌（平滑肌/ adh5 ^-/-）adh5敲除小鼠。GSNO 还原酶在人类 BPD 受试者的气道和血管中显着表达。与对照相比，BPD 平滑肌中的表达更高，尤其是在血管平滑肌中（2.4 倍；P  = 0.003）。新生儿高氧的 BPD 小鼠模型导致肺泡明显简化、气道高反应性以及右心室和血管肥大。全局adh5 ^-/-小鼠免受 BPD 的所有三个方面的影响，而平滑肌/ adh5 ^-/-小鼠仅免受肺动脉高压变化的影响。这些数据表明adh5是发展 BPD 所必需的。肺血管系统中的表达与 BPD 相关肺动脉高压的病理生理学有关。GSNO 模拟剂或 GSNO 还原酶抑制剂，两者目前都在针对其他疾病进行临床试验，可以考虑在 BPD 中进行进一步研究。