Bronchopulmonary dysplasia (BPD)-associated pulmonary hypertension (PH) is a chronic infantile lung disease that lacks curative therapies. Infants with BPD-associated PH are often exposed to hyperoxia and additional insults such as sepsis that contribute to disease pathogenesis. Animal models that simulate these scenarios are necessary to develop effective therapies; therefore, we investigated whether lipopolysaccharide (LPS) and hyperoxia exposure during saccular lung development cooperatively induce experimental BPD-PH in mice. C57BL/6J mice were exposed to normoxia or 70% O₂ (hyperoxia) during postnatal days (PNDs) 1-5 and intraperitoneally injected with varying LPS doses or a vehicle on PNDs 3-5. On PND 14, we performed morphometry, echocardiography, and gene and protein expression studies to determine the effects of hyperoxia and LPS on lung development, vascular remodeling and function, inflammation, oxidative stress, cell proliferation, and apoptosis. LPS and hyperoxia independently and cooperatively affected lung development, inflammation, and apoptosis. Growth rate and antioxidant enzyme expression were predominantly affected by LPS and hyperoxia, respectively, while cell proliferation and vascular remodeling and function were mainly affected by combined exposure to LPS and hyperoxia. Mice treated with lower LPS doses developed adaptive responses and hyperoxia exposure did not worsen their BPD phenotype, whereas those mice treated with higher LPS doses displayed the most severe BPD phenotype when exposed to hyperoxia and were the only group that developed PH. Collectively, our data suggest that an additional insult such as LPS may be necessary for models utilizing short-term exposure to moderate hyperoxia to recapitulate human BPD-PH.

中文翻译：

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早期脂多糖和高氧暴露对发育中的小鼠肺的交互和独立影响。

支气管肺发育不良 (BPD) 相关的肺动脉高压 (PH) 是一种慢性婴儿肺部疾病，缺乏治疗方法。患有 BPD 相关 PH 的婴儿经常暴露于高氧和其他损伤，例如导致疾病发病机制的败血症。模拟这些场景的动物模型是开发有效疗法所必需的；因此，我们研究了囊状肺发育过程中脂多糖 (LPS) 和高氧暴露是否协同诱导小鼠实验性 BPD-PH。C57BL/6J 小鼠暴露于常氧或 70% O ₂（缺氧）在产后天 (PNDs) 1-5 和腹腔注射不同的 LPS 剂量或在 PNDs 3-5 的载体。在 PND 14 日，我们进行了形态测量、超声心动图以及基因和蛋白质表达研究，以确定高氧和 LPS 对肺发育、血管重塑和功能、炎症、氧化应激、细胞增殖和细胞凋亡的影响。LPS 和高氧独立并协同影响肺发育、炎症和细胞凋亡。生长速率和抗氧化酶的表达分别主要受 LPS 和高氧的影响，而细胞增殖和血管重塑和功能主要受 LPS 和高氧联合暴露的影响。用较低 LPS 剂量治疗的小鼠产生了适应性反应，高氧暴露并没有使它们的 BPD 表型恶化，而那些用较高 LPS 剂量治疗的小鼠在暴露于高氧时表现出最严重的 BPD 表型，并且是唯一发生 PH 的组。总的来说，我们的数据表明，对于利用短期暴露于中度高氧的模型来概括人类 BPD-PH，可能需要额外的侮辱，例如 LPS。