Department of Pediatrics, Yongchuan Hospital of Chongqing Medical University, Chongqing, China.
Department of Pediatrics, Chongqing Jiulongpo District Maternity Child Health Care Hospital, Chongqing, China.
Br J Pharmacol. 2021 Jun;178(11):2266-2283. doi: 10.1111/bph.15371. Epub 2021 Apr 9.
Bronchopulmonary dysplasia (BPD) is the most prevalent chronic paediatric lung disease and is linked to the development of chronic obstructive pulmonary disease. MicroRNA-based regulation of type II alveolar epithelial cell (T2AEC) proliferation and apoptosis is an important factor in the pathogenesis of BPD and warrants further investigation.
Two murine models of hyperoxic lung injury (with or without miR-342-5p or Sprouty-related, EVH1 domain-containing protein 3 [Spred3] modulation) were employed: a hyperoxia-induced acute lung injury model (100% O on postnatal days 1-7) and the BPD model (100% O on postnatal days 1-4, followed by room air for 10 days). Tracheal aspirate pellets from healthy control and moderate/severe BPD neonates were randomly selected for clinical miR-342-5p analysis.
Hyperoxia decreased miR-342-5p levels in primary T2AECs, MLE12 cells and neonatal mouse lungs. Transgenic miR-342 overexpression in neonatal mice ameliorated survival rates and improved the BPD phenotype and BPD-associated pulmonary arterial hypertension (PAH). T2AEC-specific miR-342 transgenic overexpression, as well as miR-342-5p mimic therapy, also ameliorated the BPD phenotype and associated PAH. miR-342-5p targets the 3'UTR of the Raf1 regulator Spred3, inhibiting Spred3 expression. Treatment with recombinant Spred3 exacerbated the BPD phenotype and associated PAH. Notably, miR-342-5p inhibition under room air conditions did not mimic the BPD phenotype. Moderate/severe BPD tracheal aspirate pellets exhibited decreased miR-342-5p levels relative to healthy control pellets.
These findings suggest that miR-342-5p mimic therapy may show promise in the treatment or prevention of BPD.
支气管肺发育不良（BPD）是最常见的慢性儿科肺部疾病，与慢性阻塞性肺疾病的发展有关。miRNA 对 II 型肺泡上皮细胞（T2AEC）增殖和凋亡的调控是 BPD 发病机制中的一个重要因素，值得进一步研究。
采用两种高氧肺损伤的小鼠模型（有或没有 miR-342-5p 或 Sprouty 相关 EVH1 结构域蛋白 3 [Spred3]调节）：高氧诱导的急性肺损伤模型（生后 1-7 天 100%O2）和 BPD 模型（生后 1-4 天 100%O2，然后 10 天空气）。从健康对照和中度/重度 BPD 新生儿的气管吸出物中随机选择进行临床 miR-342-5p 分析。
高氧降低了原代 T2AEC、MLE12 细胞和新生鼠肺中的 miR-342-5p 水平。新生鼠中过表达转基因 miR-342 可提高存活率，并改善 BPD 表型和 BPD 相关肺动脉高压（PAH）。T2AEC 特异性 miR-342 过表达，以及 miR-342-5p 模拟治疗，也改善了 BPD 表型和相关的 PAH。miR-342-5p 靶向 Raf1 调节剂 Spred3 的 3'UTR，抑制 Spred3 表达。用重组 Spred3 治疗可加重 BPD 表型和相关的 PAH。值得注意的是，在空气条件下抑制 miR-342-5p 并不模拟 BPD 表型。中度/重度 BPD 气管吸出物颗粒的 miR-342-5p 水平相对健康对照颗粒降低。
这些发现表明，miR-342-5p 模拟治疗可能在治疗或预防 BPD 方面有希望。
