Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
Biol Sex Differ. 2023 Aug 8;14(1):50. doi: 10.1186/s13293-023-00535-6.
Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions.
Wild-type and miR-30a neonatal mice were exposed to hyperoxia [95% FiO, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a male and female lung transcriptome data.
Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand-receptor interaction. Gene expression signature in the miR-30a female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium.
miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.
支气管肺发育不良（BPD）的特征是肺发育停滞，是早产儿发病率的主要原因。有充分的文献记载，BPD 男性发病率明显高于女性，但导致这种性别依赖性偏差的分子机制尚不清楚。与雄性相比，雌性在暴露于高氧环境时，肺泡形成和血管生成的保留程度更大，同时 miR-30a 的表达增加。在这项研究中，我们假设 miR-30a 的缺失会导致雄性和雌性在高氧环境下经历类似的肺泡形成和血管生成受损。
野生型和 miR-30a 新生小鼠在高氧环境中（95%FiO2，生后第 1-5 天）或空气环境中暴露，然后在生后第 21 天安乐死。在 WT 和 miR-30a 雌雄小鼠的肺组织中评估肺泡化、肺微血管发育、肺转录组差异和 miR-30a 表达。将早产儿（有无 BPD）的血液转录组特征与 WT 和 miR-30a 雌雄鼠的肺转录组数据相关联。
显著的是，WT 小鼠在高氧环境下观察到的性别特异性差异在 miR-30a 小鼠中被消除。miR-30a 表达的缺失消除了雌性的保护作用，表明 miR-30a 在调节肺泡化和血管生成中发挥了重要作用。全肺 RNA-Seq 转录组分析显示，miR-30a 雌性高氧暴露肺中有显著的反应，富集了与细胞周期和神经活性配体-受体相互作用相关的途径。miR-30a 雌性肺与人类 BPD 血液转录组相关的基因表达特征。最后，我们显示了 miR-30a 转录本在细支气管上皮中的空间定位。
miR-30a 可能是介导女性早产儿肺对新生儿高氧肺损伤的弹性的生物学因素之一。更好地了解 miR-30a 对肺血管生成和肺泡化的影响可能为治疗 BPD 提供新的治疗方法。
