由羊膜炎和产后高氧诱导的 BPD 双重打击模型中肺免疫细胞转录组的变化。
Pulmonary immune cell transcriptome changes in double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia.
机构信息
Department of Pediatrics, Nemours AI duPont Hospital for Children, Wilmington, DE, USA.
Nemours Biomedical Research Center, Wilmington, DE, USA.
出版信息
Pediatr Res. 2021 Sep;90(3):565-575. doi: 10.1038/s41390-020-01319-z. Epub 2021 Jan 14.
BACKGROUND
Preterm infants with bronchopulmonary dysplasia (BPD) have lifelong increased risk of respiratory morbidities associated with environmental pathogen exposure and underlying mechanisms are poorly understood. The resident immune cells of the lung play vital roles in host defense. However, the effect of perinatal events associated with BPD on pulmonary-specific immune cells is not well understood.
METHODS
We used a double-hit model of BPD induced by prenatal chorioamnionitis followed by postnatal hyperoxia, and performed a global transcriptome analysis of all resident pulmonary immune cells.
RESULTS
We show significant up-regulation of genes involved in chemokine-mediated signaling and immune cell chemotaxis, and down-regulation of genes involved in multiple T lymphocyte functions. Multiple genes involved in T cell receptor signaling are downregulated and Cd8a gene expression remains downregulated at 2 months of age in spite of recovery in normoxia for 6 weeks. Furthermore, the proportion of CD8a+CD3+ pulmonary immune cells is decreased.
CONCLUSIONS
Our study has highlighted that perinatal lung inflammation in a double-hit model of BPD results in short- and long-term dysregulation of genes associated with the pulmonary T cell receptor signaling pathway, which may contribute to increased environmental pathogen-associated respiratory morbidities seen in children and adults with BPD.
IMPACT
In a translationally relevant double-hit model of BPD induced by chorioamnionitis and postnatal hyperoxia, we identified pulmonary immune cell-specific transcriptomic changes and showed that T cell receptor signaling genes are downregulated in short term and long term. This is the first comprehensive report delineating transcriptomic changes in resident immune cells of the lung in a translationally relevant double-hit model of BPD. Our study identifies novel resident pulmonary immune cell-specific targets for potential therapeutic modulation to improve short- and long-term respiratory health of preterm infants with BPD.
背景
患有支气管肺发育不良（BPD）的早产儿因暴露于环境病原体而面临终生增加的呼吸道疾病风险，但其潜在机制尚不清楚。肺部的固有免疫细胞在宿主防御中发挥着重要作用。然而，与 BPD 相关的围产期事件对肺特异性免疫细胞的影响尚不清楚。
方法
我们使用产前绒毛膜羊膜炎后再加上产后高氧诱导的 BPD 双重打击模型，对所有固有肺免疫细胞进行了全基因组转录组分析。
结果
我们发现与趋化因子介导的信号转导和免疫细胞趋化有关的基因显著上调，而与多种 T 淋巴细胞功能有关的基因下调。多个参与 T 细胞受体信号转导的基因下调，并且尽管在正常氧条件下恢复了 6 周，但 Cd8a 基因表达仍在 2 个月时下调。此外，CD8a+CD3+肺免疫细胞的比例降低。
结论
我们的研究表明，BPD 双重打击模型中的围产期肺部炎症导致与肺 T 细胞受体信号通路相关的基因在短期和长期内失调，这可能导致 BPD 患儿和成人中与环境病原体相关的呼吸道疾病增加。
影响
在由绒毛膜羊膜炎和产后高氧诱导的具有转化相关性的 BPD 双重打击模型中，我们确定了肺免疫细胞的特定转录组变化，并表明 T 细胞受体信号基因在短期和长期内均下调。这是第一个在具有转化相关性的 BPD 双重打击模型中全面描述肺固有免疫细胞转录组变化的报告。我们的研究确定了新的潜在治疗调节靶点，以改善患有 BPD 的早产儿的短期和长期呼吸健康。
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