Endothelial to mesenchymal transition in neonatal hyperoxic lung injury: role of sex as a biological variable.
Endothelial to mesenchymal transition in neonatal hyperoxic lung injury: role of sex as a biological variable.
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新生儿高氧性肺损伤中的内皮细胞向间质细胞的转变：性别作为生物变量的作用。
DOI：
10.1152/physiolgenomics.00037.2023
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发表时间：
2023
影响因子：
4.6
通讯作者：
Lingappan,Krithika
中科院分区：
文献类型：
--
作者：
Cantu,Abiud;CantuGutierrez,Manuel;Zhang,Yuhao;Dong,Xiaoyu;Lingappan,Krithika
支气管肺发育不良（BPD）的特征是肺泡化停滞、血管发育异常和早产儿肺中可变的间质纤维增生。内皮细胞间质转化（EndoMT）可能是许多器官系统中病理性纤维化的来源。EndoMT是否有助于BPD的发病机制尚不清楚。我们检验了肺内皮细胞在暴露于高氧后会显示EndoMT标志物表达增加以及性别作为生物学变量会调节表达差异的假设。野生型（WT）和Cdh 5-PAC CreERT 2（内皮报告基因）新生雄性和雌性小鼠（C57 BL 6）在肺发育的囊状期（95% FIO 2;出生后第1-5天[PND 1 -5]）或肺发育的囊状期和早期肺泡期（75% FIO 2; PND 1 -14）暴露于高氧（0.95 FIO 2）。在整个肺和内皮细胞mRNA中测量EndoMT标记物的表达。对分选的肺内皮细胞（来自暴露于室内空气和高氧的肺）进行批量RNA-Seq。我们发现新生儿肺暴露于高氧导致EndoMT关键标志物的上调。此外，使用来自新生儿肺的肺sc-RNA-Seq数据，我们能够显示包括肺毛细血管内皮细胞在内的所有内皮细胞亚群均显示EndoMT相关基因的上调。与EndoMT相关的标志物在新生儿肺中暴露于高氧后上调，并显示出性别特异性差异。在新生儿肺损伤中介导EndoMT的机制可以调节新生儿肺对高氧损伤的反应，需要进一步调查。新&值得注意的是，我们发现新生儿高氧暴露增加了肺内皮细胞中的EndoMT标记物，这一生物学过程表现出性别特异性差异。
Bronchopulmonary dysplasia (BPD) is characterized by an arrest in alveolarization, abnormal vascular development, and variable interstitial fibroproliferation in the premature lung. Endothelial to mesenchymal transition (EndoMT) may be a source of pathological fibrosis in many organ systems. Whether EndoMT contributes to the pathogenesis of BPD is not known. We tested the hypothesis that pulmonary endothelial cells will show increased expression of EndoMT markers upon exposure to hyperoxia and that sex as a biological variable will modulate differences in expression. Wild-type (WT) and Cdh5-PAC CreERT2 (endothelial reporter) neonatal male and female mice (C57BL6) were exposed to hyperoxia (0.95 FIO2) either during the saccular stage of lung development (95% FIO2;postnatal day 1–5[PND1–5]) or through the saccular and early alveolar stages of lung development (75% FIO2;PND1–14). Expression of EndoMT markers was measured in whole lung and endothelial cell mRNA. Sorted lung endothelial cells (from room air- and hyperoxia-exposed lungs) were subjected to bulk RNA-Seq. We show that exposure of the neonatal lung to hyperoxia leads to upregulation of key markers of EndoMT. Furthermore, using lung sc-RNA-Seq data from neonatal lung we were able to show that all endothelial cell subpopulations including the lung capillary endothelial cells show upregulation of EndoMT-related genes. Markers related to EndoMT are upregulated in the neonatal lung upon exposure to hyperoxia and show sex-specific differences. Mechanisms mediating EndoMT in the injured neonatal lung can modulate the response of the neonatal lung to hyperoxic injury and need further investigation.NEW & NOTEWORTHYWe show that neonatal hyperoxia exposure increased EndoMT markers in the lung endothelial cells and this biological process exhibits sex-specific differences.