Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats.
Hyperoxia-activated circulating extracellular vesicles induce lung and brain injury in neonatal rats.
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DOI：
10.1038/s41598-021-87706-w
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发表时间：
2021-04-22
影响因子：
4.6
通讯作者：
Wu S
中科院分区：
文献类型：
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作者：
Ali A;Zambrano R;Duncan MR;Chen S;Luo S;Yuan H;Chen P;Benny M;Schmidt A;Young K;Kerr N;de Rivero Vaccari JP;Keane RW;Dietrich WD;Wu S
高氧诱导的肺损伤在以炎性损伤和早产儿肺发育受损为特征的支气管肺发育不良（BPD）的发展中起关键作用。尽管BPD是神经发育不良的预测因子，但目前尚不清楚肺损伤如何导致早产儿脑损伤。细胞外囊泡（EV）是一组异质的细胞衍生的膜结构，调节细胞间和器官间的通信。Gasdermin D（GSDMD）已成为炎性小体介导的细胞死亡和炎症的关键执行者。在这项研究中，我们利用新生大鼠模型的BPD，以评估是否高氧刺激肺释放的循环EV，如果这些EV诱导肺和脑损伤。我们发现，与保持在室内空气中的大鼠相比，高氧暴露的大鼠血浆来源的EV数量增加。这些EV还具有增加的表面活性蛋白C（II型肺泡上皮细胞（AEC）的标记物）和GSDMD的活性（p30）形式的货物。当这些EV通过静脉注射过继转移到正常新生大鼠时，它们被肺和脑组织摄取。此外，来自高氧动物的EV不仅诱导BPD的病理学特征，还诱导受体大鼠的脑炎症损伤，以及诱导培养的肺血管内皮细胞和神经干细胞（NSC）的细胞死亡。类似地，高氧暴露培养的AEC样细胞释放EV，其也含有增加的GSDMD-p30，并且这些EV诱导NSC中的细胞死亡。总体而言，这些数据表明，高氧激活的循环EV介导肺与脑的串扰，导致脑损伤，并提出了一种将BPD婴儿的肺损伤和神经发育障碍联系起来的机制。
Hyperoxia-induced lung injury plays a key role in the development of bronchopulmonary dysplasia (BPD), characterized by inflammatory injury and impaired lung development in preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, currently it is uncertain how lung injury contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that regulate intercellular and inter-organ communications. Gasdermin D (GSDMD) has emerged as a key executor of inflammasome-mediated cell death and inflammation. In this study, we utilized a neonatal rat model of BPD to assess if hyperoxia stimulates lung release of circulating EVs and if these EVs induce lung and brain injury. We found that hyperoxia-exposed rats had elevated numbers of plasma-derived EVs compared to rats maintained in room air. These EVs also had increased cargos of surfactant protein C, a marker of type II alveolar epithelial cells (AEC), and the active (p30) form of GSDMD. When these EVs were adoptively transferred into normal newborn rats via intravenous injection, they were taken up both by lung and brain tissues. Moreover, EVs from hyperoxic animals induced not only the pathological hallmarks of BPD, but also brain inflammatory injury in recipient rats, as well as inducing cell death in cultured pulmonary vascular endothelial cells and neural stem cells (NSC). Similarly, hyperoxia-exposed cultured AEC-like cells released EVs that also contained increased GSDMD-p30 and these EVs induced pyroptotic cell death in NSC. Overall, these data indicate that hyperoxia-activated circulating EVs mediate a lung to brain crosstalk resulting in brain injury and suggest a mechanism that links lung injury and neurodevelopmental impairment in BPD infants.