Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: a) animals raised in ambient air for 6 weeks (n=10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with b) IT-administered saline solution (n=10), or c) MSC-EVs (n=10) on postnatal days 3, 7, 10 and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings furtherly support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodelling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.

中文翻译：

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气管内施用间充质干细胞衍生的细胞外囊泡可减轻支气管肺发育不良的慢性大鼠模型中的肺损伤

由气管内（IT）施用的间充质干细胞（MSC-EVs）分泌的细胞外囊泡的早期治疗作用已在涉及出生后前两周高氧暴露的支气管肺发育不良（BPD）大鼠模型中得到证实。这项研究的目的是长期评估IT管理的MSC-EV的保护作用。电动汽车是按照GMP标准从MSC生产的。在出生时，将大鼠分为三组：a）在环境空气中饲养6周的动物（n = 10）；以及暴露于60％高氧的动物2周，再暴露于室内空气4周，并在出生后第3天用b）IT施用盐溶液（n = 10）或c）MSC-EV（n = 10）处理动物， 7、10和21。高氧暴露导致肺泡总数明显减少，肺泡气隙的总表面积和增殖指数，以及平均肺泡体积，平均线性截距和纤维化百分比的增加；MSC-EVs处理可防止所有这些形态变化。高氧暴露/假处理的<100 µm血管的中层厚度指数高于常氧暴露的大鼠；MSC-EV处理显着降低了该指数。间质/肺泡和血管周围F4 / 8阳性和CD86阳性巨噬细胞无显着差异。相反，高氧暴露减少了间质/肺泡和血管周围人群的CD163阳性巨噬细胞，而MSC-EV阻止了这些高氧诱导的减少。这些发现进一步支持了IT管理的电动汽车可能是预防/治疗BPD的有效方法，在长期模型中也可以改善肺泡受损和肺动脉重构。M2巨噬细胞极化可能通过抗炎和增殖机制发挥作用。