Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 173 Ashley Ave., MSC 908, CRI Room 610, Charleston, SC, 29425, USA.
Department of Biopharmaceutics College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210000, China.
Crit Care. 2019 Feb 13;23(1):44. doi: 10.1186/s13054-019-2339-3.
The acute respiratory distress syndrome (ARDS) is characterized by disruption of the alveolar-capillary barrier resulting in accumulation of proteinaceous edema and increased inflammatory cells in the alveolar space. We previously found that endothelial progenitor cell (EPC) exosomes prevent endothelial dysfunction and lung injury in sepsis in part due to their encapsulation of miRNA-126. However, the effects of EPC exosomes in acute lung injury (ALI) remain unknown.
To determine if EPC exosomes would have beneficial effects in ALI, intratracheal administration of lipopolysaccharide (LPS) was used to induce ALI in mice. Lung permeability, inflammation, and the role of miRNA-126 in the alveolar-epithelial barrier function were examined.
The intratracheal administration of EPC exosomes reduced lung injury following LPS-induced ALI at 24 and 48 h. Compared to placebo, intratracheal administration of EPC exosomes significantly reduced the cell number, protein concentration, and cytokines/chemokines in the bronchoalveolar lavage fluid (BALF), indicating a reduction in permeability and inflammation. Further, EPC exosomes reduced myeloperoxidase (MPO) activity, lung injury score, and pulmonary edema, demonstrating protection against lung injury. Murine fibroblast (NIH3T3) exosomes, which do not contain abundant miRNA-126, did not provide these beneficial effects. In human small airway epithelial cells (SAECs), we found that overexpression of miRNA-126-3p can target phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), while overexpression of miRNA-126-5p inhibits the inflammatory alarmin HMGB1 and permeability factor VEGFα. Interestingly, both miR-126-3p and 5p increase the expression of tight junction proteins suggesting a potential mechanism by which miRNA-126 may mitigate LPS-induced lung injury.
Our data demonstrated that human EPC exosomes are beneficial in LPS-induced ALI mice, in part through the delivery of miRNA-126 into the injured alveolus.
急性呼吸窘迫综合征（ARDS）的特征是肺泡-毛细血管屏障破坏，导致肺泡空间中蛋白质性水肿和炎症细胞增加。我们之前发现内皮祖细胞（EPC）外泌体通过包裹 miRNA-126 来预防脓毒症中的内皮功能障碍和肺损伤。然而，EPC 外泌体在急性肺损伤（ALI）中的作用尚不清楚。
为了确定 EPC 外泌体是否对 ALI 有有益作用，我们使用气管内给予脂多糖（LPS）诱导小鼠 ALI。检查了肺通透性、炎症以及 miRNA-126 在肺泡上皮屏障功能中的作用。
与安慰剂相比，气管内给予 EPC 外泌体可显著降低 LPS 诱导的 ALI 后 24 和 48 小时的肺损伤。与安慰剂相比，气管内给予 EPC 外泌体可显著降低支气管肺泡灌洗液（BALF）中的细胞数、蛋白浓度和细胞因子/趋化因子，表明通透性和炎症减少。此外，EPC 外泌体降低髓过氧化物酶（MPO）活性、肺损伤评分和肺水肿，表明对肺损伤有保护作用。不含有丰富 miRNA-126 的鼠成纤维细胞（NIH3T3）外泌体没有提供这些有益作用。在人小气道上皮细胞（SAEC）中，我们发现 miRNA-126-3p 的过表达可以靶向磷酸肌醇-3-激酶调节亚基 2（PIK3R2），而过表达 miRNA-126-5p 可抑制炎症警报素 HMGB1 和通透性因子 VEGFα。有趣的是，miR-126-3p 和 5p 均增加了紧密连接蛋白的表达，这表明 miRNA-126 可能减轻 LPS 诱导的肺损伤的潜在机制。
我们的数据表明，人 EPC 外泌体对 LPS 诱导的 ALI 小鼠有益，部分原因是将 miRNA-126 递送至受损的肺泡。
