Objective

Emerging evidence has revealed that exosomal microRNAs (miRNAs) are implicated in human diseases. However, role of exosomal miR-125b-5p in sepsis-induced acute lung injury (ALI) remains further explored. We focused on the effect of exosomal miR-125b-5p on ALI progression via targeting topoisomerase II alpha (TOP2A).

Methods

The ALI mouse models were established by cecal ligation and perforation, which were then treated with miR-125b-5p agomir or overexpressed TOP2A. Next, the pathological structure of ALI mouse lung tissues were observed, miR-125b-5p, TOP2A and vascular endothelial growth factor (VEGF) expression was determined, and the lung water content, inflammatory response, protein content in bronchoalveolar lavage fluid (BALF) and cell apoptosis in ALI mouse lung tissues were assessed. Exosomes were extracted from endothelial cells (ECs) and identified, which were then injected into the modeled mice to observe their roles in ALI. The targeting relationship between miR-125b-5p and TOP2A was confirmed.

Results

MiR-125b-5p was downregulated while TOP2A was upregulated in ALI mice. MiR-125b-5p elevation or ECs-derived exosomes promoted VEGF expression, improved pathological changes and restrained lung water content, inflammatory response, protein content in BALF and cell apoptosis in lung tissues ALI mice. TOP2A overexpression reversed the repressive role of miR-125b-5p upregulation in ALI, while downregulated miR-125b-5p abrogated the effect of ECs-derived exosomes on ALI. TOP2A was confirmed as a direct target gene of miR-125b-5p.

Conclusion

Our study indicates that ECs-derived exosomes overexpressed miR-125b-5p to protect from sepsis-induced ALI by inhibiting TOP2A, which may contribute to ALI therapeutic strategies.

中文翻译：

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内皮细胞衍生的外泌体 microRNA-125b-5p 的上调通过抑制拓扑异构酶 II α 来防止败血症诱导的急性肺损伤

客观的

新出现的证据表明外泌体 microRNA (miRNA) 与人类疾病有关。然而，外泌体 miR-125b-5p 在败血症诱导的急性肺损伤 (ALI) 中的作用仍有待进一步探索。我们通过靶向拓扑异构酶 II α（TOP2A）关注外泌体 miR-125b-5p 对 ALI 进展的影响。

方法

ALI 小鼠模型通过盲肠结扎和穿孔建立，然后用 miR-125b-5p agomir 或过表达的 TOP2A 处理。接下来，观察ALI小鼠肺组织病理结构，测定miR-125b-5p、TOP2A和血管内皮生长因子（VEGF）的表达，以及支气管肺泡灌洗液（BALF）中肺水含量、炎症反应、蛋白质含量并评估了 ALI 小鼠肺组织中的细胞凋亡。从内皮细胞 (EC) 中提取外泌体并进行鉴定，然后将其注射到模型小鼠中以观察它们在 ALI 中的作用。证实了miR-125b-5p与TOP2A之间的靶向关系。

结果

MiR-125b-5p 在 ALI 小鼠中下调而 TOP2A 上调。MiR-125b-5p升高或ECs衍生的外泌体促进VEGF表达，改善病理变化并抑制BALF中的肺含水量、炎症反应、蛋白质含量和肺组织ALI小鼠的细胞凋亡。TOP2A 过表达逆转了 miR-125b-5p 上调在 ALI 中的抑制作用，而下调 miR-125b-5p 则消除了 ECs 衍生的外泌体对 ALI 的影响。TOP2A 被确认为 miR-125b-5p 的直接靶基因。

结论

我们的研究表明，ECs 衍生的外泌体过表达 miR-125b-5p 以通过抑制 TOP2A 来防止败血症诱导的 ALI，这可能有助于 ALI 治疗策略。