Background

ALI/ARDS is a severe lung injury leading to refractory respiratory failure, accounting for high morbidity and mortality. However, therapeutic approaches are rather limited. Targeting long non-coding RNA MALAT1 and microRNA miR-181a-5p might be potential option for ALI/ARDS intervention.

Objective

We aimed to investigate the role of MALAT and miR-181a-5p in the pathogenesis of ALI/ARDS, and test the therapeutic effects of targeting MALAT and miR-181a-5p for ALI/ARDS intervention in vitro.

Methods

MALAT1 and miR-181a-5p levels were measured in plasma from ALI/ARDS patients. In vitro human pulmonary microvascular endothelial cell (HPMEC) injury was induced by LPS treatment, and molecular targets of MALAT1 and miR-181a-5p were explored by molecular biology approaches, mainly focusing on cell apoptosis and vascular inflammation. Interaction between MALAT1 and miR-181a-5p was also detected. Finally, the effects of targeting MALAT1 and miR-181a-5p for ALI/ARDS intervention were validated in a rat ALI/ARDS model.

Results

MALAT1 upregulation and miR-181a-5p downregulation were observed in ALI/ARDS patients. Transfection of mimic miR-181a-5p into HPMECs revealed decreased Fas and apoptosis, along with reduced inflammatory factors. Fas was proved to be a direct target of miR-181a-5p. Similar effects were also present upon MALAT1 knockdown. As for the interaction between MALAT1 and miR-181a-5p, MALAT1 knockdown increased miR-181a-5p expression. Knocking down of MALAT1 and miR-181a-5p could both improve the outcome in ALI/ARDS rats.

Conclusion

MALAT1 antagonism or miR-181a-5p could both be potential therapeutic strategies for ALI/ARDS. Mechanistically, miR-181a-5p directly inhibits Fas and apoptosis, along with reduced inflammation. MALAT1 negatively regulates miR-181a-5p.

中文翻译：

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靶向 MALAT1 和 miRNA-181a-5p 干预急性肺损伤/急性呼吸窘迫综合征

背景

ALI/ARDS 是一种严重的肺损伤，导致难治性呼吸衰竭，发病率和死亡率很高。然而，治疗方法相当有限。靶向长链非编码 RNA MALAT1 和 microRNA miR-181a-5p 可能是 ALI/ARDS 干预的潜在选择。

客观的

我们旨在研究 MALAT 和 miR-181a-5p 在 ALI/ARDS 发病机制中的作用，并在体外测试靶向 MALAT 和 miR-181a-5p 对 ALI/ARDS 干预的治疗效果。

方法

在 ALI/ARDS 患者的血浆中测量 MALAT1 和 miR-181a-5p 水平。LPS处理诱导体外人肺微血管内皮细胞（HPMEC）损伤，通过分子生物学方法探索MALAT1和miR-181a-5p的分子靶点，主要关注细胞凋亡和血管炎症。还检测到 MALAT1 和 miR-181a-5p 之间的相互作用。最后，在大鼠 ALI/ARDS 模型中验证了靶向 MALAT1 和 miR-181a-5p 对 ALI/ARDS 干预的影响。

结果

在 ALI/ARDS 患者中观察到 MALAT1 上调和 miR-181a-5p 下调。将模拟 miR-181a-5p 转染到 HPMEC 中显示 Fas 和细胞凋亡减少，以及炎症因子减少。Fas 被证明是 miR-181a-5p 的直接靶标。对 MALAT1 敲低也存在类似的影响。至于 MALAT1 和 miR-181a-5p 之间的相互作用，MALAT1 敲低会增加 miR-181a-5p 的表达。敲除 MALAT1 和 miR-181a-5p 都可以改善 ALI/ARDS 大鼠的结果。

结论

MALAT1 拮抗作用或 miR-181a-5p 都可能是 ALI/ARDS 的潜在治疗策略。从机制上讲，miR-181a-5p 直接抑制 Fas 和细胞凋亡，同时减少炎症。MALAT1 负调控 miR-181a-5p。