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

Targeting MALAT1 and miRNA-181a-5p for the intervention of acute lung injury/acute respiratory distress syndrome.

机构信息

Department of Anesthesiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Department of Anesthesiology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.

出版信息

Respir Med. 2020 Dec;175:106210. doi: 10.1016/j.rmed.2020.106210. Epub 2020 Nov 4.

DOI:10.1016/j.rmed.2020.106210

PMID:33197806

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8375441/

Abstract

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.

摘要

背景

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

目的

我们旨在研究 MALAT 和 miR-181a-5p 在 ALI/ARDS 发病机制中的作用，并测试针对 MALAT 和 miR-181a-5p 治疗 ALI/ARDS 的体外疗效。

方法

测量 ALI/ARDS 患者血浆中的 MALAT1 和 miR-181a-5p 水平。用 LPS 处理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，主要集中在细胞凋亡和血管炎症上。还检测了 MALAT1 和 miR-181a-5p 之间的相互作用。最后，在大鼠 ALI/ARDS 模型中验证了针对 MALAT1 和 miR-181a-5p 治疗 ALI/ARDS 的效果。

结果

在 ALI/ARDS 患者中观察到 MALAT1 上调和 miR-181a-5p 下调。转染 mimic miR-181a-5p 到 HPMECs 中发现 Fas 和凋亡减少，同时炎症因子减少。Fas 被证明是 miR-181a-5p 的直接靶标。MALAT1 敲低也有类似的效果。至于 MALAT1 和 miR-181a-5p 之间的相互作用，MALAT1 敲低增加了 miR-181a-5p 的表达。MALAT1 和 miR-181a-5p 的敲低都可以改善 ALI/ARDS 大鼠的预后。