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

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

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.

Keywords: Acute lung injury; Factor associated suicide; Lipopolysaccharide; Metastasis-associated lung adenocarcinoma transcript-1; Pro-inflammatory factor; miRNA-181a-5p.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Acute Lung Injury / genetics*
  • Acute Lung Injury / therapy*
  • Aged
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Gene Expression / genetics
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Male
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Middle Aged
  • Molecular Targeted Therapy*
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Rats, Sprague-Dawley
  • Respiratory Distress Syndrome / genetics*
  • Respiratory Distress Syndrome / therapy*

Substances

  • MALAT1 long non-coding RNA, human
  • MIRN181 microRNA, rat
  • MicroRNAs
  • RNA, Long Noncoding