Int Immunopharmacol. 2024 Apr 20:131:111864.doi: 10.1016/j.intimp.2024.111864. Epub 2024 Mar 13.

本文采用的英格恩产品: Entranster-H4000

miR-186-5p improves alveolar epithelial barrier function by targeting the wnt5a/β-catenin signaling pathway in sepsis-acute lung injury

Affiliations

Affiliations

  • 1 Ningxia Medical University, Yinchuan, China; Department of Critical Care Medicine, Harrison International Peace Hospital, Hengshui, China. Electronic address: 867189610@qq.com.
  • 2 Key Laboratory of Ningxia Stem Cell and Regenerative Medicine, Institute of Medical Sciences, General Hospital of Ningxia Medical University, Yinchuan, China. Electronic address: 1224592480@qq.com.
  • 3 Ningxia Medical University, Yinchuan, China. Electronic address: 18487207582@163.com.
  • 4 Department of Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan, China. Electronic address: nyfyicu@163.com.

Abstract

Background: Alveolar epithelial barrier dysfunction is one of the pathological features of sepsis-acute lung injury(ALI). However, the molecular mechanisms that regulate the function of alveolar epithelial barrier remain unclear. This study aimed to determine the regulatory role of miR-186-5p in alveolar epithelial barrier function in sepsis-ALI and its underlying molecular mechanism.

Methods: We established sepsis-ALI models in vivo and in vitro, detected the miR-186-5p and wnt5a/β-catenin expressions, and observed the functional changes of the alveolar epithelial barrier by miR-186-5p overexpression. We used rescue experiments to clarify whether miR-186-5p works through wnt5a/β-catenin.

Results: miR-186-5p expression was decreased, wnt5a expression was increased, and the wnt5a/β-catenin signaling pathway was activated in mouse lung tissues and A549 cells after inflammatory stimulation. miR-186-5p overexpression resulted in wnt5a/β-catenin signaling pathway inhibition, decreased apoptosis in A549 cells, improved alveolar epithelial barrier function, reduced lung tissue injury in ALI mice, decreased IL-6 and TNF-α levels, and increased claudin4 and ZO-1 expression. Using miRNA-related database prediction and dual-luciferase reporter gene analysis, the targeting relationship between miR-186-5p and wnt5a was determined. The protective effect produced by miR-186-5p overexpression on the alveolar barrier was reversed after the application of the wnt5a/β-catenin activator Licl.

Conclusion: Our experimental data suggest miR-186-5p targets the wnt5a/β-catenin pathway, thereby regulating alveolar epithelial barrier function. Furthermore, both miR-186-5p and wnt5a/β-catenin are potential therapeutic targets that could impact sepsis-ALI.

Keywords: Acute lung injury; Alveolar barrier; Sepsis; Tight junction; miR-186-5p; wnt5a/β-catenin.

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