Irisin alleviates pulmonary epithelial barrier dysfunction in sepsis-induced acute lung injury via activation of AMPK/SIRT1 pathways

Biomed Pharmacother. 2019 Oct;118:109363. doi: 10.1016/j.biopha.2019.109363. Epub 2019 Aug 21.

Abstract

Objective: Alveolar epithelial barrier dysfunction in response to inflammatory reaction contributes to pulmonary edema in acute lung injury(ALI).Irisin,a newly-found myokine,exerts the anti-inflammatory effects. This study aims to investigate the protective effects of irisin on lipopolysaccharide (LPS)-induced ALIin vivo and in vitro, and to explore its underlying mechanism.

Methods: Male SD rats and A549 cells were divided into 4 groups: control group, LPS group, Irisin pretreated group, and Irisin/Compound C(a special inhibitor of AMPK)-treated group. The ALI model was established by intravenous injection of LPS in rats, and LPS challenge in A549 cells. Pulmonary specimens were harvested for microscopic examination of the pathological changes, and the expression of AMPK,SIRT1,NF-κB, p66Shc and caspase-3 in lung tissues. The pulmonary permeability were examined by wet/dry lung weight ratio(W/D) and lung permeability index(LPI). The apoptotic index, and the expression of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), monocyte chemoattractant activating protein-1 (MCP-1), tight junctions (occludin,ZO-1) were determined both in lung tissue and A549 cells.

Results: Irisin alleviated lung histological changes and decreased pulmonary microvascular permeability in LPS-induced rats. Irisin up-regulated the expression of occludin, ZO-1,AMPK,SIRT1, down-regulated the expression of TNF-α,IL-1β,MCP-1,NF-κB, p66Shc caspase-3, and decreased the apoptotic index in LPS-induced rats and A549 cells. All these protective effects of irisin could be reversed by Compound C.

Conclusion: Irisin improved LPS-induced alveolar epithelial barrier dysfunction via suppressing inflammation and apoptosis, and this protective effect might be mediated by activating AMPK/SIRT1 pathways.

Keywords: AMPK/SIRT1 pathways; Acute lung injury; Epithelial barrier dysfunction; Irisin.

MeSH terms

  • A549 Cells
  • AMP-Activated Protein Kinases / metabolism*
  • Acute Lung Injury / pathology
  • Acute Lung Injury / physiopathology*
  • Animals
  • Apoptosis / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Epithelial Cells / ultrastructure
  • Epithelium / physiopathology*
  • Epithelium / ultrastructure
  • Fibronectins / pharmacology
  • Fibronectins / therapeutic use*
  • Humans
  • Inflammation / pathology
  • Lung / pathology
  • Lung / physiopathology*
  • Lung / ultrastructure
  • Male
  • Permeability
  • Rats, Sprague-Dawley
  • Signal Transduction* / drug effects
  • Sirtuin 1 / metabolism*
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Up-Regulation / drug effects

Substances

  • Fibronectins
  • AMP-Activated Protein Kinases
  • Sirtuin 1