Background: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury which may trigger persistent fibrosis. Exosomes are small extracellular vesicles that reflecthost cell conditions and contain functional molecules including miRNAs. Methods: In this study, we isolated plasma exosomes from 53 ARDS patients and 53 controls. Six candidate miRNAs levels were determined by qRT-PCR. The H3K27me3 level on the promoter region of Smad2 was detected by ChIP assay followed by qPCR. Dual luciferase assay and immunoblotting were employed to verify the interaction between miRNA and target genes. The cells proliferation was determined by MTT dependent cell viability assay. Results: miR-425 was reduced in the ARDS patient exosomes. Cytokine treatment also reduced the miR-425 level in A549 and HFL-1 cells. miR-425 inhibition induced Smad2 overexpression by increasing KDM6A level and demethylated H3K27me3 in the Smad2 promoter region. miR-425 reduction induced collagen expression after TGF-β1 treatment and promoted fibroblast proliferation. Conclusion: We identified miR-425 reduction in the exosomes from ARDS patients' peripheral blood, which has the potential to be used as a biomarker for ARDS diagnosis. We demonstrated that miR-425 reduction in lung fibroblasts contributes to the fibrosis through upregulating KDM6A and then activates the TGF-β signaling pathway. This sheds light on the mechanism of lung fibrosis during ARDS.
Keywords: ARDS; histone methylation; lung fibrosis; miRNA.
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