Alleviation of Lipopolysaccharides-Induced Acute Lung Injury by MiR-454

Background/Aims: Although acute lung injury (ALI) is an important and common disease in humans, its pathogenesis is poorly understood and its therapeutic outcome has not been significantly improved in the past years. Here, we examined whether application of microRNAs might inhibit the ALI-associated lung inflammatory, and subsequently reduce the injury. Methods: In vitro, we performed bioinformatics analyses to identify the miRNAs that target the most important chemo-attractive factor CXCL12, and confirmed that the binding was functional by luciferase reporter assay. We prepared adeno-associated virus (AAV) carrying miRNA mimics or null control. We expressed miRNA in mouse lung through i.v. injection of AAV and then we used Lipopolysaccharides (LPS) to induce ALI in mice. We analyzed the changes in permeability index and production of inflammatory cytokines in mouse lung, and we also verified the effects of virus-mediated gene expression by examining the levels of miRNAs and CXCL12 in lung by RT-qPCR and ELISA, and by quantifying the recruited inflammatory cells in mouse lung by flow cytometry. Results: We found that miR-454 targeted the 3'-UTR of CXCL12 mRNA to inhibit its protein translation in human lung epithelial cells. Overexpression of miR-454 in mouse lung significantly reduced the LPS-induced increases in permeability index and production of inflammatory cytokines CXCL1, CXCL2, IL6 and TNFα, possibly through suppression of CXCL12/CXCR4-mediated recruitment of inflammatory cells. Conclusion: Overexpression of miR-454 in lung may be a promising therapeutic approach to reduce the severity of ALI.