MiRNAs play an important role in lung cells, where they have been implicated in cell proliferation, apoptosis and differentiation which are key events in etiology and progression of fibrotic diseases.Toward this, we sought to investigate whether the study of miRNAs in the context of pulmonary fibrosis could inform new perspectives on mechanisms, as well as diagnostic and therapeutic opportunities.We performed genome-wide profiling of miRNA expression in lung tissues of silica-induced mouse pulmonary fibrosis by microarray.Seventeen miRNAs were selected to be validated by qRT-PCR according to the fold changes between silica and control groups at each time point.Five miRNAs, miR-21, miR-455, miR-151-3p,miR-486-5p and miR-3107, were identified to consistent with microarray results which also confirmed in bleomycin-induced mouse lung fibrosis.In addition,miR-486-5p levels were found to be decreased in the serum of patients with silicosis as well as in lung tissues from cases with silicosis and IPF.Therefor, we hypothesized that over-expression of miR-486-5p could relieve pulmonary fibrosis.Cholesterol-modified miR-486-5p mimics (agomiR-486-5p) were used to restore its expressions in both animal models of silica-and bleomyein-induced pulmonary fibrosis.The over-expression of miR-486-5p could attenuate severity and distribution of fibrotic lesions in both animal models.Bioinformatic softwares were used to predict that SMAD2 and Col6α6 might be the potential targets of miR-486-5p and further dual luciferase reporter gene assays validating that miR-486-5p could regulate SMAD2 and Col6α6 directly.Above all, our dominant finding was that over-expression of miR-486-5p could alleviate pulmonary fibrosis induced by silica particulates and bleomycin.Those suggested that miR-486-5p could be a potential therapeutic target for lung fibrotic diseases.