Study on the role and mechanism of miR506 affecting ARDS-related pulmonary fibrosis through NF-κB/TGF-β pathway
Objective To explore the effect and mechanism of miR506 on acute respiratory distress syndrome(ARDS)-associated pulmonary fibrosis through nuclear factor-κB(NF-κB)/transforming growth factor-β(TGF-β)pathway and to provide new ideas for the prevention and treatment of ARDS-associated pulmonary fibrosis and the improvement of prognosis.Methods A total of 39 mice were randomly divided into control group(n=10),lipopolysaccharide(LPS)group(n=9),LPS+NF-κB inhibitor group(n=10)and LPS+miR506 inhibitor group(n=10).Except for the control group,the other three groups of mice were induced by LPS to establish ARDS-associated pulmonary fibrosis models.LPS+NF-κB inhibitor group and LPS+miR506 inhibitor group were treated with NF-κB inhibitor(BAY 11-7082)and miR506 inhibitor(miR506-antagomir),and control group and LPS group did not intervene.After 28 days,hematoxylin-eosin(HE)staining was used to observe the pathological changes in the lung tissues of mice in each group;the body mass,lung wet/dry weight ratio(W/D),lung coefficient,tumor necrosis factor-α(TNF-α),interleukin-4(IL-4),interleukin-6(IL-6),interleukin-1β(IL-1β),epithelial cadherin(E-cadherin),α-smooth muscle actin(α-SMA),Vimentin,NF-κB,TGF-β1,mothers against decapentaplegic homolog 3(SMAD3)and SMAD7 levels were compared among the groups.Results The results of HE staining showed that the structure of the alveoli in the control group was intact,no edema and inflammatory cell infiltration were observed,the lung tissues of the LPS group were obviously changed,the alveolar septum was thickened and the alveoli were depressed;in LPS+NF-κB inhibitor group,the alveolar structure of mice was relatively intact,the alveolar septum was thickened and the alveolar depression was obviously improved compared with that in LPS group;in the LPS+miR506 inhibitor group,the structure of the alveoli was severely damaged,the alveolar septum and depression were more severe,the proliferation and alveolar fusion were more obvious than those in the LPS group,congestion and inflammatory cell infiltration were more severe.Compared with control group,the body mass of mice in LPS group,LPS+NF-κB inhibitor group and LPS+miR506 inhibitor group was reduced while the W/D and lung coefficient were enhanced;the differences were statistically significant(all P＜0.05).Compared with LPS group,the body mass was increased while the W/D and lung coefficient were decreased in LPS+NF-κB inhibitor group;the differences were statistically significant(all P＜0.05).Compared with LPS+NF-κB inhibitor group,the body mass of mice was reduced while the W/D and lung coefficient were enhanced in LPS+miR506 inhibitor group,with statistical differences(all P＜0.05).Compared with the control group,the levels of TNF-α,IL-6,IL-8 and IL-1β were increased,and the expression levels of E-cadherin and SMAD7 protein in the lung tissue were down-regulated,the expression levels of α-SMA,Vimentin,NF-κB,TGF-β1 and SMAD3 protein were up-regulated in in LPS group,LPS+NF-κB inhibitor group and LPS+miR506 inhibitor group;the differences were statistically significant(all P＜0.05).Compared with LPS group,the levels of TNF-α,IL-6,IL-8 and IL-1β decreased,and the expression levels of E-cadherin and SMAD7 protein in lung tissue were up-regulated;the expressions levels of α-SMA,Vimentin,NF-κB,TGF-β1 and SMAD3 protein were all down-regulated in LPS+NF-κB inhibitor group;the differences were statistically significant(all P＜0.05).Compared with LPS+NF-κB inhibitor group,the levels of TNF-α,IL-6,IL-8 and IL-1β were increased,and the expression levels of E-cadherin and SMAD7 protein in lung tissue were down-regulated;the expression levels of α-SMA,Vimentin,NF-κB,TGF-β1 and SMAD3 protein were up-regulated in LPS+miR506 inhibitor group;the differences were statistically significant(all P＜0.05).Conclusion miR506 could inhibit the progression of ARDS-associated pulmonary fibrosis by inhibiting the inflammatory response and expressions of α-SMA,Vimentin,NF-κB,TGF-β1 and SMAD3 and up-regulating the SMAD7 expression,and its mechanism might be related to the regulation of NF-κB/TGF-β signaling pathway.
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