Abstract
Purpose: To investigate the protective effect of miR-574-5p pretreatment against acute lung injury (ALI) induced by sepsis.Methods: A male C57BL/6 mouse model of sepsis-induced ALI was established by cecal ligation and puncture (CLP) and treated with miR-574-5p agomir (intravenous injection, 80 mg/kg per day, 3 days). After that, blood and lung samples were obtained for histopathological observation. Myeloperoxidase (MPO) activity, inflammatory cell infiltration, and cytokine expression were analyzed. The target gene of miR-574-5p was predicted using TargetScan prediction, and verified by luciferase assay and western blot.Results: In sepsis-induced ALI mice model, downregulation of miR-574-5p was observed. Pretreatment of miR-574-5p significantly alleviated ALI by suppressing histological damage, and reducing MPO activity and inflammatory cell infiltration, as well as decreasing cytokine expression. The underlying mechanism was that miR-574-5p targeted TNF receptor associated factor 6 (TRAF6) and suppressed the downstream NF-κB pathway. Moreover, TRAF6 overexpression reversed the effects of miR-574-5p on ALI.Conclusion: MiR-574-5p pretreatment suppresses inflammatory responses, thus reducing lung injury induced by sepsis in mice, partly via the regulation of TRAF6 and NF-κB pathway. Therefore, this approach can potentially be used for the clinical management of ALI in humans
 Keywords: Sepsis, Acute lung injury, MiR-574-5p, TRAF6, NF-κB pathway
Highlights
Sepsis refers to the systemic inflammatory response caused by some bioactive chemicals, such as infectious pathogen-produced lipopolysaccharide (LPS) [1]
MiR-146a inhibits the expression of IRAK1and TNF receptor associated factor 6 (TRAF6) by targeting erb-b2 receptor tyrosine kinase 4 (ErbB4), thereby reducing the myocardial dysfunction caused by sepsis [4]
This study indicated thatmiR-574-5p could be a new approach for the treatment of acute lung injury (ALI) induced by sepsis
Summary
Sepsis refers to the systemic inflammatory response caused by some bioactive chemicals, such as infectious pathogen-produced lipopolysaccharide (LPS) [1]. Little studies considering the molecular mechanism of sepsis-induced ALI. MicroRNAs (miRNA) regulate the posttranscriptional expression level of target genes by binding to its 3’-untranslation region (UTR), which have abilities to regulate sepsis-induced organ damage. MiR-146a inhibits the expression of IRAK1and TNF receptor associated factor 6 (TRAF6) by targeting erb-b2 receptor tyrosine kinase 4 (ErbB4), thereby reducing the myocardial dysfunction caused by sepsis [4]. In the serum from patients with type 2 diabetes, studies have shown that miR-574-5p was decreased and is associated with miR-146a due to its anti-inflammatory effects [6].
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