RP-102124

MicroRNAs have been shown to play a critical role in lung inflammatory diseases. Here, we report that knocking out miR‐144/451 in mice exacerbates lipopolysaccharide (LPS)‐induced lung inflammation. The lung inflammation in mice was induced by intratracheal instillation of LPS. Loss‐of‐function experiments demonstrated that miR‐144/451 gene knockout (KO) increased LPS‐induced lung inflammation and oxidant stress compared with wild‐type (WT) mice, as manifested by increased total bronchoalveolar lavage fluid cells and neutrophil counts, elevated TNF‐α and IL‐6 levels in bronchoalveolar lavage fluid, enhanced myeloperoxidase activity, and reduced catalase and glutathione peroxidase activity in lung tissues. We also found that LPS significantly decreased miR‐451 expression in lung tissues and macrophages; while miR‐451 overexpression in LPS‐induced RAW264.7 cells remarkably reduced TNF‐α and IL‐6 levels as well as reactive oxygen species (ROS) production, suggesting a feedback loop might exist in inflammatory cells. Rac1 mRNA and protein levels were downregulated in miR‐451‐overexpressed RAW264.7 cells. Ex vivo stimulation experiments, performed using alveolar macrophages isolated from miR‐144/451 KO mice, confirmed that Rac1 inhibitor alleviated levels of TNF‐α and ROS in response to LPS stimulation compared with WT controls. Luciferase reporter assay demonstrated that STAT‐3 is a direct target of miR‐451. STAT‐3 protein levels were elevated in miR‐144/451 KO macrophages. LPS treatment also resulted in higher phosphorylation levels of STAT‐3 in macrophages from KO mice than in WT cells. Our study identified miR‐144/451 as an anti‐inflammatory factor in LPS‐induced lung inflammation that acts by downregulating Rac1 and STAT‐3.