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Late Breaking Abstract - Vitamin D suppresses LPS-induced ER stress and inflammation via modulation of mir-34a/Sirt1 axis in acute lung injury

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression in many lung diseases, although the contribution of miRNAs to the pathophysiology of lung injury remains unclear. We hypothesized that dysregulation of miRNA-34a expression in macrophages and endothelial cells drive the variations in key genes associated with ER stress and inflammation in lung injury. To test our hypothesis, we utilized a model of lung injury induced early after administration of intra-tracheal (IT) LPS. Here we show that microRNA-34a (miR-34a-5p) promotes ER stress and endothelial dysfunction by targeting the Sirtuin1 (Sirt1). Inhibition of miR-34a improves the pulmonary phenotype in LPS IT mouse models as well as markers of ER stress, which, conversely, is worsened by miR-34a overexpression. We have confirmed miR-34a showed its effect via Sirt1, which is one of the downstream targets of miR34a. Administration of sirt1 agonist is able to ameliorate lung injury phenotype and ER stress. We further examined the protective effects of vitamin D against LPS induced lung injury and ER Stress. We have found the administration of vitD improved lung histology, inflammatory markers and reduced miR-34a expression in IT LPS model. Our data suggest that miR-34a inhibition via vitD may be a therapeutic option to prevent or ameliorate acute lung injury.