Abstract Acute Respiratory Distress Syndrome (ARDS) is a life-threatening disease that has been identified following pneumonia, inflammation, as well as accompained with COVID19 cases. In this study, we investigated the effect of Sodium Butyrate (BUT) in ARDS induced by Staphylococcus Enterotoxin B (SEB). To that end, C3H/HeJ mice were administered BUT through oral gavage with a dose of 200mg/kg and 30mins later followed by a dual dose of SEB, starting with an intranasal dose of 7ug (i.n.) and 2hrs later with another dose of 2ug intraperitoneally (i.p.). The adminstration of BUT continued as same daily and the sacrifice was 72 hrs after SEB exposure. Our data demonstrated that the mortality rate was 80% in SEB+VEH mice compared to 0% mortality in SEB+BUT mice. Plethysmography data indicated a significant improvement in the clinical pulomonary functions. ELISA results indicated that the cytokine storm parameters including IFNγ were significantly decreased after BUT treatment compared to SEB+VEH. Furthermore, flow cytometry data indicated that CD4+ T cells, Vβ8+ T cells and NK T cells were significantly decreased in SEB+BUT compared to SEB+VEH. Analysis of miRNA from MNCs of lungs indicated that anti-inflammatory genes related to T-regulatory cells (Tregs) and Myeloid Derived Suppressor Cells (MDSCs) were targeted by many downregulated miRNAs which were then validated by qRT-PCR. Furthermore, flowcytometry data indicated a significant increase in T regs and MDSCs. Together, our data indicated that BUT prevented mortality and improved Lungs clinical functions in ARDS through modulation of the miRNAs in MNCs in lungs leading to induction of anti-inflammatory genes and suppression of inflammatory T cell subsets as well as increase in Tregs and MDSCs. Supported by NIH P01AT003961, P20GM103641, R01AI129788, R01ES030144, R01AI160896 and R01AI123947
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