SR9009 Regulates Acute Lung Injury in Mice Induced by Sepsis

Abstract

Rev-Erbα is a nuclear heme receptor, transcriptional repressor, and critical component of the molecular clock that drives daily rhythms of metabolism. However, the roles of Rev-Erbα in acute lung injury (ALI) remain unclarified. Hence, the effect of Rev-Erbα on lung injury of sepsis mice is investigated here. The mice sepsis model is established using lipopolysaccharide (LPS) injection, and the expression levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and interleukin-10 (IL-10) in both RAW246.7 cells and lung tissues, are tested. The inflammatory response is obviously enhanced in LPS-constructed sepsis mice and alleviated by SR9009 agonist treatment. Cell-based experiments reveal that pharmacological activation of Rev-Erbα via SR9009 attenuates the LPS-induced inflammatory response by suppressing TLR4-regulated NF-κB activation. Sepsis induces the increase in W/D ratio; promotes the levels of malondialdehyde (MDA), lactic acid (LA), and superoxide dismutase (SOD); and inhibits the levels of glutathione (GSH), whereas SR9009 treatment could effectively yield beneficial effects on metabolism. In addition, SR9009 treatment ameliorates acidosis and hypoxemia by efficiently decreasing arterial PaCO2 and increasing arterial PaO2, SO2, HCO3–, lactic acid concentration, and blood PH. These findings confirm that SR9009 treatment can alleviate the sepsis-induced lung injury and targeting Rev-Erbα may represent a promising approach for the prevention and management of ALI.

SerpinB1 is required for Rev‐erbα‐mediated protection against acute lung injury induced by lipopolysaccharide‐in mice

“…In hepatocytes and the circulating blood of obese mice, Rev‐erbα represses plasminogen activator inhibitor 1 (PAI‐1) expression by binding to a pair of Rev‐erbα binding sites in the PAI‐1 promoter (Wang et al, 2006; Zheng et al, 2020). In LPS‐induced ALI or LPS‐treated macrophages, administration of Rev‐erbα agonist SR9009 reduced LPS‐induced inflammatory response by blocking TLR4‐mediated NF‐κB activation (Hu et al, 2022). Hence, Rev‐erbα functions as a co‐transcription factor in regulating inflammation.…”