Rhein ameliorates septic lung injury and intervenes in macrophage metabolic reprogramming in the inflammatory state by Sirtuin 1

Sepsis is an organ dysfunction syndrome caused by the maladjustment of response to infection. Acute lung injury (ALI) appears the earliest, with urgent onset and limited treatments. Previous pharmacological studies have found that rhein (RH), an active ingredient rich in rhubarb, has multiple pharmacological activities such as anti-inflammatory, anti-infection and metabolic regulation. This research aimed to explore whether RH alleviates septic acute lung injury and probe possible mechanisms.In this study, the septic ALI mouse model was established by cecal ligation and perforation (CLP). LPS-induced RAW264.7 model was selected to further explore the protective mechanism of RH. H&E staining, Western blot, qRT-PCR, and 1H NMR analysis were used to verify the protective effect of RH on ALI in vivo and vitro.RH could relieve pathological lung injury and pulmonary edema, reduce the serum LPS and inhibit inflammatory response in CLP mice. Further studies displayed that RH affected the metabolism in vivo, with significant changes in serum and lung metabolomics. In vitro results demonstrated that RH inhibited the expression of inflammatory mediators and factors in macrophages by affecting metabolic reprogramming and upregulating the expression of Sirtuin 1.RH improved the overall metabolic condition of sepsis mice by up-regulating and activating SIRT1, and inhibited the over activation of macrophages by regulating metabolism. These findings reveal the therapeutic mechanism of RH on sepsis ALI from the perspective of metabolism.