Inhibitory functions of maslinic acid, a natural triterpene, on HMGB1-mediated septic responses

Background: Maslinic acid (MA), a natural triterpenoid from Olea europaea, prevents oxidative stress and pro-inflammatory cytokine generation. High mobility group box 1 (HMGB1) has been recognized as a late mediator of sepsis, and the inhibition of the release of HMGB1 and the recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. Methods: We tested the hypothesis that MA induces sirtuin 1 and heme oxygenase-1, which inhibit the release of HMGB1 in lipopolysaccharide (LPS)-stimulated cells, thus inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. MA was administered after LPS or HMGB1 challenge, and the antiseptic activity of MA was determined based on permeability, the activation of pro-inflammatory proteins, and the production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model. Results: MA significantly reduced the release of HMGB1 in LPS-activated HUVECs and attenuated the CLP-induced release of HMGB1. Additionally, MA alleviated HMGB1-mediated vascular disruption and inhibited hyperpermeability in mice, and in vivo analysis revealed that MA reduced sepsis-related mortality and tissue injury. Conclusion: Taken together, the present results suggest that MA reduced HMGB1 release and septic mortality and thus may be useful in the treatment of sepsis.