JH‐4 reduces HMGB1‐mediated septic responses and improves survival rate in septic mice

AbstractInhibition of high mobility group box 1 (HMGB1) and restoration of endothelial integrity are emerging as attractive therapeutic strategies for the management of severe vascular inflammatory diseases. Recently, we found that JH‐4, a synthesized decursin derivative, exhibited a strong anti‐Hutchinson‐Gilford progeria syndrome by efficiently blocking progerin‐lamin A/C binding. In this study, we examined the effects of JH‐4 on HMGB1‐mediated septic responses and the survival rate in a mouse sepsis model. The anti‐inflammatory activities of JH‐4 were monitored based on its effects on lipopolysaccharide‐ or cecal ligation and puncture (CLP)‐mediated release of HMGB1. The antiseptic activities of JH‐4 were determined by measuring permeability, leukocyte adhesion, migration, and the activation of proinflammatory proteins in HMGB1‐activated human umbilical vein endothelial cells and mice. JH‐4 inhibited the release of HMGB1 and downregulated HMGB1‐dependent inflammatory responses in human endothelial cells. JH‐4 also inhibited HMGB1‐mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with JH‐4 reduced CLP‐induced release of HMGB1, sepsis‐related mortality, and pulmonary injury in vivo. Our results indicate that JH‐4 is a possible therapeutic agent to treat various severe vascular inflammatory diseases via the inhibition of the HMGB1 signaling pathway.