Antiseptic Effects of New 3'-N-Substituted Carbazole Derivatives In Vitro and In Vivo.

Abstract

Inhibition of high-mobility group box 1 (HMGB1) protein and restoration of endothelial integrity are emerging as attractive therapeutic strategies in the management of sepsis. Here, new five structurally related 3'-N-substituted carbazole derivatives were examined for their effects on lipopolysaccharide (LPS)-mediated or cecal ligation and puncture (CLP)-mediated release of HMGB1 and on modulation of HMGB1-mediated inflammatory responses. We accessed this question by monitoring the effects of posttreatment carbazole derivatives on LPS- and CLP-mediated release of HMGB1 and HMGB1-mediated regulation of proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. The new 3'-N-substituted carbazole derivatives 1-5 inhibited the release of HMGB1 and downregulated HMGB1-dependent inflammatory responses in human endothelial cells. New compounds also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with each compound reduced CLP-induced release of HMGB1 and sepsis-related mortality and pulmonary injury in mice. These results indicate that the new 3'-N-substituted carbazole derivatives could be candidate therapeutic agents for various severe vascular inflammatory diseases owing to their inhibition of the HMGB1 signaling pathway.