Lee Wonhwa, Kwak Soyoung, Yun Eunju, Lee Jee Hyun, Na MinKyun, Song Gyu-Yong, Bae Jong-Sup
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 702-701, Republic of Korea.
Inflammation. 2015 Aug;38(4):1649-61. doi: 10.1007/s10753-015-0141-1.
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.
抑制高迁移率族蛋白B1（HMGB1）并恢复内皮完整性，正成为脓毒症治疗中颇具吸引力的治疗策略。在此，研究了五种新的结构相关的3'-N-取代咔唑衍生物对脂多糖（LPS）介导的或盲肠结扎穿刺（CLP）介导的HMGB1释放以及对HMGB1介导的炎症反应调节的影响。我们通过监测咔唑衍生物后处理对人脐静脉内皮细胞（HUVECs）和脓毒症小鼠中LPS和CLP介导的HMGB1释放以及HMGB1介导的促炎反应调节的影响来探讨这个问题。新的3'-N-取代咔唑衍生物1-5抑制了人内皮细胞中HMGB1的释放，并下调了HMGB1依赖性炎症反应。新化合物还抑制了小鼠中HMGB1介导的高通透性和白细胞迁移。此外，用每种化合物处理均可降低CLP诱导的小鼠HMGB1释放以及脓毒症相关死亡率和肺损伤。这些结果表明，新的3'-N-取代咔唑衍生物因其对HMGB1信号通路的抑制作用，可能成为各种严重血管炎性疾病的候选治疗药物。
