Treatment of Sepsis Pathogenesis with High Mobility Group Box Protein 1-Regulating Anti-inflammatory Agents
Treatment of Sepsis Pathogenesis with High Mobility Group Box Protein 1-Regulating Anti-inflammatory Agents
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DOI：
10.1021/acs.jmedchem.6b00954
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发表时间：
2017-01-12
影响因子：
7.3
通讯作者：
Park, Seung Bum
中科院分区：
文献类型：
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作者：
Cho, Wansang;Koo, Ja Young;Park, Seung Bum
脓毒症是世界范围内与多器官衰竭相关的主要死亡原因之一。然而，由于其发病机制的多样性，严重缺乏足够的脓毒症治疗方法。脓毒症的发病机制是由促炎细胞因子级联反应介导的，高迁移率族蛋白（HMGBs）作为晚期细胞因子发挥重要作用。我们先前报道了小分子调节剂，inflachromene（1d），它抑制HMGBs的释放，从而减少促炎细胞因子的产生。在这种情况下，我们腹腔内给予Id盲肠结扎穿孔（CLP）诱导的脓毒症小鼠模型，并证实它成功地改善脓毒症的发病机制。在构效关系研究的基础上，我们发现了新的候选化合物2j和21，具有改善的体内治疗功效。因此，我们的研究清楚地表明，使用小分子调节HMGB1释放是治疗脓毒症的一种有前途的策略。
Sepsis is one of the major causes of death worldwide when associated with multiple organ failure. However, there is a critical lack of adequate sepsis therapies because of its diverse patterns of pathogenesis. The pro-inflammatory cytokine cascade mediates sepsis pathogenesis, and high mobility group box proteins (HMGBs) play an important role as late-stage cytokines. We previously reported the small-molecule modulator, inflachromene (1d), which inhibits the release of HMGBs and, thereby, reduces the production of pro-inflammatory cytokines. In this context, we intraperitoneally administered Id to a cecal ligation and puncture (CLP)-induced mouse model of sepsis and confirmed that it successfully ameliorated sepsis pathogenesis. On the basis of a structure activity relationship study, we discovered new candidate compounds, 2j and 21, with improved therapeutic efficacy in vivo. Therefore, our study clearly demonstrates that the regulation of HMGB1 release using small molecules is a promising strategy for the treatment of sepsis.