KPT-330, a potent and selective CRM1 inhibitor, exhibits anti-inflammation effects and protection against sepsis
KPT-330, a potent and selective CRM1 inhibitor, exhibits anti-inflammation effects and protection against sepsis
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KPT-330 是一种有效的选择性 CRM1 抑制剂，具有抗炎作用和预防败血症的作用。
DOI：
10.1016/j.bbrc.2018.07.112
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发表时间：
2018-09-10
影响因子：
3.1
通讯作者：
Zhou, Huiting
中科院分区：
文献类型：
--
作者：
Wu, Ming;Gui, Huan;Zhou, Huiting
脓毒症是一种由感染或损伤引起的全身炎症反应，目前仍是临床患者死亡的重要原因之一。目前，对脓毒症的发病机制和新的治疗方法的研究非常紧迫。在这项研究中，我们假设KPT 330，一种有效和特异性的CRM 1小分子抑制剂，可以减少炎症和减轻脓毒症的严重程度。在体内LPS诱导的脓毒症模型中，给予KPT 330可提高存活率，改善LPS诱导的肺损伤，抑制循环中TNF-α、IL-6和HMGB 1的水平，减少腹腔中巨噬细胞和PMN亚群。体外研究表明，KPT 330剂量依赖性地抑制LPS触发的促炎细胞因子的产生，包括巨噬细胞中的TNF-α、IL-6和HMGB 1。此外，KPT 330处理显著抑制TNF-α和IL-6 mRNA表达，并通过抑制CRM 1分布来抑制HMGB 1核质易位。KPT 330通过抑制NF-κ B B和p38信号通路的活化，抑制促炎细胞因子的产生，从而发挥抗炎作用。因此，药理学刺激KPT 330可能是脓毒症的一种有希望的治疗策略。(C)2018爱思唯尔公司All rights reserved.
Sepsis, a systemic inflammatory response caused by infection or injury, is still one of the most important causes of death in clinical patients. The ongoing search for the pathogenesis of sepsis and novel therapeutic methods are highly urgent. In this study, we hypothesized that KPT330, a potent and specific small molecule inhibitor of CRM1, could reduce inflammation and attenuate the severity of sepsis. In LPS-induced sepsis model in vivo, administration of KPT330 increased survival rate and ameliorated LPS-induced lung injury, with suppressed levels of TNF-alpha, IL-6 and HMGB1 in the circulation and decreased macrophage and PMN subpopulations in peritoneal cavity. In vitro investigations showed that KPT330 dose-dependently inhibited LPS-triggered proinflammatory cytokines production including TNF-alpha, IL-6 and HMGB1 in macrophages. Furthermore, KPT330 treatment significantly suppressed TNF-alpha and IL-6 mRNA expression and inhibited HMGB1 necleocytoplasmic translocation by inhibiting CRM1 distribution. Moreover, the mechanism analysis demonstrated that KPT330 exerted anti-inflammation effects by inhibiting the production of pro-inflammatory cytokines through suppressing activation of NF-kappa B and p38 signaling. Thus, pharmacologic stimulation of KPT330 may present a promising therapeutic strategy for sepsis. (C) 2018 Elsevier Inc. All rights reserved.