Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients
Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients
复制标题
Maresin 1 通过 ALX/cAMP/ROS 通路减轻盲肠结扎和穿刺小鼠模型和脓毒症患者的线粒体功能障碍
DOI：
10.1038/s41374-018-0031-x
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发表时间：
2018-06-01
影响因子：
5
通讯作者：
Jin, Sheng-Wei
中科院分区：
文献类型：
--
作者：
Gu, Jiaqi;Luo, Lingchun;Jin, Sheng-Wei
脓毒症期间炎症总是伴随感染。线粒体功能障碍和线粒体产生的活性氧（ROS）在脓毒症发病机制中的作用已被提出。Maresins在感染的实验模型中具有保护和解决作用。在本研究中，我们研究了maresin 1（MaR1）对盲肠结扎穿孔（CLP）诱导的脓毒症和脓毒症患者线粒体功能的影响，以确定maresin 1介导的线粒体ROS刺激的机制。我们发现，MaR1治疗显着抑制细胞因子的产生，减少腹腔灌洗液中的细菌负荷，减少中性粒细胞的数量，降低乳酸水平和上调环磷酸腺苷（cAMP）浓度，减少CLP诱导的脓毒症小鼠肺损伤的结果。MaR 1通过抑制线粒体内一氧化氮（NOX）活性、提高CAT和SOD活性来抑制ROS的产生，其作用依赖于脂氧素受体（ALX）和cAMP。在用MaR1治疗小鼠后，存活率显著增加。在LPS刺激的BMDM模型中，MaR1抑制ROS的产生，下调酶活性，减少线粒体O2的产生，增加线粒体膜电位，提高三磷酸腺苷（ATP）含量和线粒体DNA拷贝数。最后，MaR1对LPS刺激的健康志愿者或脓毒症患者血液中ROS产生的影响与ALX和cAMP有关。综上所述，这些数据表明，MaR1治疗可以通过调节ROS产生来减轻脓毒症期间的线粒体功能障碍。
Inflammation always accompanies infection during sepsis. Mitochondrial dysfunction and the role of reactive oxygen species (ROS) produced by mitochondria have been proposed in the pathogenesis of sepsis. Maresins have protective and resolving effects in experimental models of infection. In the present study, we investigated the effects of maresin 1 (MaR1) on mitochondrial function in cecal ligation and puncture (CLP)-induced sepsis and sepsis patients to identify mechanisms underlying maresin 1-mediated stimulation of ROS in mitochondria. We found that treatment with MaR1 significantly inhibited production of cytokines, decreased bacterial load in the peritoneal lavage fluid, reduced the number of neutrophils, decreased lactic acid level and upregulated cyclic AMP (cAMP) concentration, with the outcome of decreased lung injury in CLP-induced sepsis in mice. The effects of MaR1 on downregulation nitric oxide (NOX) activity, improvement CAT and SOD activity to inhibit ROS production in mitochondria was dependent on lipoxin receptor (ALX) and cAMP. Survival rates were significantly increased after the treatment of mice with MaR1. In BMDM stimulated with LPS, MaR1 inhibited the ROS production, downregulated enzyme activity, reduced mtO2 production, increased mitochondrial membrane potential, improved adenosine triphosphate (ATP) content and mitochondrial DNA (mtDNA) copy number. Finally, the effects of MaR1 on ROS production in the blood of healthy volunteers stimulated with LPS or sepsis patients were associated with ALX and cAMP. Taken together, these data suggest that treatment with MaR1 could attenuate mitochondrial dysfunction during sepsis through regulating ROS production.