Peripheral Blood Mononuclear Cells Demonstrate Mitochondrial Damage Clearance During Sepsis
Peripheral Blood Mononuclear Cells Demonstrate Mitochondrial Damage Clearance During Sepsis
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DOI：
10.1097/ccm.0000000000003681
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发表时间：
2019-05-01
影响因子：
8.8
通讯作者：
Welty-Wolf, Karen E.
中科院分区：
文献类型：
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作者：
Kraft, Bryan D.;Chen, Lingye;Welty-Wolf, Karen E.
目的：脓毒症中的代谢紊乱源于线粒体损伤，并显著导致器官衰竭和死亡率;然而，对人类脓毒症中线粒体的恢复知之甚少。我们试图在败血症患者外周血单核细胞中无创检测线粒体损伤和恢复（线粒体生物发生）的标志物，并将系列测量与临床结果相关联。设计：前瞻性病例对照研究。单位：学术医学中心和退伍军人事务医院。患者：未感染对照患者（n = 20）和脓毒症ICU患者（n = 37）。干预措施：从对照患者中采集一次血样，并在第1、3和5天从脓毒症患者中连续采集临床数据。通过定量逆转录-聚合酶链反应测定HMOX 1、NRF 1、PPARGC 1A和TFAM基因产物以及线粒体DNA ND 1和D-环。在血浆和中性粒细胞裂解物中测量促炎细胞因子。测量和主要结果：中位（四分位距）急性生理学和慢性健康评估II和序贯器官衰竭评估评分分别为21（8）和10（4），90天死亡率为19%。败血症患者外周血单核细胞中所有四种基因的转录水平在第1天显著降低（p < 0.05），而线粒体DNA拷贝数下降，血浆D-环增加（均p < 0.05），表明线粒体损伤。D环含量与肿瘤坏死因子-a和高迁移率族蛋白B1细胞因子表达成正比。到第5天，我们观察到线粒体生物合成的转录激活和线粒体DNA拷贝数的恢复（p < 0.05）。线粒体生物合成早期激活的患者在1周内无ICU。结论：我们的研究结果支持的数据，脓毒症诱导的线粒体损伤被逆转的线粒体生物合成的激活和非侵入性测量外周血单核细胞中的基因转录可以作为脓毒症恢复的新的生物标志物。
Objectives: Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes. Design: Prospective case-control study. Setting: Academic Medical Center and Veterans Affairs Hospital. Patients: Uninfected control patients (n = 20) and septic ICU patients (n = 37). Interventions: Blood samples were collected once from control patients and serially with clinical data on days 1, 3, and 5 from septic patients. Gene products for HMOX1, NRF1, PPARGC1A, and TFAM, and mitochondrial DNA ND1 and D-loop were measured by quantitative reverse transcriptase-polymerase chain reaction. Proinflammatory cytokines were measured in plasma and neutrophil lysates. Measurements and Main Results: Median (interquartile range) Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 21 (8) and 10 (4), respectively, and 90-day mortality was 19%. Transcript levels of all four genes in peripheral blood mononuclear cells were significantly reduced in septic patients on day 1 (p < 0.05), whereas mitochondrial DNA copy number fell and plasma D-loop increased (both p < 0.05), indicative of mitochondrial damage. D-loop content was directly proportional to tumor necrosis factor-a and high-mobility group protein B1 cytokine expression. By day 5, we observed transcriptional activation of mitochondrial biogenesis and restoration of mitochondrial DNA copy number (p < 0.05). Patients with early activation of mitochondrial biogenesis were ICU-free by 1 week. Conclusions: Our findings support data that sepsis-induced mitochondrial damage is reversed by activation of mitochondrial biogenesis and that gene transcripts measured noninvasively in peripheral blood mononuclear cells can serve as novel biomarkers of sepsis recovery.