Plasma bacterial and mitochondrial DNA distinguish bacterial sepsis from sterile systemic inflammatory response syndrome and quantify inflammatory tissue injury in nonhuman primates.
Plasma bacterial and mitochondrial DNA distinguish bacterial sepsis from sterile systemic inflammatory response syndrome and quantify inflammatory tissue injury in nonhuman primates.
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DOI：
10.1097/shk.0b013e318276f4ca
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发表时间：
2013-01
期刊：
影响因子：
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通讯作者：
Hauser CJ
中科院分区：
文献类型：
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作者：
Sursal T;Stearns-Kurosawa DJ;Itagaki K;Oh SY;Sun S;Kurosawa S;Hauser CJ
全身性炎症反应综合征（SIRS）是细菌感染和无菌组织损伤时常见的一种基本宿主反应。SIRS可引起器官功能障碍和死亡，但其机制尚不完全清楚。此外，SIRS可发展为器官衰竭或死亡，尽管无菌或控制煽动性感染。因此，区分败血症、无菌SIRS和感染后SIRS的生物标志物将有助于直接护理。循环线粒体DNA （mtDNA）是一种反映细胞损伤的损伤相关分子模式（DAMP）。循环细菌16S-DNA （bDNA）是反映持续感染的病原体相关模式（PAMP）。我们开发了qPCR方法来量化这些标记物，并预测它们的血浆水平可能有助于区分无菌损伤和感染。为了在灵长类动物中研究这些事件，我们分析了papio狒狒的血清，这些狒狒经历了短暂的静脉注射炭疽芽孢杆菌（经过修饰以去除毒素），然后是抗生素（炭疽），导致器官衰竭和死亡。为了研究脓毒症向“严重”脓毒症和死亡的进展，我们研究了炭疽用原trecogin α (aPC)预处理的动物，aPC可以减轻狒狒的脓毒症。我们还将致死性炭疽菌血症与非致死性大肠杆菌菌血症以及志贺样毒素-1 （Stx1）造成的无菌组织损伤进行了对比。定时样本中的bDNA和mtDNA水平与血培养结果和器官功能测定相关。Stx1无菌损伤增加了mtDNA，但检测不到bDNA：与没有感染一致。细菌挑战引起平行的早期bDNA和mtDNA增加，但bDNA检测到病原体，即使细菌在培养中无法检测到。亚致死性大肠杆菌攻击仅引起mtDNA的短暂升高，与自限性损伤一致。在致死性炭疽感染（n=4）中，bDNA短暂升高，但mtDNA水平一直升高直到死亡，这与细菌清除后持续性脓毒性组织损伤一致。关键的是，aPC预处理（n=4）允许mtDNA水平在细菌清除后下降，同时保留器官功能和存活。总之，宿主组织损伤与mtDNA相关，无论是感染性的还是无菌的。mtDNA和bDNA pcr可以量化败血性或无菌机制引起的组织损伤，并提示不明来源的SIRS的来源。
Systemic inflammatory response syndrome (SIRS) is a fundamental host response common to bacterial infection and sterile tissue injury. SIRS can cause organ dysfunction and death but its mechanisms are incompletely understood. Moreover, SIRS can progress to organ failure or death despite being sterile or after control of the inciting infection. Biomarkers discriminating between sepsis, sterile SIRS and post-infective SIRS would therefore help direct care. Circulating mitochondrial DNA (mtDNA) is a damage-associated molecular pattern (DAMP) reflecting cellular injury. Circulating bacterial 16S-DNA (bDNA) is a pathogen-associated pattern (PAMP) reflecting ongoing infection. We developed qPCR assays to quantify these markers and predicted their plasma levels might help distinguish sterile injury from infection. To study these events in primates we assayed banked serum from papio baboons that had undergone a brief challenge of intravenous Bacillus anthracis deltaSterne (modified to remove toxins) followed by antibiotics (anthrax) that causes organ failure and death. To investigate the progression of sepsis to “severe” sepsis and death we studied animals where anthrax was pretreated with drotrecogin alfa (aPC), which attenuates sepsis in baboons. We also contrasted lethal anthrax bacteremia against non-lethal E.coli bacteremia and against sterile tissue injury from Shiga-like toxin-1 (Stx1). bDNA and mtDNA levels in timed samples were correlated with blood culture results and assays of organ function. Sterile injury by Stx1 increased mtDNA but bDNA was undetectable: consistent with the absence of infection. The bacterial challenges caused parallel early bDNA and mtDNA increases, but bDNA detected pathogens even after bacteria were undetectable by culture. Sub-lethal E.coli challenge only caused transient rises in mtDNA consistent with a self-limited injury. In lethal anthrax challenge (n=4) bDNA increased transiently but mtDNA levels remained elevated until death, consistent with persistent septic tissue damage after bacterial clearance. Critically, aPC pre-treatment (n=4) allowed mtDNA levels to decay after bacterial clearance with sparing of organ function and survival. In summary, host tissue injury correlates with mtDNA whether infective or sterile. mtDNA and bDNA PCRs can quantify tissue injury incurred by septic or sterile mechanisms and suggest the source of SIRS of unknown origin.