血浆线粒体 DNA DAMPs 水平升高与严重创伤人类患者的临床结局相关。
Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects.
机构信息
Departments of *Surgery †Center for Lung Biology ‡Pharmacology, University of South Alabama College of Medicine, Mobile.
出版信息
Ann Surg. 2013 Oct;258(4):591-6; discussion 596-8. doi: 10.1097/SLA.0b013e3182a4ea46.
OBJECTIVE
Our objective was to execute a prospective cohort study to determine relationships between plasma mtDNA DAMP levels and the occurrence of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), and mortality.
BACKGROUND
Mitochondrial DNA damage-associated molecular patterns (DAMPs) accumulate in the circulation after severe injury. Observations in animal models demonstrate that mtDNA DAMPs contribute to organ dysfunction; however, the link between plasma mtDNA DAMPs and outcome in severely injured human subjects has not been established.
METHODS
DNA was isolated from plasma samples taken from severely injured patients at hospital days 0, 1, and 2. Real-time PCR was used to quantify selected ≈200 base pair sequences of mtDNA within the COX1, ND1, and ND6 genes, as well as from the D-Loop transcriptional regulatory region. MODS was defined as a Denver Multiple Organ Failure score of 4 or greater.
RESULTS
MtDNA DAMPs were quantified as PCR threshold cycle number. Lower threshold cycles indicate increased mtDNA DAMP content. Patients with SIRS had significantly increased mtDNA DAMP levels in all 4 sequences examined (32.14 ± 0.90 vs 29.00 ± 1.15 for COX1, 31.90 ± 0.47 vs 30.16 ± 1.42 for ND1, 32.40 ± 0.61 vs 28.94 ± 1.13 for ND6, and 33.12 ± 0.83 vs 28.30 ± 1.14 for D-Loop). Patients who developed MODS also had elevated mtDNA DAMP levels compared with those who did not (32.57 ± 0.74 vs 27.12 ± 0.66 for COX1, 32.45 ± 0.65 vs 28.20 ± 0.73 for ND1, 32.52 ± 0.56 vs 27.60 ± 0.79 for ND6, and 32.85 ± 0.75 vs 27.86 ± 1.27 for D-Loop). Patients with above-median mtDNA DAMP levels had a significantly elevated relative risk for mortality. Four patients died secondary to severe MODS.
CONCLUSIONS
These findings comprise the first observational evidence that plasma mtDNA DAMPs is associated with the evolution of SIRS, MODS, and mortality in severely injured human subjects.
目的
我们的目的是进行一项前瞻性队列研究，以确定血浆 mtDNA DAMPs 水平与全身炎症反应综合征 (SIRS)、多器官功能障碍综合征 (MODS) 和死亡率的发生之间的关系。
背景
线粒体 DNA 损伤相关分子模式 (DAMPs) 在严重损伤后会在循环中积聚。动物模型的观察结果表明，mtDNA DAMPs 有助于器官功能障碍；然而，严重受伤的人体中血浆 mtDNA DAMPs 与结局之间的联系尚未建立。
方法
从入院第 0、1 和 2 天的严重受伤患者的血浆样本中分离 DNA。实时 PCR 用于定量 COX1、ND1 和 ND6 基因以及 D-Loop 转录调节区中约 200 个碱基对的选定序列。MODS 定义为丹佛多器官衰竭评分≥4 分。
结果
mtDNA DAMPs 被量化为 PCR 阈值循环数。较低的阈值循环表示 mtDNA DAMP 含量增加。患有 SIRS 的患者在所有 4 个检查的序列中 mtDNA DAMP 水平均显著升高 (COX1 为 32.14±0.90 vs 29.00±1.15，ND1 为 31.90±0.47 vs 30.16±1.42，ND6 为 32.40±0.61 vs 28.94±1.13，D-Loop 为 33.12±0.83 vs 28.30±1.14)。与未发生 MODS 的患者相比，发生 MODS 的患者 mtDNA DAMP 水平也升高 (COX1 为 32.57±0.74 vs 27.12±0.66，ND1 为 32.45±0.65 vs 28.20±0.73，ND6 为 32.52±0.56 vs 27.60±0.79，D-Loop 为 32.85±0.75 vs 27.86±1.27)。血浆 mtDNA DAMP 水平中位数以上的患者死亡的相对风险显著升高。有 4 名患者因严重 MODS 而死亡。
结论
这些发现构成了第一个观察性证据，表明血浆 mtDNA DAMPs 与严重受伤人体中 SIRS、MODS 和死亡率的演变有关。
Zotero 插件