BackgroundCirculating cell-free DNA (cfDNA) may contribute to the pathophysiology of post-injury inflammation and coagulation in trauma. However, the source and mechanism of release of cfDNA in trauma is not well understood. One potential source of cfDNA is from Neutrophil Extracellular Traps (NETs), released by activated neutrophils during the process of NETosis. The primary objective of our study was to determine if cfDNA has prognostic utility in trauma. The secondary objective of this study was to determine the source of cfDNA in trauma compared to sepsis.MethodsWe studied trauma patients from two prospective observational cohort studies: the DNA as a Prognostic Marker in ICU Patients (DYNAMICS) study and the Endotoxin in Polytrauma (ENPOLY) study. We also studied septic patients from the DYNAMICS study. Citrated plasma samples were collected longitudinally from the patients (days 1 to 7). The following molecules were measured in the plasma samples: cfDNA, protein C (PC), myeloperoxidase (MPO) (a marker of neutrophil activation), citrullinated Histone H3 (H3Cit, a marker of NETosis), cyclophilin A (a marker of necrosis), and caspase-cleaved K18 (a marker of apoptosis).ResultsA total of 77 trauma patients were included (n = 38 from DYNAMICS and n = 39 from ENPOLY). The median age was 49 years; 27.3% were female, and mortality was 16.9% at 28 days. Levels of cfDNA were elevated compared to healthy values but not significantly different between survivors and non-survivors. There was a positive correlation between MPO and cfDNA in septic patients (r = 0.424, p < 0.001). In contrast, there was no correlation between MPO and cfDNA in trauma patients (r = – 0.192, p = 0.115). Levels of H3Cit, a marker of NETosis, were significantly elevated in septic patients compared to trauma patients (p < 0.01) while apoptosis and necrosis markers did not differ between the two groups.ConclusionOur studies suggest that the source and mechanism of release of cfDNA differ between trauma and sepsis patients. In sepsis, cfDNA is likely primarily released by activated neutrophils via the process of NETosis. In contrast, cfDNA in trauma appears to originate mainly from injured or necrotic cells. Although cfDNA is elevated in trauma and sepsis patients compared to healthy controls, cfDNA does not appear to have prognostic utility in trauma patients.Trial registrationClinicalTrials.gov Identifier: NCT01355042. Registered May 17, 2011

中文翻译：

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cfDNA 的来源和预后效用在创伤和脓毒症中的比较


背景循环游离 DNA (cfDNA) 可能有助于损伤后炎症和创伤凝血的病理生理学。然而，创伤中 cfDNA 释放的来源和机制尚不清楚。 cfDNA 的一个潜在来源是中性粒细胞胞外陷阱 (NET)，在 NETosis 过程中由激活的中性粒细胞释放。我们研究的主要目的是确定 cfDNA 在创伤中是否具有预后作用。本研究的次要目标是确定创伤与脓毒症中 cfDNA 的来源。方法我们研究了两项前瞻性观察队列研究中的创伤患者：DNA 作为 ICU 患者预后标志物 (DYNAMICS) 研究和多发伤中的内毒素 (ENPOLY) ） 学习。我们还研究了 DYNAMICS 研究中的脓毒症患者。从患者身上纵向收集柠檬酸血浆样本（第 1 天至第 7 天）。在血浆样本中测量了以下分子：cfDNA、蛋白 C (PC)、髓过氧化物酶 (MPO)（中性粒细胞活化标记）、瓜氨酸组蛋白 H3（H3Cit，NETosis 标记）、亲环蛋白 A（坏死标记）和 caspase 裂解的 K18（细胞凋亡标记物）。 结果 总共纳入 77 名创伤患者（n = 38 来自 DYNAMICS，n = 39 来自 ENPOLY）。中位年龄为 49 岁； 27.3% 为女性，28 天死亡率为 16.9%。与健康值相比，cfDNA 水平有所升高，但幸存者和非幸存者之间没有显着差异。脓毒症患者中 MPO 和 cfDNA 呈正相关 (r = 0.424，p < 0.001)。相反，创伤患者的 MPO 和 cfDNA 之间不存在相关性 (r = – 0.192，p = 0.115)。 与创伤患者相比，脓毒症患者的 NETosis 标志物 H3Cit 水平显着升高 (p < 0.01)，而两组之间的细胞凋亡和坏死标志物没有差异。结论我们的研究表明 cfDNA 释放的来源和机制创伤和脓毒症患者之间存在差异。在脓毒症中，cfDNA 可能主要由活化的中性粒细胞通过 NETosis 过程释放。相比之下，创伤中的 cfDNA 似乎主要源自受伤或坏死的细胞。尽管与健康对照相比，创伤和脓毒症患者的 cfDNA 升高，但 cfDNA 似乎对创伤患者没有预后效用。试验注册ClinicalTrials.gov 标识符：NCT01355042。注册日期：2011 年 5 月 17 日