Background Traumatic injury is associated with increased concentrations of cell-free DNA (cfDNA) in the circulation, which contribute to post-injury complications. The endonuclease deoxyribonuclease 1 (DNase-1) is responsible for removing 90% of circulating cfDNA. Recently, DNase activity was reported to be significantly reduced following major non-traumatic brain injury (TBI), but the processes responsible were not investigated. Moreover, it is not known how quickly following injury DNase activity is reduced and whether this also occurs after TBI. Methods At 3 post-injury time points (≤1, 4–12 and 48–72 hours), blood samples were obtained from 155 adult trauma patients that had sustained an isolated TBI (n = 21), TBI with accompanying extracranial injury (TBI+) (n = 53) or an extracranial injury only (ECI) (n = 81). In addition to measuring cfDNA levels and the activity and expression of DNase, circulating concentrations of monomeric globular action (G-actin), an inhibitor of DNase-1, and the actin scavenging proteins gelsolin (GSN) and vitamin D binding protein (VDBP) were determined and values compared to a cohort of healthy controls. Results Significantly elevated concentrations of plasma cfDNA were seen in TBI, TBI+ and ECI patients at all study time points when compared to healthy controls. cfDNA levels were significantly higher at ≤1 hour post-injury in ECI patients who subsequently developed multiple organ dysfunction syndrome when compared to those who did not. Plasma DNase-1 protein was significantly elevated in all patient groups at all sampling time points. In contrast, DNase enzyme activity was significantly reduced, with this impaired function evident in TBI+ patients within minutes of injury. Circulating concentrations of G-actin were elevated in all patient cohorts in the immediate aftermath of injury and this was accompanied by a significant reduction in the levels of GSN and VDBP. Conclusions The post-traumatic increase in circulating cfDNA that occurs following extracranial trauma and TBI is accompanied by reduced DNase activity. We propose that, secondary to reduced GSN and VDBP levels, elevated circulating concentrations of G-actin underlie the post-injury reduction in DNase activity. Reducing circulating cfDNA levels via therapeutic restoration of DNase-1 activity may improve clinical outcomes post-injury.

中文翻译：

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创伤性损伤与脱氧核糖核酸酶活性降低和肌动蛋白清除系统失调有关

背景创伤性损伤与循环中游离 DNA (cfDNA) 浓度增加有关，这会导致损伤后并发症。核酸内切酶脱氧核糖核酸酶 1 (DNase-1) 负责去除 90% 的循环 cfDNA。最近，据报道，在主要的非创伤性脑损伤 (TBI) 后 DNase 活性显着降低，但没有调查负责的过程。此外，尚不清楚损伤后 DNA 酶活性降低的速度有多快，以及 TBI 后是否也会发生这种情况。方法 在伤后 3 个时间点（≤1、4-12 和 48-72 小时），从 155 名患有孤立性 TBI（n = 21）、TBI 伴颅外损伤（TBI+ ) (n = 53) 或仅颅外损伤 (ECI) (n = 81)。除了测量 cfDNA 水平和 DNase 的活性和表达，单体球状作用 (G-actin)、DNase-1 抑制剂和肌动蛋白清除蛋白凝溶胶蛋白 (GSN) 和维生素 D 结合蛋白 (VDBP) 的循环浓度确定并与一组健康对照进行比较。结果 与健康对照相比，在所有研究时间点，TBI、TBI+ 和 ECI 患者的血浆 cfDNA 浓度均显着升高。与未发生多器官功能障碍综合征的 ECI 患者相比，在受伤后 1 小时内，cfDNA 水平显着升高。在所有采样时间点，所有患者组的血浆 DNase-1 蛋白均显着升高。相比之下，DNase酶活性显着降低，在受伤几分钟内，TBI+ 患者的这种功能受损就很明显了。受伤后所有患者队列中 G-actin 的循环浓度均升高，同时 GSN 和 VDBP 水平显着降低。结论 颅外创伤和 TBI 后循环 cfDNA 的创伤后增加伴随着 DNase 活性降低。我们提出，继 GSN 和 VDBP 水平降低后，G-肌动蛋白的循环浓度升高是 DNase 活性受伤后降低的基础。通过治疗性恢复 DNase-1 活性来降低循环 cfDNA 水平可能会改善损伤后的临床结果。受伤后所有患者队列中 G-actin 的循环浓度均升高，同时 GSN 和 VDBP 水平显着降低。结论 颅外创伤和 TBI 后循环 cfDNA 的创伤后增加伴随着 DNase 活性降低。我们提出，继 GSN 和 VDBP 水平降低后，G-肌动蛋白的循环浓度升高是 DNase 活性受伤后降低的基础。通过治疗性恢复 DNase-1 活性来降低循环 cfDNA 水平可能会改善损伤后的临床结果。受伤后所有患者队列中 G-actin 的循环浓度均升高，同时 GSN 和 VDBP 水平显着降低。结论 颅外创伤和 TBI 后循环 cfDNA 的创伤后增加伴随着 DNase 活性降低。我们提出，继 GSN 和 VDBP 水平降低后，G-肌动蛋白的循环浓度升高是 DNase 活性受伤后降低的基础。通过治疗性恢复 DNase-1 活性来降低循环 cfDNA 水平可能会改善损伤后的临床结果。结论 颅外创伤和 TBI 后循环 cfDNA 的创伤后增加伴随着 DNase 活性降低。我们提出，继 GSN 和 VDBP 水平降低后，G-肌动蛋白的循环浓度升高是 DNase 活性受伤后降低的基础。通过治疗性恢复 DNase-1 活性来降低循环 cfDNA 水平可能会改善损伤后的临床结果。结论 颅外创伤和 TBI 后循环 cfDNA 的创伤后增加伴随着 DNase 活性降低。我们提出，继 GSN 和 VDBP 水平降低后，G-肌动蛋白的循环浓度升高是 DNase 活性受伤后降低的基础。通过治疗性恢复 DNase-1 活性来降低循环 cfDNA 水平可能会改善损伤后的临床结果。