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 responsib...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.展开更多
基金funded by the National Institute for Health Research(NIHR)Surgical Reconstruction and Microbiology Research Centre and the Scar Free Foundation.JML is supported by the NIHR Birmingham Biomedical Research Centre and the Medical Research Council(MRC)Versus Arthritis Centre for Musculoskeletal Ageing Research.The funding bodies had no role in the design of the study,the collection,analysis or interpretation of the data or in the writing of the manuscript.
文摘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.
