title: Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery.
abstract: BACKGROUND
  Mitochondrial DNA (mtDNA), a potent proinflammatory damage-associated molecular pattern, is released in large titers following trauma. The effect of trauma surgery on mtDNA concentration is unknown. We hypothesized that mtDNA and nuclear DNA (nDNA) levels would increase proportionately with the magnitude of surgery and both would then decrease rapidly.
  
  
  METHODS
  In this prospective pilot, plasma was sampled from 35 trauma patients requiring orthopedic surgical intervention at six perioperative time points. Healthy control subjects (n = 20) were sampled. DNA was extracted, and the mtDNA and nDNA were assessed using quantitative polymerase chain reaction. Markers of cell necrosis were also assayed (creatine kinase, lactate dehydrogenase, and aspartate aminotransferase).
  
  
  RESULTS
  The free plasma mtDNA and nDNA levels (ng/mL) were increased in trauma patients compared with healthy controls at all time points (mtDNA: preoperative period, 108 [46-284]; postoperative period, 96 [29-200]; 7 hours postoperatively, 88 [43-178]; 24 hours, 79 [36-172]; 3 days, 136 [65-263]; 5 days, 166 [101-434] [healthy controls, 11 (5-19)]) (nDNA: preoperative period, 52 [25-130]; postoperative period, 100 [35-208]; 7 hours postoperatively, 75 [36-139]; 24 hours postoperatively, 85 [47-133]; 3 days, 79 [48-117]; 5 days, 99 [41-154] [healthy controls, 29 (16-54)]). Elevated DNA levels did not correlate with markers of cellular necrosis. mtDNA was significantly elevated compared with nDNA at preoperative period (p = 0.003), 3 days (p = 0.003), and 5 days (p = 0.0014). Preoperative mtDNA levels were greater with shorter time from injury to surgery (p = 0.0085). Postoperative mtDNA level negatively correlated with intraoperative crystalloid infusion (p = 0.0017). Major pelvic surgery (vs. minor) was associated with greater mtDNA release 5 days postoperatively (p < 0.05).
  
  
  CONCLUSIONS
  This pilot of heterogeneous orthopedic trauma patients showed that the release of mtDNA and nDNA is sustained for 5 days following orthopedic trauma surgery. Postoperative, circulating DNA is not associated with markers of tissue necrosis but is associated with surgical invasiveness and is inversely related to intraoperative fluid administration. Sustained elevation of mtDNA levels could be of inflammatory origin and may contribute to postinjury dysfunctional inflammation.
  
  
  METHODS
  Prospective study, level III.
authors.affiliation: From the Department of Traumatology (D.J.M.), School of Medicine (A.E.W., B.M.H.), Department of Traumatology (N.L., Z.J.B.), John Hunter Hospital, and Priority Research Centre for Translational Neuroscience and Mental Health (M.B., D.W.S.), Discipline of Anatomy, School of Biomedical Sciences and Pharmacy, University of Newcastle; and Hunter Medical Research Institute (M.B., D.W.S.), Newcastle, New South Wales, Australia.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: McIlroy
authors.forename: Mark
authors.initials: M
authors.lastname: Bigland
authors.forename: Amanda E
authors.initials: AE
authors.lastname: White
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Hardy
authors.forename: Natalie
authors.initials: N
authors.lastname: Lott
authors.forename: Doug W
authors.initials: DW
authors.lastname: Smith
authors.forename: Zsolt J
authors.initials: ZJ
authors.lastname: Balogh
mesh_terms: D000328:Adult; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood; D001803:Blood Transfusion / Q000706:statistics & numerical data; D016022:Case-Control Studies; D003402:Creatine Kinase / Q000097:blood; D004247:DNA / Q000097:blood*; D004272:DNA, Mitochondrial / Q000097:blood*; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D015601:Injury Severity Score; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D009336:Necrosis; D019637:Orthopedic Procedures; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D014947:Wounds and Injuries / Q000601:surgery*
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D004247:DNA; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D003402:Creatine Kinase