Cell necrosis–independent sustained mitochondrial and nuclear DNA release following trauma surgery

McIlroy, Daniel J.; Bigland, Mark J.; White, Amanda; Hardy, Benjamin; Lott, Natalie; Dw, Smith; Balogh, Zsolt J.

doi:10.1097/ta.0000000000000519

Cited by 55 publications

(68 citation statements)

References 33 publications

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“…Ten studies included nonspecific trauma patients while five studies included patients with TBI with or without extracranial trauma [16, 30–36]. Nine of the nonspecific trauma studies based severity of trauma on the Injury Severity Score (ISS) [14, 15, 29, 34–38], while one used both the Acute Physiology and Chronic Health Evaluation (APACHE) II and Sepsis-related Organ Failure Assessment (SOFA) score [39]. All TBI studies used the Glasgow Coma Scale (GCS) to classify the effects of the trauma while using either the abbreviated injury scale (AIS), ISS, or APACHE II to describe the severity of trauma.…”

Section: Resultsmentioning

confidence: 99%

“…Treatment strategies during ICU admission were not described, which mean that different treatments might have been used. There is a risk of bacterial DNA contamination in DNA assessment methods, but only one study reported on bacterial DNA analyses [38]. …”

Section: Resultsmentioning

confidence: 99%

“…Two studies were considered as high-quality studies based on DNA processing [15, 39] while nine were deemed of acceptable quality [14, 16, 29, 33, 35–38] and three presented with an unacceptable quality of DNA processing [30, 32, 34]. One study was not assessed as no information regarding blood sampling and processing was available [31].…”

Section: Resultsmentioning

confidence: 99%

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The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review

2017

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BackgroundCell-free DNA has been proposed as a means of predicting complications among severely injured patients. The purpose of this systematic review was to assess whether cell-free DNA was useful as a prognostic biomarker for outcomes in trauma patients in the intensive care unit.MethodsWe searched Pubmed, Embase, Scopus and the Cochrane Central Register for Controlled Trials and reference lists of relevant articles for studies that assessed the prognostic value of cell-free DNA detection in trauma patients in the intensive care unit. Outcomes of interest included survival, posttraumatic complications and severity of trauma. Due to considerable heterogeneity between the included studies, a checklist was formed to assess quality of cell-free DNA measurement.ResultsA total of 14 observational studies, including 904 patients, were eligible for analysis. Ten studies were designed as prospective cohort studies; three studies included selected patients from a cohort while one study was of a retrospective design. We found a significant correlation between higher values of cell-free DNA and higher mortality. This significant correlation was evident as early as on intensive care unit admission. Likewise, cell-free DNA predicted the severity of trauma and posttraumatic complications in a majority of patients.ConclusionThe amount of cell-free DNA can function as a prognostic tool for mortality and to a lesser extent severity of trauma and posttraumatic complications. Standardizing cell-free DNA measurement is paramount to ensure further research in cell-free DNA as a prognostic tool.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-016-1578-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review

2017

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“…Our predictions parallel those of Simmons et al (4) and Nkahira et al (16) where a reduction in mtDAMPs is associated in time with clinical improvement (3) and increased mtDNA levels are associated with increased ICU mortality (11). Moreover, a pilot study involving orthopedic trauma patients demonstrated a correlation between preoperative mtDNA levels and time from injury to surgery indicating that mtDNA could serve as a marker for optimal surgical timing (17). This study also showed a correlation between the timing and the magnitude of surgical intervention with mtDNA concentration, presenting the possibility of mtDNA as a risk indicator for development of post-injury complications and the need for secondary interventions.…”

Section: Discussionmentioning

confidence: 99%

Peritoneal cavity lavage reduces the presence of mitochondrial damage associated molecular patterns in open abdomen patients

Martinez‐Quinones

McCarthy

Mentzer

et al. 2017

J Trauma Acute Care Surg

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Background Mitochondrial damage-associated molecular patterns (mtDAMPs), such as mitochondrial DNA and N-formylated peptides, are endogenous molecules released from tissue after traumatic injury. mtDAMPs are potent activators of the innate immune system. They have similarities with bacteria, which allow mtDAMPs to interact with the same pattern recognition receptors and mediate the development of Systemic Inflammatory Response Syndrome (SIRS). Current recommendations for management of an open abdomen include returning to the operating room every 48 hours for peritoneal cavity lavage until definitive procedure. These patients are often critically ill and develop SIRS. We hypothesized that mitochondrial DAMPs are present in the peritoneal cavity fluid in this setting, and that they accumulate in the interval between washouts. Methods We conducted a prospective pilot study of critically ill adult patients undergoing open abdomen management in the Surgical and Trauma ICUs. Peritoneal fluid was collected daily from 10 open abdomen patients. Specimens were analyzed via qPCR for mitochondrial DNA (mtDNA), via enzyme immunoassay for DNAse activity and via Western blot analysis for the ND6 subunit of the NADH: ubiquinone oxidoreductase, an N-formylated peptide. Results We observed a reduction in the expression of ND6 the day following lavage of the peritoneal cavity, that was statistically different from the days with no lavage (% change in ND6 expression, Post-Op from washout: −50±11 vs. No Washout day: 42±9, p<0.05). Contrary to expectation, the mtDNA levels remained relatively constant from sample to sample. We then hypothesized that DNAse present in the effluent may be degrading mtDNA. Conclusions These results indicate the peritoneal cavity irrigation reduces the presence of mitochondrial DAMPs in the open abdomen. It is possible that, increased frequency of peritoneal cavity lavage may lead to decreased systemic absorption of mtDAMPs, and thereby reducing the risk of SIRS. Level of Evidence Prospective study, Case Series, level V Study Type Prognostic

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“…Blood from trauma patients and in other disease states such as sepsis, cancer, and SLE has been shown to contain neutrophil extracellular traps (NETs) [27, 50]. NETs are web-like structures of chromatin from DNA with interspersed histone and protein granules that are released by neutrophils to trap bacteria.…”

Section: Active Release: Neutrophil Extracellular Trapsmentioning

confidence: 99%

The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

Thurairajah

Briggs

Balogh

2018

Eur J Trauma Emerg Surg

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Mitochondria play a key role in the pathophysiology of post-injury inflammation. Cell-free mitochondrial DNA (cf-mtDNA) is now understood to catalyse sterile inflammation after trauma. Observations in trauma cohorts have identified high cf-mtDNA in patients with systemic inflammatory response syndrome and multiple organ failure as well as following major surgery. The source of cf-mtDNA can be various cells affected by mechanical and hypoxic injury (passive mechanism) or induced by inflammatory mechanisms (active mechanism). Multiple forms of cf-mtDNA exist; mtDNA fragments, mtDNA in microparticles/vesicles and cell-free mitochondria. Trauma to cells that are rich in mitochondria are believed to release more cf-mtDNA. This review describes the current understanding of the mechanisms of cf-mtDNA release, its systemic effects and the potential therapeutic implications related to its modification. Although current understanding is insufficient to change trauma management, focussed research goals have been identified to pave the way for monitoring and manipulation of cf-mtDNA release and effects in trauma.

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Cell necrosis–independent sustained mitochondrial and nuclear DNA release following trauma surgery

Abstract: Supplemental digital content is available in the text.

Cited by 55 publications

References 33 publications

The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review

The role of total cell-free DNA in predicting outcomes among trauma patients in the intensive care unit: a systematic review

Peritoneal cavity lavage reduces the presence of mitochondrial damage associated molecular patterns in open abdomen patients

The source of cell-free mitochondrial DNA in trauma and potential therapeutic strategies

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