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Cerebrospinal Fluid Mitochondrial DNA: A Novel DAMP in Pediatric Traumatic Brain Injury

Walko, Thomas D. III*; Bola, R. Aaron; Hong, John D.; Au, Alicia K.§; Bell, Michael J.; Kochanek, Patrick M.§; Clark, Robert S.B.§; Aneja, Rajesh K.§

doi: 10.1097/SHK.0000000000000160
Clinical Science Aspects

ABSTRACT Danger-associated molecular patterns (DAMPs) are nuclear or cytoplasmic proteins that are released from the injured tissues and activate the innate immune system. Mitochondrial DNA (mtDNA) is a novel DAMP that is released into the extracellular milieu subsequent to cell death and injury. We hypothesized that cell death within the central nervous system in children with traumatic brain injury (TBI) would lead to the release of mtDNA into the cerebrospinal fluid (CSF) and has the potential to predict the outcome after trauma. Cerebrospinal fluid was collected from children with severe TBI who required intracranial pressure monitoring with Glasgow Coma Scale (GCS) scores of 8 or less via an externalized ventricular drain. Control CSF was obtained in children without TBI or meningoencephalitis who demonstrated no leukocytes in the diagnostic lumbar puncture. The median age for patients with TBI was 6.3 years, and 62% were male. The common mechanisms of injury included motor vehicle collision (35.8%), followed by falls (21.5%) and inflicted TBI (19%); six children (14.2%) died during their intensive care unit course. The mean CSF mtDNA concentration was 1.10E+05 ± 2.07E+05 and 1.63E+03 ± 1.80E+03 copies/μL in the pediatric TBI and control populations, respectively. Furthermore, the mean CSF mtDNA concentration in pediatric patients who later died or had severe disability was significantly higher than that of the survivors (1.63E+05 ± 2.77E+05 vs. 5.05E+04 ± 6.21E+04 copies/μL) (P < 0.0001). We found a significant correlation between CSF mtDNA and high mobility group box 1, another prototypical DAMP, concentrations (ρ = 0.574, P < 0.05), supporting the notion that both DAMPs are increased in the CSF after TBI. Our data suggest that CSF mtDNA is a novel DAMP in TBI and appears to be a useful biomarker that correlates with neurological outcome after TBI. Further inquiry into the components of mtDNA that modulate the innate immune response will be helpful in understanding the mechanism of local and systemic inflammation after TBI.

*Department of Critical Care Medicine, University at Buffalo, State University of New York, Buffalo, New York; Department of Chemistry, Carnegie Mellon University; and §Departments of Critical Care Medicine and Pediatrics, and Critical Care Medicine and Neurosurgery, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania

Received 5 Dec 2013; first review completed 26 Dec 2013; accepted in final form 18 Feb 2014

Address reprint requests to Rajesh K. Aneja, MD, Department of Critical Care Medicine, Children’s Hospital of Pittsburgh, 4401 Penn Ave, Faculty Pavilion Bldg, Suite 2000, Pittsburgh, PA 15224. E-mail:

© 2014 by the Shock Society