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Elevated Levels of Plasma Mitochondrial DNA DAMPs are Linked to Clinical Outcome in Severely Injured Human Subjects
Jon D Simmons*, Y Larry Lee*, Sujata Mulekar*, Jamie K Hill*, Sidney B Brevard*, Richard P Gonzalez*, Mark N Gillespie*, William O Richards
University of South Alabama, Mobile, AL

Objectives
Mitochondrial (mt) DNA Damage Associated Molecular Patterns (DAMPs) accumulate in the circulation after severe injury. Observations in animal models demonstrate that mtDNA DAMPs contribute to organ dysfunction; however, the link between plasma mtDNA DAMPs and outcome in severely injured human subjects has not been established. We therefore executed a prospective cohort study to determine relationships between plasma mtDNA DAMP levels and the occurrence of Systemic Inflammatory Response Syndrome (SIRS), Multiple Organ Dysfunction Syndrome (MODS), and mortality.
Methods
DNA was isolated from blood samples taken from severely injured patients at hospital days 0, 1, and 2. Real time PCR was used to quantify selected ≈200 base pair sequences corresponding to the COX1, ND1, ND6, and D-Loop mitochondrial genomic regions. MODS was defined as a Denver Multiple Organ Failure score ≥4. Statistically significant differences* (p<0.05) were detected by non-parametric analyses.
Results
MtDNA DAMPs were quantified as threshold cycle number (lower threshold cycles indicate increased mtDNA DAMP content) and expressed as mean±SE (Table 1). Four patients died secondary to severe MODS.
Conclusions
These findings comprise the first evidence that plasma mtDNA DAMPs are linked to the evolution of SIRS, MODS, and mortality in severely injured human subjects.
Table 1. Associations of Plasma mtDNA DAMP Levels with SIRS, MODS, and Mortality
MtDNA
DAMP
No SIRS
(n=8)
SIRS
(n=5)
Fold increaseNo MODS
(n=9)
MODS
(n=4)
Fold
increase
Mortality Relative Risk
(95% CI)
COX132.1±0.929.0±1.28.8*32.6±0.727.1±0.743.7*20.4*
(1.3-318)
ND131.9±0.530.2±1.43.3*32.5±0.728.2±0.719.0*8.0*
(1.15-55.8)
ND632.4±0.628.9±1.111.0*32.5±0.527.6±0.830.3*20.4*
(1.3-318)
D-Loop33.1±0.828.3±1.128.3*32.9±0.827.9±1.331.8*8.0*
(1.16-55.2)


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