Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation

Nakahira, Kiichi; Kyung, Sunyoung; Rogers, Angela J.; Gazourian, Lee; Youn, Sojung; Massaro, Anthony F.; Quintana, Carolina; Osorio, Juan C.; Wang, Zhaoxi; Zhao, Yang; Lawler, Laurie; Christie, Jason D.; Meyer, Nuala J.; Causland, Finnian R. Mc; Waikar, Sushrut S.; Waxman, Aaron B.; Chung, Raymond T.; Bueno, Raphael; Rosas, Iván O.; Fredenburgh, Laura E.; Baron, Rebecca M.; Christiani, David C.; Hunninghake, Gary M.; Choi, Augustine M.K.

doi:10.1371/journal.pmed.1001577

Cited by 366 publications

(368 citation statements)

References 42 publications

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“…Recent evidence further suggests that in response to stimuli such as trauma [32] and microbial infection [33] cellular mtDNA levels decrease while circulating cell-free mtDNA levels are increased [34]. To that effect, Nakahira et al showed that mtDNA could serve as a viable plasma biomarker in medical ICU patients and that increased circulating mtDNA was associated with mortality [35]. Our study shows beneficial trends in total mtDNA levels in patients receiving intravenous ascorbic acid.…”

Section: Discussionsupporting

confidence: 57%

Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis

Natarajan¹

2014

J Pulm Respir Med

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Objective: Severe sepsis is a leading cause of mortality and morbidity in the critically ill with no reliably effective treatments. The goal of this study was to determine whether intravenous ascorbic acid impacted novel biomarkers in sepsis.Methods: This is a retrospective study of a phase I, randomized, double-blinded, placebo controlled safety trial of intravenous ascorbic acid in severe sepsis. In the safety trial, 24 patients were randomized to receive full ICU standard of care support plus intravenous ascorbic acid (50 or 200 mg/kg/24h) for 4 days or placebo. Novel biomarkers of sepsis such as circulating cell free DNA (cf-DNA), mitochondrial DNA (mtDNA), endogenous antimicrobial proteins (alpha-4-defensin [α4D] and bactericidal permeability interacting protein [BPI]) and the red cell distribution width (RDW) were measured.Results: Cf-DNA values were higher in non-survivors at baseline and remained elevated for 96 hours. MtDNA levels increased in the placebo group, but declined in the treatment groups without reaching statistical significance. RDW increased significantly only in the placebo group, while expression of the antimicrobial proteins increased significantly only in the treatment groups. Conclusion:Ascorbic acid infusion may improve sepsis outcomes by reducing cf-and mtDNA levels while augmenting endogenous antimicrobial proteins and preserving RDW.

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Section: Discussionsupporting

confidence: 57%

Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis

Natarajan¹

2014

J Pulm Respir Med

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“…Further, although previous studies have revealed a positive association of elevated plasma mtDNA with excessive inflammation in critically ill surgery patients 21,24,25 we observed reduced copy number of plasma mtDNA in both hypo-and hyper-responsive individuals following surgery. This may be indicative of the fact that increased plasma cytokines along with high copy number of mtDNA are responsible for post-surgical complications while in uncomplicated situations although the plasma cytokines increase the host system takes control over excessive inflammation by reducing the number of plasma mtDNA.…”

Section: Discussioncontrasting

confidence: 91%

“…Real copy number of mtDNA was calculated from reference standard curve by using observed cT values. Protocol was adapted from Kiichi Nakahira et al 21 .…”

Section: Measurement Of Plasma Cytokinesmentioning

confidence: 99%

Pre-surgery status determines inflammation levels post-elective surgery

Barman

Mukherjee

Mohapatra³

et al. 2015

F1000Res

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In the present study we quantified a panel of systemic inflammation parameters in patients undergoing elective surgery with a view to evaluate pre-surgical inflammation status in relation to consequences post-surgery. The investigation revealed significantly decreased levels of plasma TNF-α, IL1-β, IL7, IL-8, MIP-1a and IL-1Ra in 79% of patients at 6 hrs post-surgery which have been designated by us a 'hypo-responsive' cases and the balance 21% of patients displayed significantly elevated levels of the above cytokines in plasma that have been designated a 'hyper-responsive' phenotype by us. Expression of HLA-DR, CD40, CD80, TLR-2, TLR-4 and CD36 on circulating monocytes as shown by multicolour flow-cytometry was significantly decreased post-surgery in hypo-responsive patients. Similarly, PBMCs of hypo-responsive cases responded very poorly when stimulated with toll-like receptor (TLR) in vitro agonists. There was an inverse association between levels of plasma inflammatory cytokines pre-surgery and hypo-responsive consequences post-surgery. Similarly, patients displaying the hyper-responsive phenotype were found to express very low levels of inflammatory cytokines pre-surgery. Taken together the current study offers two novel findings: a) a bimodal inflammatory response post-elective surgery viz., one major cohort displaying hypo-responsive state and another minor group a hyper-responsive phenotype and b) pre-surgery inflammation status determining the direction of inflammation consequence post-surgery. These findings seem to offer laboratory tools for predicting onset of inflammation post-surgery -considering that SIRS and sepsis are consequences of surgery induced inflammation this study offers predictive indicators for clinical complications post-surgery.

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“…12,18,24 However, it remains controversial as to whether the level of mtDNA is elevated and related to death in patients with sepsis. [24][25][26][27] Here, we first showed that the levels of mtDNA are elevated in the systemic circulation and peritoneal cavity from the early phase of polymicrobial peritonitis but not endotoxemia. Our findings suggest that the circulating mtDNA originated, at least in part, from the inflammatory cells that migrated to the peritoneal cavity to attack the invading bacteria.…”

Section: Discussionmentioning

confidence: 96%

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

Tsuji¹,

Tsuji²,

Ohashi³

et al. 2015

JASN

118

110

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Toll-like receptor 9 (TLR9) contributes to the development of polymicrobial septic AKI. However, the mechanisms that activate the TLR9 pathway and cause kidney injury during sepsis remain unknown. To determine the role of mitochondrial DNA (mtDNA) in TLR9-associated septic AKI, we established a cecal ligation and puncture (CLP) model of sepsis in wild-type (WT) and Tlr9-knockout (Tlr9KO) mice. We evaluated systemic circulation and peritoneal cavity dynamics and immune response and tubular mitochondrial dysfunction to determine upstream and downstream effects on the TLR9 pathway, respectively. CLP increased mtDNA levels in the plasma and peritoneal cavity of WT and Tlr9KO mice in the early phase, but the increase in the peritoneal cavity was significantly higher in Tlr9KO mice than in WT mice. Concomitantly, leukocyte migration to the peritoneal cavity increased, and plasma cytokine production and splenic apoptosis decreased in Tlr9KO mice compared with WT mice. Furthermore, CLP-generated renal mitochondrial oxidative stress and mitochondrial vacuolization in the proximal tubules in the early phase were reversed in Tlr9KO mice. To elucidate the effects of mtDNA on immune response and kidney injury, we intravenously injected mice with mitochondrial debris (MTD), including substantial amounts of mtDNA. MTD caused an immune response similar to that induced by CLP, including upregulated levels of plasma IL-12, splenic apoptosis, and mitochondrial injury, but this effect was attenuated by Tlr9KO. Moreover, MTD-induced renal mitochondrial injury was abolished by DNase pretreatment. These findings suggest that mtDNA activates TLR9 and contributes to cytokine production, splenic apoptosis, and kidney injury during polymicrobial sepsis.

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Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation

Cited by 366 publications

References 42 publications

Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis

Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis

Pre-surgery status determines inflammation levels post-elective surgery

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

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