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

Thurairajah, Kabilan; Briggs, Gabrielle D.; Balogh, Zsolt J.

doi:10.1007/s00068-018-0954-3

Cited by 92 publications

(86 citation statements)

References 71 publications

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“…In critically ill patients, mtDNA may be released into plasma by unregulated necrosis from direct cellular injury, programmed necrosis, or active ejection by leukocytes such as NETosis. [10][11][12] mtDNA is also present in blood products and therefore may be introduced into circulation through transfusion, a potential mechanism of transfusion-associated organ dysfunction previously studied in surgical populations. 13,14 In both populations, plasma mtDNA is elevated and associated with mortality, [15][16][17][18][19] but clinical data linking mtDNA to ARDS are limited to one study in elderly patients with hip fractures and an unadjusted association of plasma mtDNA and ARDS in a mixed ICU population.…”

mentioning

confidence: 99%

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Faust

Reilly

Anderson

et al. 2020

Chest

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BACKGROUND: Critically ill patients who develop ARDS have substantial associated morbidity and mortality. Circulating mitochondrial DNA (mtDNA) released during critical illness causes endothelial dysfunction and lung injury in experimental models. This study hypothesized that elevated plasma mtDNA is associated with ARDS in critically ill patients with trauma and sepsis.METHODS: Plasma mtDNA concentrations were measured at ED presentation and approximately 48 h later in separate prospective cohorts of critically ill patients with trauma and sepsis. ARDS was classified according to the Berlin definition. The association of mtDNA with ARDS was tested by using multivariable logistic regression, adjusted for covariates previously shown to contribute to ARDS risk in each population.RESULTS: ARDS developed in 41 of 224 (18%) trauma patients and in 45 of 120 (38%) patients with sepsis. Forty-eight-hour mtDNA levels were significantly associated with ARDS (trauma: OR, 1.58/log copies/mL; 95% CI, 1.14-2.19 [P ¼ .006]; sepsis: OR, 1.52/log copies/ mL; 95% CI, 1.12-2.06 [P ¼ .007]). Plasma mtDNA on presentation was not significantly associated with ARDS in either cohort. In patients with sepsis, 48-h mtDNA was more strongly associated with ARDS among those with a nonpulmonary infectious source (OR, 2.20/log copies/mL; 95% CI, 1.36-3.55 [P ¼ .001], n ¼ 69) than those with a pulmonary source (OR, 1.04/log copies/mL; 95% CI, 0.68-1.59 [P ¼ .84], n ¼ 51; P ¼ .014 for interaction).CONCLUSIONS: Plasma mtDNA levels were associated with incident ARDS in two critical illness populations. Given supportive preclinical data, our findings suggest a potential link between circulating mtDNA and lung injury and merit further investigation as a potentially targetable mediator of ARDS. CHEST 2020; 157(1):67-76

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mentioning

confidence: 99%

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Faust

Reilly

Anderson

et al. 2020

Chest

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“…Intracellular mechanisms of mtDNA inflammation include inflammasome activation and stimulator of interferon gene pathway activation [261]. However, although these mechanisms have not been confirmed directly in the trauma setting, based on available scientific research plausible mechanisms exist [262]. The cfDNA released from mammalian cells and bacteria is a potent stimulator of the innate immunity.…”

Section: Nucleic Acidsmentioning

confidence: 99%

“…As recently reviewed by Thurairajah et al [262], clinicians have regarded DNA and mitochondria as intracellular structures, unrelated to the pathophysiology of trauma. Meanwhile, we are beginning to understand the large impact of cfDNA on posttraumatic inflammation.…”

Section: Nucleic Acidsmentioning

confidence: 99%

Damage-associated molecular patterns in trauma

Relja

Land

2019

Eur J Trauma Emerg Surg

129

131

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In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.

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“…Tissue mitochondria also play a major role in the pathophysiology of TIC and inflammation linking the CNS control of VA function and endothelial injury. 147,148 Mitochondria are the cell's oxygen consumers and energy generators that turn over approximately 40 kg of adenosine triphosphate (ATP) per day at rest (►Fig. 5).…”

Section: Third Pillar: Mitochondrial Integrity and Organ Dysfunctionmentioning

confidence: 99%

Traumatic-Induced Coagulopathy as a Systems Failure: A New Window into Hemostasis

Dobson

Morris

Davenport

et al. 2020

Semin Thromb Hemost

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Traumatic-induced coagulopathy (TIC) is often associated with significant bleeding, transfusion requirements, inflammation, morbidity, and mortality. This review considers TIC as a systems failure, not as a single-event manifestation of trauma. After briefly reviewing the meaning of TIC and the bewildering array of fibrinolysis phenotypes, we will discuss the role of platelets and fibrinogen in coagulopathy. Next, we will review the different TIC hypotheses and drill down to a single mechanistic domain comprising (1) thrombin's differential binding to thrombomodulin, (2) the expression of annexin II-S100A10 complex, and (3) the functional integrity of the endothelial glycocalyx. This triad forms the basis of the “switch” hypothesis of TIC. We will next address the potential limitations of current practice in treating a coagulation or fibrinolytic defect, and the next defect, and so on down the line, which often leads to what U.S. surgeon William C. Shoemaker considered “an uncoordinated and sometimes contradictory therapeutic outcome.” The treat-as-you-go approach using sequential, single-target treatments appears to be a by-product of decades of highly reductionist thinking and research. Lastly, we will present a unified systems hypothesis of TIC involving three pillars of physiology: the central nervous system (CNS)–cardiovascular system, the endothelial glycocalyx, and mitochondrial integrity. If CNS control of ventriculoarterial coupling is maintained close to unity following trauma, we hypothesize that the endothelium will be protected, mitochondrial energetics will be maintained, and TIC (and inflammation) will be minimized. The Systems Hypothesis of Trauma (SHOT) also helps to answer why certain groups of severely bleeding trauma patients are still dying despite receiving the best care. Currently, no drug therapy exists that targets the whole system.

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

Cited by 92 publications

References 71 publications

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Plasma Mitochondrial DNA Levels Are Associated With ARDS in Trauma and Sepsis Patients

Damage-associated molecular patterns in trauma

Traumatic-Induced Coagulopathy as a Systems Failure: A New Window into Hemostasis

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