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Peripheral Blood Mononuclear Cells Demonstrate Mitochondrial Damage Clearance During Sepsis

Kraft, Bryan D. MD1,2; Chen, Lingye MD1,2; Suliman, Hagir B. DVM, PhD3; Piantadosi, Claude A. MD1–,3; Welty-Wolf, Karen E. MD1,2

doi: 10.1097/CCM.0000000000003681
Clinical Investigations

Objectives: Metabolic derangements in sepsis stem from mitochondrial injury and contribute significantly to organ failure and mortality; however, little is known about mitochondrial recovery in human sepsis. We sought to test markers of mitochondrial injury and recovery (mitochondrial biogenesis) noninvasively in peripheral blood mononuclear cells from patients with sepsis and correlate serial measurements with clinical outcomes.

Design: Prospective case-control study.

Setting: Academic Medical Center and Veterans Affairs Hospital.

Patients: Uninfected control patients (n = 20) and septic ICU patients (n = 37).

Interventions: Blood samples were collected once from control patients and serially with clinical data on days 1, 3, and 5 from septic patients. Gene products for HMOX1, NRF1, PPARGC1A, and TFAM, and mitochondrial DNA ND1 and D-loop were measured by quantitative reverse transcriptase-polymerase chain reaction. Proinflammatory cytokines were measured in plasma and neutrophil lysates.

Measurements and Main Results: Median (interquartile range) Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were 21 (8) and 10 (4), respectively, and 90-day mortality was 19%. Transcript levels of all four genes in peripheral blood mononuclear cells were significantly reduced in septic patients on day 1 (p < 0.05), whereas mitochondrial DNA copy number fell and plasma D-loop increased (both p < 0.05), indicative of mitochondrial damage. D-loop content was directly proportional to tumor necrosis factor-α and high-mobility group protein B1 cytokine expression. By day 5, we observed transcriptional activation of mitochondrial biogenesis and restoration of mitochondrial DNA copy number (p < 0.05). Patients with early activation of mitochondrial biogenesis were ICU-free by 1 week.

Conclusions: Our findings support data that sepsis-induced mitochondrial damage is reversed by activation of mitochondrial biogenesis and that gene transcripts measured noninvasively in peripheral blood mononuclear cells can serve as novel biomarkers of sepsis recovery.

1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, NC.

2Department of Medicine, Durham Veteran Affairs Medical Center, Durham, NC.

3Department of Anesthesiology, Duke University Medical Center, Durham, NC.

Drs. Kraft and Chen contributed equally.

Dr. Welty-Wolf conceived of the overall experimental design. Drs. Kraft and Chen drafted the article. All authors performed data analysis and interpretation, revised the article, and approved of the final draft.

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All authors received support for article research from the National Institutes of Health (NIH). Dr. Kraft’s institution received funding from the NIH/National Heart, Lung, and Blood Institute, and the National Institute of General Medical Sciences, and he received funding from Shionogi Pharmaceuticals (Advisory Board). Dr. Kraft receives funding from the National Institutes of Health (K08HL130557) and has received honoraria from Shionogi Pharmaceuticals and La Jolla Pharmaceutical Company. Dr. Suliman receives funding from the National Institutes of Health (R01-HL135239-01A1). Dr. Piantadosi receives funding from the National Institutes of Health (R01-HL135239-01A1) and the Office of Naval Research (ONR N00014011240). Dr. Welty-Wolf received funding from the National Institutes of Health (R01GM084116). Drs. Chen’s and Welty-Wolf’s institutions received funding from the NIH.

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