TY - JOUR
T1 - Peripheral Blood Mononuclear Cells Demonstrate Mitochondrial Damage Clearance during Sepsis
AU - Kraft, Bryan D.
AU - Chen, Lingye
AU - Suliman, Hagir B.
AU - Piantadosi, Claude A.
AU - Welty-Wolf, Karen E.
N1 - Funding Information:
ccmjournal).versions of this article on the journal’s website (http://journals.lww.com/ Metabolic derangements in sepsis in experimental All authors received support for article research from the National Insti- animal studies have been reliably linked to sepsis-tutes of Health (NIH). Dr. Kraft’s institution received funding from the NIH/ induced mitochondrial injury and dysfunction National Heart, Lung, and Blood Institute, and the National Institute of (1–16). Mitochondrial damage in turn stimulates mitochon-maceuticals (Advisory Board). Dr. Kraft receives funding from the Na-General Medical Sciences, and he received funding from Shionogi Phar- drial biogenesis, a highly regulated nuclear-encoded genetic tional Institutes of Health (K08HL130557) and has received honoraria program that promotes maintenance of healthy mitochondrial from Shionogi Pharmaceuticals and La Jolla Pharmaceutical Company. mass, is linked to antiinflammatory, antioxidant, and anti-HL135239-01A1). Dr. Piantadosi receives funding from the National Dr. Suliman receives funding from the National Institutes of Health (R01- apoptotic cellular defenses and is essential for organ recovery Institutes of Health (R01-HL135239-01A1) and the Office of Naval Re-and survival in sepsis (1, 2, 4–9, 17). In critically ill patients National Institutes of Health (R01GM084116). Drs. Chen’s and Welty-search (ONR N00014011240). Dr. Welty-Wolf received funding from the with sepsis, respiration and mitochondrial biogenesis signaling Wolf’s institutions received funding from the NIH. are impaired based on analysis of skeletal muscle biopsies (1, For information regarding this article, E-mail: [email protected] 4, 18–20). However, the ability to measure mitochondrial bio-Copyright © 2019 by the Society of Critical Care Medicine and Wolters genesis noninvasively, that is, in peripheral blood cells, has not Kluwer Health, Inc. All Rights Reserved. been demonstrated convincingly and would make monitoring DOI: 10.1097/CCM.0000000000003681 of ongoing mitochondrial damage or recovery easier. Using
Publisher Copyright:
© 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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.
AB - 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.
KW - biomarkers
KW - mitochondrial biogenesis
KW - mononuclear leukocytes
KW - sepsis
UR - http://www.scopus.com/inward/record.url?scp=85064852846&partnerID=8YFLogxK
U2 - 10.1097/CCM.0000000000003681
DO - 10.1097/CCM.0000000000003681
M3 - Article
C2 - 30730439
AN - SCOPUS:85064852846
SN - 0090-3493
VL - 47
SP - 651
EP - 658
JO - Critical care medicine
JF - Critical care medicine
IS - 5
ER -