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Human Sepsis Eicosanoid and Proresolving Lipid Mediator Temporal Profiles: Correlations With Survival and Clinical Outcomes.
Dalli, J, Colas, RA, Quintana, C, Barragan-Bradford, D, Hurwitz, S, Levy, BD, Choi, AM, Serhan, CN, Baron, RM
Critical care medicine. 2017;(1):58-68
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Abstract
OBJECTIVE To identify and measure recently described chemical mediators, termed specialized pro-resolving mediators that actively regulate the resolution of acute-inflammation, and correlate measurements with clinical outcomes. DESIGN Herein, deidentified plasma was collected from sepsis patients (n = 22 subjects) within 48 hours of admission to the ICU and on days 3 and 7 thereafter and subjected to lipid mediator profiling. SETTING Brigham and Women's Hospital Medical Intensive Care Unit. SUBJECTS Patients in the medical ICU with sepsis. MEASUREMENTS AND MAIN RESULTS In all patients, we identified more than 30 bioactive mediators and pathway markers in peripheral blood using established criteria for arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid metabolomes. These included inflammation initiating mediators leukotriene B4 and prostaglandin E2 and pro-resolving mediators resolvin D1, resolvin D2, and protectin D1. In sepsis nonsurvivors, we found significantly higher inflammation-initiating mediators including prostaglandin F2α and leukotriene B4 and pro-resolving mediators, including resolvin E1, resolvin D5, and 17R-protectin D1 than was observed in surviving sepsis subjects. This signature was present at ICU admission and persisted for 7 days. Further analysis revealed increased respiratory failure in nonsurvivors. Higher inflammation-initiating mediators (including prostaglandin F2α) and select proresolving pathways were associated with the development of acute respiratory distress syndrome, whereas other traditional clinical indices were not predictive of acute respiratory distress syndrome development. CONCLUSIONS These results provide peripheral blood lipid mediator profiles in sepsis that correlate with survival and acute respiratory distress syndrome development, thus suggesting plausible novel biomarkers and biologic targets for critical illness.
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Plasma metabolomics in human pulmonary tuberculosis disease: a pilot study.
Frediani, JK, Jones, DP, Tukvadze, N, Uppal, K, Sanikidze, E, Kipiani, M, Tran, VT, Hebbar, G, Walker, DI, Kempker, RR, et al
PloS one. 2014;(10):e108854
Abstract
We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution.