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Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways
Journal article   Open access   Peer reviewed

Metabolomic profiling of amines in sepsis predicts changes in NOS canonical pathways

Abel Tesfai, Niall MacCallum, Nicholas S Kirkby, Hime Gashaw, Nicola Gray, Elizabeth Want, Gregory J Quinlan, Sharon Mumby, James M Leiper, Mark Paul-Clark, …
PloS one, Vol.12(8), e0183025
2017
DOI: https://doi.org/10.1371/journal.pone.0183025
PMCID: PMC5557592
PMID: 28813479
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Published4.20 MBDownloadView
CC BY V4.0,  Open Access

Abstract

Adult Aged Amines - metabolism Animals Arginine - metabolism Cell Line Chromatography, Liquid Enzyme-Linked Immunosorbent Assay Female Humans Male Mass Spectrometry Metabolomics Mice Middle Aged Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type II - metabolism omega-N-Methylarginine - metabolism Sepsis - metabolism Sepsis - physiopathology
Rationale Nitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known. Objective Our objective was to apply a metabolomics approach to determine the influence of sepsis on a full array of amines and what consequence these changes may have on predicted iNOS activity. Methods and measurements 34 amino acids were measured using ultra purification mass spectrometry in the plasma of septic patients (n = 38) taken at the time of diagnosis and 24–72 hours post diagnosis and of healthy volunteers (n = 21). L-arginine and methylarginines were measured using liquid-chromatography mass spectrometry and ELISA. A top down approach was also taken to examine the most changed metabolic pathways by Ingenuity Pathway Analysis. The iNOS supporting capacity of plasma was determined using a mouse macrophage cell-based bioassay. Main results Of all the amines measured 22, including L-arginine and ADMA, displayed significant differences in samples from patients with sepsis. The functional consequence of increased ADMA and decreased L-arginine in context of all cumulative metabolic changes in plasma resulted in reduced iNOS supporting activity associated with sepsis. Conclusions In early sepsis profound changes in amine levels were defined by dominant changes in the iNOS canonical pathway resulting in functionally meaningful changes in the ability of plasma to regulate iNOS activity ex vivo.

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Collaboration types
Domestic collaboration
Citation topics
1 Clinical & Life Sciences
1.127 Molecular & Cell Biology - Pharmacology
1.127.87 Nitric Oxide Roles
Web Of Science research areas
Multidisciplinary Sciences
ESI research areas
Clinical Medicine
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