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Metabolic systems analysis of LPS induced endothelial dysfunction applied to sepsis patient stratification

Metabolic systems analysis of LPS induced endothelial dysfunction applied to sepsis patient stratification


Title: Metabolic systems analysis of LPS induced endothelial dysfunction applied to sepsis patient stratification
Author: McGarrity, Sarah   orcid.org/0000-0002-2878-6194
Anuforo, Ósk   orcid.org/0000-0002-4208-8536
Halldórsson, Haraldur
Bergmann, Andreas   orcid.org/0000-0001-8006-4888
Halldórsson, Skarphéðinn
Palsson, Sirus
Henriksen, Hanne H.
Johansson, Pär Ingemar   orcid.org/0000-0001-9778-5964
Rolfsson, Óttar   orcid.org/0000-0003-4258-6057
Date: 2018-05-01
Language: English
University/Institute: Háskóli Íslands
University of Iceland
School: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
Department: Rannsóknarsetur í kerfislíffræði (HÍ)
Center for Systems Biology (UI)
Læknadeild (HÍ)
Faculty of Medicine (UI)
Series: Scientific Reports;8(1)
ISSN: 2045-2322
DOI: 10.1038/s41598-018-25015-5
Subject: Biochemical reaction networks; Computational models; Predictive medicine; Lífeðlisfræði; Blóðeitrun
URI: https://hdl.handle.net/20.500.11815/1059

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Citation:

McGarrity, S., Anuforo, Ó., Halldórsson, H., Bergmann, A., Halldórsson, S., Palsson, S., . . . Rolfsson, Ó. (2018). Metabolic systems analysis of LPS induced endothelial dysfunction applied to sepsis patient stratification. Scientific Reports, 8(1), 6811. doi:10.1038/s41598-018-25015-5

Abstract:

Endothelial dysfunction contributes to sepsis outcome. Metabolic phenotypes associated with endothelial dysfunction are not well characterised in part due to difficulties in assessing endothelial metabolism in situ. Here, we describe the construction of iEC2812, a genome scale metabolic reconstruction of endothelial cells and its application to describe metabolic changes that occur following endothelial dysfunction. Metabolic gene expression analysis of three endothelial subtypes using iEC2812 suggested their similar metabolism in culture. To mimic endothelial dysfunction, an in vitro sepsis endothelial cell culture model was established and the metabotypes associated with increased endothelial permeability and glycocalyx loss after inflammatory stimuli were quantitatively defined through metabolomics. These data and transcriptomic data were then used to parametrize iEC2812 and investigate the metabotypes of endothelial dysfunction. Glycan production and increased fatty acid metabolism accompany increased glycocalyx shedding and endothelial permeability after inflammatory stimulation. iEC2812 was then used to analyse sepsis patient plasma metabolome profiles and predict changes to endothelial derived biomarkers. These analyses revealed increased changes in glycan metabolism in sepsis non-survivors corresponding to metabolism of endothelial dysfunction in culture. The results show concordance between endothelial health and sepsis survival in particular between endothelial cell metabolism and the plasma metabolome in patients with sepsis.

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