LASSO regression shows histidine and sphingosine 1 phosphate are linked to both sepsis mortality and endothelial damage.

Sepsis is a major cause of death worldwide, with a mortality rate that has remained stubbornly high. The current gold standard of risk stratifying sepsis patients provides limited mechanistic insight for therapeutic targeting. An improved ability to predict sepsis mortality and to understand the risk factors would allow better treatment targeting. Sepsis causes metabolic dysregulation in patients; therefore, metabolomics offers a promising tool to study sepsis. It is also known that that in sepsis endothelial cells affecting their function regarding blood clotting and vascular permeability. We integrated metabolomics data from patients admitted to an intensive care unit for sepsis, with commonly collected clinical features of their cases and two measures of endothelial function relevant to blood vessel function, platelet endothelial cell adhesion molecule and soluble thrombomodulin concentrations in plasma. We used least absolute shrinkage and selection operator penalized regression, and pathway enrichment analysis to identify features most able to predict 30-day survival. The features important to sepsis survival include carnitines, and amino acids. Endothelial proteins in plasma also predict 30-day mortality and the levels of these proteins also correlate with a somewhat overlapping set of metabolites. Overall metabolic dysregulation, particularly in endothelial cells, may be a contributory factor to sepsis response. By exploring sepsis metabolomics data in conjunction with clinical features and endothelial proteins we have gained a better understanding of sepsis risk factors.

Endothelial Cell Phenotypes Demonstrate Different Metabolic Patterns and Predict Mortality in Trauma Patients.

In trauma patients, shock-induced endotheliopathy (SHINE) is associated with a poor prognosis. We have previously identified four metabolic phenotypes in a small cohort of trauma patients (N = 20) and displayed the intracellular metabolic profile of the endothelial cell by integrating quantified plasma metabolomic profiles into a genome-scale metabolic model (iEC-GEM). A retrospective observational study of 99 trauma patients admitted to a Level 1 Trauma Center. Mass spectrometry was conducted on admission samples of plasma metabolites. Quantified metabolites were analyzed by computational network analysis of the iEC-GEM. Four plasma metabolic phenotypes (A-D) were identified, of which phenotype D was associated with an increased injury severity score (p < 0.001); 90% (91.6%) of the patients who died within 72 h possessed this phenotype. The inferred EC metabolic patterns were found to be different between phenotype A and D. Phenotype D was unable to maintain adequate redox homeostasis. We confirm that trauma patients presented four metabolic phenotypes at admission. Phenotype D was associated with increased mortality. Different EC metabolic patterns were identified between phenotypes A and D, and the inability to maintain adequate redox balance may be linked to the high mortality.

Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma.

BACKGROUND: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. METHODS: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. RESULTS: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. CONCLUSIONS: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

Comparative Metabolic Network Flux Analysis to Identify Differences in Cellular Metabolism.

Metabolic network flux analysis uses genome-scale metabolic reconstructions to integrate transcriptomics, proteomics, and/or metabolomics data to allow for comprehensive interpretation of genotype to metabolic phenotype relationships. The compilation of many Constraint-based model analysis methods into one MATLAB package, the COBRAtoolbox, has opened the possibility of using these methods to the many biologists with some knowledge of the commonly used statistical program, MATLAB. Here we outline the steps required to take a published genome-scale metabolic reconstruction and interrogate its consistency and biological feasibility. Subsequently, we demonstrate how mRNA expression data and metabolomics data, relating to one or more cell types or biological contexts, can be applied to constrain and generate metabolic models descriptive of metabolic flux phenotypes. Finally, we describe the comparison of the resulting models and model outputs with the aim of identifying metabolic biomarkers and changes in cellular metabolism.