Metabolic Systems Analysis of Shock-Induced Endotheliopathy (SHINE) in Trauma

Abstract

Objective: Investigate the endothelial cell phenotype (s) that causes Shock-Induced Endotheliopathy in trauma. Background: We have studied more than 2750 trauma patients and identified that patients with high circulating syndecan-1 (endothelial glycocalyx damage marker) in plasma have an increased mortality rate compared with patients with lower levels. Notably, we found that patients suffering from the same trauma severity could develop significantly different degrees of endothelial dysfunction as measured by syndecan-1. Methods: Prospective observational study of 20 trauma patients admitted to a Level 1 Trauma Centre and 20 healthy controls. Admission plasma syndecan-1 level and mass spectrometry were measured and analyzed by computational network analysis of our genome-scale metabolic model of the microvascular endothelial cell function. Results: Trauma patients had a significantly different endothelial metabolic profile compared with controls. Among the patients, 4 phenotypes were identified. Three phenotypes were independent of syndecan-1 levels. We developed genome-scale metabolic models representative of the observed phenotypes. Within these phenotypes, we observed differences in the cell fluxes from glucose and palmitate to produce Acetyl-CoA, and secretion of heparan sulfate proteoglycan (component of syndecan-1). Conclusions: We confirm that trauma patients have a significantly different metabolic profile compared with controls. A minimum of 4 shock-induced endotheliopathy phenotypes were identified, which were independent of syndecan-1level (except 1 phenotype) verifying that the endothelial response to trauma is heterogeneous and most likely driven by a genetic component. Moreover, we introduced a new research tool in trauma by using metabolic systems biology, laying the foundation for personalized medicine.

Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC4

“…Based on prior work with critically ill trauma patients, we selected 62 metabolites to quantify ( Table 3 ) [13] , [15] .…”

“…To integrate all the measured metabolites in this study, the latest reconstruction of endothelial cell metabolism [13] was upgraded. To that end, the original model’s annotation was improved and new reactions were added (see Methods).…”

“…The vascular compartment encompasses more than one trillion endothelial cells that are in constant contact with the circulating blood [12] . Previously, when parameterizing EC-GEM with the plasma metabolome from trauma patients, four shock-induced endotheliopathic phenotypes were displayed, of which one cluster depended on the syndecan-1 level [13] . Based on that finding, the present study aimed to comparatively analyze the endothelial cell metabolism in EoT vs. non-EoT patients, focusing on the glycan and lipid metabolism as these are pivotal for the cell membrane phenotype, including that of the glycocalyx [14] .…”

Hypobaria Exposure Worsens Cardiac Function and Endothelial Injury in AN Animal Model of Polytrauma: Implications for Aeromedical Evacuation

“…We observed a close correlation of the plasma IL-6 level with shock severity as measured by core temperature and cardiac dysfunction as measured by CO, SV, EF, and FS in the trauma mice (Table 2). Moreover, endothelial injury has been shown to correlate with trauma injury severity and independently predict poor outcomes in several studies of trauma patients (22,23). We noticed a close correlation between the plasma endothelial injury markers, i.e., thrombomodulin, syndecan-1, E-selectin, and cardiac dysfunction in trauma mice under hypobaric conditions.…”

The polyanionic drug suramin neutralizes histones and prevents endotheliopathy

“…Furthermore, histones deposited on the lumen of blood vessels can also attract monocytes in a surface-charge dependent fashion causing atherosclerosis (4). Elevated histone levels have been linked to widespread endothelial injury and organ damage in human patients after trauma (19,(32)(33)(34)(35)(36)(37)(38) and other conditions including ischemic stroke (39), sepsis (3), pancreatitis (40), and acute respiratory distress syndrome (ARDS) (41,42).…”