Metabolic Response in Endothelial Cells to Catecholamine Stimulation Associated with Increased Vascular Permeability.

Disruption to endothelial cell homeostasis results in an extensive variety of human pathologies that are particularly relevant to major trauma. Circulating catecholamines, such as adrenaline and noradrenaline, activate endothelial adrenergic receptors triggering a potent response in endothelial function. The regulation of the endothelial cell metabolism is distinct and profoundly important to endothelium homeostasis. However, a precise catalogue of the metabolic alterations caused by sustained high catecholamine levels that results in endothelial dysfunction is still underexplored. Here, we uncover a set of up to 46 metabolites that exhibit a dose-response relationship to adrenaline-noradrenaline equimolar treatment. The identified metabolites align with the glutathione-ascorbate cycle and the nitric oxide biosynthesis pathway. Certain key metabolites, such as arginine and reduced glutathione, displayed a differential response to treatment in early (4 h) compared to late (24 h) stages of sustained stimulation, indicative of homeostatic metabolic feedback loops. Furthermore, we quantified an increase in the glucose consumption and aerobic respiration in endothelial cells upon catecholamine stimulation. Our results indicate that oxidative stress and nitric oxide metabolic pathways are downstream consequences of endothelial cell stimulation with sustained high levels of catecholamines. A precise understanding of the metabolic response in endothelial cells to pathological levels of catecholamines will facilitate the identification of more efficient clinical interventions in trauma patients.

Wound healing grafts: Omega-3 fatty acid lipid content differentiates the lipid profiles of acellular Atlantic cod skin from traditional dermal substitutes.

Acellular fish skin (ACS) has emerged as a dermal substitute used to promote wound healing with decreased scar formation and pain relief that may be due to polyunsaturated fatty acid (PUFA) content. However, the PUFA content of ACS is still unknown. The aim of this study was to compare the total fatty acids and lipid profiles of ACS to two bovine-based grafts and standard of care human cadaver skin (HCS). Furthermore, there was also the goal to assess the capability of ACS lipid content to enhance wound healing. The fatty acid analysis was performed with GC-FID, and an LC-MS untargeted method was developed in order to the analyse the lipid profiles of the grafts was. The enhancement of wound healing by the ACS extract was investigated in vitro on HaCat cells. Our results showed that ACS had the highest content of PUFA (27.0 ± 1.43% of their total fatty acids), followed by HCS (20.6 ± 3.9%). The two grafts of bovine origin presented insignificant PUFA amounts. The majority of the PUFAs found in ACS were omega-3, and in HCS, they were omega-6. The untargeted lipidomics analysis demonstrated that ACS grafts were characterized by phosphatidylcholine containing either 20:5 or 22:6 omega-3 PUFA. The ACS lipid extract increased the HaCat cells migration and enhanced wound closure 4 hr earlier versus control. Our study demonstrated that ACS has a lipid profile that is distinct from other wound healing grafts, that PUFAs are maintained in ACS post-processing as phosphatidylcholine, and that ACS lipid content influences wound healing properties.

Metabolic Systems Analysis of Shock-Induced Endotheliopathy (SHINE) in Trauma: A New Research Paradigm.

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.