Clinical Metabolomics of Acute Critical Illness and Links to The Endothelium

Date: Thursday, February 22nd at 12:30-13:10 in Askja, room N-132

Title: Clinical Metabolomics of Acute Critical Illness and Links to The Endothelium

Speaker: Sarah McGarrity PhD, Research Specialist

Abstract: Sepsis and trauma are major causes of death worldwide, with stubbornly high mortality. One quarter of patients suffering from acute critical illness such as severe trauma, and sepsis develop severe coagulopathy. It has been suggested by several previous studies that shock-induced sympatho-adrenal hyperactivation driving endothelial cell damage (endotheliopathy) contributes to this coagulopathy. These patients also show disordered metabolism. Better understanding of the metabolic dysregulation, and potential links to endotheliopathy in these patients could offer a way to better understand and ultimately treat them; therefore, metabolomics offers a promising tool to study acute critical illnesses. 
In two recent studies we integrated metabolomics data from sepsis or trauma patients with commonly collected clinical features of their cases and measures of endothelial function relevant and used regression techniques to examine the links between the two. This has been carried out in parallel with examinations of in vitro studies of endothelial cell response to adrenal stimulation.
In sepsis we showed that metabolites associated with sepsis survival include carnitines, and amino acids. Endothelial proteins in plasma also predict 30-day mortality and the metabolites associated with the levels of these proteins overlaps with those associated with mortality.
In HUVECs we demonstrated a set of metabolites that exhibit a dose–response relationship to adrenaline-noradrenaline equimolar treatment. The identified metabolites aligned with the glutathione-ascorbate cycle and the nitric oxide biosynthesis pathway. This aligned with the metabolites associated with PECAM in sepsis patients.
Its hoped that this expanding understanding of the metabolic response in endothelial cells to pathological levels of adrenaline will facilitate the identification of more efficient clinical interventions in acute critical illness patients.

About the Speaker: Sarah McGarrity first joined Óttar Rolfsson’s group at the University of Iceland in 2015 after her PhD at the University of Newcastle. She worked on endothelial metabolic modelling with Óttar Rolfsson at HÍ and metabolic modelling of mesenchymal stem cells with Ólafur Sigurjonsson at HR. Between February 2020 and January 2023 she worked at Brigham and Women’s Hospital Harvard Medical School in the Oldham Lab as a recipient of a Novo Nordisk Foundation Postdoctoral Fellowship for research abroad in the field of endocrinology and metabolism. There she studied how the endothelial glycocalyx contributes to endothelial cell redox homeostasis through effects on glutathione peroxidase and endothelial nitric oxide synthase enzymatic activities. For the last year she has been back at the University of Iceland working with Óttar and they have recently received a RANNIS grant of excellence for this project.