Investigation of the mechanisms driving endothelial dysfunction in patients with sepsis and COVID-19

Gant, Poppy (2024). Investigation of the mechanisms driving endothelial dysfunction in patients with sepsis and COVID-19. University of Birmingham. M.Sc.

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Abstract

Endothelial cells play a crucial role in the active regulation of a quiescent anti-inflammatory and anti-thrombotic vascular surface. Controlled activation is also vital for mounting an appropriate immune response during inflammation. However, systemic endothelial activation can lead to an exaggerated immune response and thrombosis, independent of the original stimulus. We aimed to assess endothelial cell activation markers in the plasma of patients with sepsis and COVID-19 and to explore possible mechanisms driving endothelial dysfunction in patients. We also investigated the impact of two key damage-associated molecular patterns released during neutrophil extracellular trap formation, histone H4 and S100A8/A9, on endothelial cells under hyperglycaemic conditions and in the plasma of patients with sepsis. We showed that systemic endothelial cell activation is present in patients with both sepsis and COVID-19 as assessed by the increased levels of markers regulating immune recruitment, immunothrombosis and vascular permeability. Markers of NETosis were also observed in patients and these levels correlate with disease severity. Mechanistically, we show that hyperglycaemia alters the response of endothelial cells to histone 4 and increases its binding. Endothelial cell activation by histone 4 is significantly increased in the plasma of patients with sepsis, in particular patients who developed acute respiratory distress syndrome (ARDS) compared to healthy controls. In conclusion, endothelial activation in patients with sepsis and COVID-19 is a hallmark of disease severity. Immune cell activation, through the release of histone H4, increases endothelial cell activation and exacerbates immunothrombosis.

Type of Work:

Thesis (Masters by Research > M.Sc.)

Award Type:

Masters by Research > M.Sc.

Supervisor(s):