Myeloperoxidase inhibition may protect against endothelial glycocalyx shedding induced by COVID-19 plasma

Abstract

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), significantly threatens public health. Accumulating evidence suggests increased neutrophil activation and endothelial glycocalyx (EG) damage to be independently associated with severe COVID-19 outcomes. However, pathways that are involved in EG breakdown in COVID-19 remains unclear. Here, we hypothesised that increased blood neutrophil myeloperoxidase (MPO) level is associated with soluble EG breakdown, and inhibiting MPO activities can reduce EG damage. MethodsFrom a subset of acute and convalescent COVID-19 plasma, 10 severe and 15 non-severe COVID-19 cases, and 9 pre-COVID-19 controls (single timepoint), we determined MPO, MPO activities and soluble EG proteins (syndecan-1 and glypican-1) levels by enzyme-linked immunosorbent assay. In vitro primary human aortic endothelial cells were cultured in the presence of untreated or treated plasma with specific MPO inhibitors (MPO-IN-28, AZD-5904) to determine soluble EG shedding. We then investigated the association between MPO and soluble EG breakdown, and whether inhibiting MPO activities decrease EG disruption.ResultsIn COVID-19 plasma, MPO levels, MPO activity and soluble EG proteins levels were significantly raised compared to controls, and proteins levels increased in proportion to disease severity. Despite clinical recovery, proteins concentrations remained significantly elevated compared to controls. Interestingly, there is a trend of increasing MPO activity in convalescent plasma in both severe and non-severe groups. Importantly, MPO levels and MPO activity correlated significantly with soluble EG levels in plasma, and inhibiting MPO activity led to reduced syndecan-1 shedding, in vitro. ConclusionsOur work highlights the link between neutrophil MPO involvement and EG shedding in COVID-19, and inhibiting MPO activity may protect against EG disruption. Further research is needed to evaluate the utility of MPO inhibitors as potential therapeutics against severe COVID-19 outcomes.