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COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction
Kimberly A. Queisser, … , Robert A. Campbell, Aaron C. Petrey
Kimberly A. Queisser, … , Robert A. Campbell, Aaron C. Petrey
Published July 27, 2021
Citation Information: JCI Insight. 2021;6(17):e147472. https://doi.org/10.1172/jci.insight.147472.
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Research Article COVID-19 Vascular biology

COVID-19 generates hyaluronan fragments that directly induce endothelial barrier dysfunction

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Abstract

Vascular injury has emerged as a complication contributing to morbidity in coronavirus disease 2019 (COVID-19). The glycosaminoglycan hyaluronan (HA) is a major component of the glycocalyx, a protective layer of glycoconjugates that lines the vascular lumen and regulates key endothelial cell functions. During critical illness, as in the case of sepsis, enzymes degrade the glycocalyx, releasing fragments with pathologic activities into circulation and thereby exacerbating disease. Here, we analyzed levels of circulating glycosaminoglycans in 46 patients with COVID-19 ranging from moderate to severe clinical severity and measured activities of corresponding degradative enzymes. This report provides evidence that the glycocalyx becomes significantly damaged in patients with COVID-19 and corresponds with severity of disease. Circulating HA fragments and hyaluronidase, 2 signatures of glycocalyx injury, strongly associate with sequential organ failure assessment scores and with increased inflammatory cytokine levels in patients with COVID-19. Pulmonary microvascular endothelial cells exposed to COVID-19 milieu show dysregulated HA biosynthesis and degradation, leading to production of pathological HA fragments that are released into circulation. Finally, we show that HA fragments present at high levels in COVID-19 patient plasma can directly induce endothelial barrier dysfunction in a ROCK- and CD44-dependent manner, indicating a role for HA in the vascular pathology of COVID-19.

Authors

Kimberly A. Queisser, Rebecca A. Mellema, Elizabeth A. Middleton, Irina Portier, Bhanu Kanth Manne, Frederik Denorme, Ellen J. Beswick, Matthew T. Rondina, Robert A. Campbell, Aaron C. Petrey

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Figure 3

Circulating levels of HA and hyaluronidase activity correlate with clinical and inflammatory signatures of COVID-19.

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Circulating levels of HA and hyaluronidase activity correlate with clini...
(A–D) Correlation analysis severity of sequential organ failure assessment (SOFA) scores with plasma HA concentration and hyaluronidase activity levels in COVID-19 (n = 46) (A and C) and sepsis (n = 23) (B and D) patients. (E) Spearman correlation matrix of plasma HA, hyaluronidase (HA’ase) activity, and cytokines in patients with COVID-19 (n = 46) demonstrated to be statistically significant (*P < 0.05) between healthy controls and patients with COVID-19. Yellow indicates a positive correlation, and purple indicates a negative correlation. Pearson correlation coefficient was used to determine the r value of the correlation between the 2 groups.

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