Abstract
After millions of deaths, COVID-19 caused by SARS-CoV-2 has often been attributed to acute respiratory distress syndrome (ARDS). While COVID-19 ARDS has an acute clinical course, some patients experience non-resolvable (NR)-COVID-19 with fibroproliferation, inflammation, and vascular dysfunction. Hyaluronan (HA) has been implicated in multiple disease processes including ARDS, COVID-19, and pulmonary hypertension (PH). HA is synthesized by hyaluronidases (HAS) and its cleared by CD44. We hypothesized that HA levels were elevated in COVID-19 ARDS and persisted in NR-COVID-19.We utilized two distinct models of infection: exposure of mouse-adapted SARS-CoV-2 virus strain (MA10) and human angiotensin converting enzyme 2 (<i>hACE2</i>) transgenic mice exposed to the Washington SARS-CoV-2 strain (WA1). Lung tissue samples from COVID-19 ARDS patients, NR-COVID-19, and discarded donor lungs for transplantation were utilized for immunohistochemistry (IHC), RT-qPCR, and Western blots. Our experimental models of infection revealed increased <i>mHas1</i> and <i>mHas2</i> expression in MA10 infected mice. This was consistent with increased perivascular and parenchymal signals for HA following MA10 infection which was also seen in the <i>hACE2</i> model. Human tissues revealed an increase in perivascular HA levels in COVID-19 ARDS and in NR COVID-19. Intriguingly, no significant differences in <i>hHAS1-2</i> expression were detected, however transcript and protein levels of CD44 were reduced in NR-COVID-19, hinting at disrupted HA clearance. Taken together our data demonstrates that SARS-CoV-2 infection leads to increased HA levels that persist in NR-COVID-19 and may contribute to lung fibrosis and vascular injury.
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