The role of hyaluronan synthesis and degradation in the critical respiratory illness COVID-19

Abstract

Hyaluronan (HA), a massive extracellular matrix (ECM) component, has a central regulatory role in inflammation. In fact, HA matrices (mass length and distribution) are increasingly considered as a barometer of inflammation. Moreover, inflamed airways are remarkably rich with hyaluronan matrices and are been associated with various inflammatory diseases including cystic fibrosis, influenza, sepsis, and more recently COVID-19. COVID-19 is a worldwide pandemic caused by a novel coronavirus called SARS-CoV-2. People infected with the virus reported a wide range of disease manifestations, ranging from asymptomatic to severe illness. Critically ill COVID-19 patient cases are frequently complicated by development of acute respiratory distress syndrome (ARDS) which typically leads to poor outcomes with high mortality rate. In general, ARDS is characterized by poor oxygenation accompanied with severe lung inflammation and damage, and has been suggested to be linked to an accumulate of HA within the airways. Here, we provide a succinct overview of known inflammatory mechanisms regulated by HA in general, and those both observed and postulated in critically ill patients with COVID-19.

Hyaluronan in the pathogenesis of acute and post-acute COVID-19 infection

“…The amount and size of HA polymers are regulated both at the level of HA synthesis and HA catabolism. HA is synthesized by three membrane-bound synthase enzymes (HAS1, HAS2, HAS3), found on the inner surface of the plasma membrane, which extrude HA as a polymer of repeating disaccharide units of N-acetylglucosamine and glucuronic acid [50] . The HA synthases generate HA polymers of distinct lengths [51] in response to inflammatory cytokines (i.e.…”

“…Severe cases of COVID-19 can manifest as ARDS [ 104 , 105 ], a respiratory syndrome characterized by widespread pulmonary inflammation, airway edema, and poor oxygenation [50] which often necessitates prolonged, challenging mechanical ventilation. Many computed tomographic images of patients with severe COVID-19 disease revealed “ground glass opacities”, often associated with areas of airway edema, in the patient's lungs.…”

Functional organization of extracellular hyaluronan, CD44, and RHAMM

“…Purified HMW HA is anti‐inflammatory, nonantigenic, linked to cancer resistance and has numerous medical applications 114–118 . However, synthesis and buildup of excess HA can be associated with poor prognosis in many cancers, 111,119 and impaired lung function in COVID‐19 patients 120,121 . However, LMW‐HA and HA oligosaccharides that are present in diseases are generally not detected in heathy tissues.…”

“…[114][115][116][117][118] However, synthesis and buildup of excess HA can be associated with poor prognosis in many cancers, 111,119 and impaired lung function in COVID-19 patients. 120,121 However, LMW-HA and HA oligosaccharides that are present in diseases are generally not detected in heathy tissues.…”

Pulmonary function and survival one year after dupilumab treatment of acute moderate to severe COVID-19: A follow up study from a Phase IIa trial

“…RNA-seq analysis of whole lung tissue taken from infected mice who underwent IL-13 neutralization revealed the most downregulated gene to be Has1 5 . This gene encodes a synthase responsible for the synthesis of hyaluronan (HA), a major polysaccharide component of the extracellular matrix that has been implicated in viral mediated inflammatory pulmonary diseases, including acute COVID-19 9,10 . This was mechanistically further supported by an increase in HA deposition in human and mouse lung with SARS CoV-2 infection 5 .…”