Harnessing the power of extracellular matrix to treat COVID-19 ARDS

National Institute Of Environmental Health Sciences

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Abstract

COVID-19 is a potentially life-threatening infection leading to respiratory failure through the development of Acute Lung Injury and its more severe form Adult Respiratory Distress Syndrome (ARDS). Although many studies are underway to determine therapeutic approaches to treating COVID-19 ARDS, no breakthroughs have been achieved to date. ARDS leads to significant inflammation and matrix accumulation in the lung, and extracellular matrix is a known modulator of inflammation. Hyaluronan (HA) is a glycosaminoglycan sugar, abundant component of the lung extracellular matrix, and is a powerful modulator of lung injury, inflammation and repair. Recent reports suggest that HA may be a crucial mediator of the COVID-19 response. In particular, HMW-HA has both antiviral, anti-inflammatory and pro-lung repair properties. We have shown that HMW-HA ameliorates lung injury after a number of infectious and toxic exposures. The HA-binding protein inter--inhibitor (II) is a powerful protease inhibitor which ameliorates epithelial and endothelial injury in the lung. We therefore hypothesized that HMW-HA and II are effective treatments of COVID-19-associated ARDS through antiviral and pro-homeostatic actions on lung epithelia and endothelia. We have demonstrated that hyaluronan (HA) and inter-alpha-inhibitor (IaI) can inhibit SARS-CoV-2 entry into cells in several models. We have also demonstrated that HA can ameliorate inflammation after infection in a mouse model. We have completed a clinical trial showing benefit of inhaled HA in patients with severe COVID-19. We have applied for a patent based on these findings and we are in the process of submitting a paper with our results. Importantly, we were able to show that the mechanism of action applies not only to SARS-CoV2 but also other viral infections (e.g. influenza) thus making our findings broadly applicable to endemic and pandemic infections