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

新冠肺炎是一种潜在威胁生命的感染，通过急性肺损伤及其更严重的形式成人呼吸窘迫综合征的发展而导致呼吸衰竭。尽管许多研究正在进行中，以确定治疗新冠肺炎急性呼吸窘迫综合征的治疗方法，但到目前为止还没有取得突破。ARDS导致肺部大量炎症和基质堆积，而细胞外基质是已知的炎症调节剂。透明质酸(HA)是一种糖胺多聚糖，是肺细胞外基质的丰富组成部分，是肺损伤、炎症和修复的强大调节剂。最近的报道表明，HA可能是新冠肺炎反应的关键调节因子。特别是，HMW-HA具有抗病毒、抗炎和促进肺修复的特性。我们已经证明，HMW-HA可以改善多次感染和中毒暴露后的肺损伤。透明质酸结合蛋白中间抑制物(II)是一种有效的蛋白水解酶抑制物，可改善肺上皮和内皮损伤。因此，我们假设HMW-HA和II是通过对肺上皮细胞和内皮细胞的抗病毒和促进内环境平衡作用来有效治疗新冠肺炎相关的ARDS。 我们已经在几个模型中证明了透明质酸(HA)和间α-抑制物(IAI)可以抑制SARS-CoV-2进入细胞。我们还在小鼠模型中证明了HA可以减轻感染后的炎症。我们已经完成了一项临床试验，显示吸入HA对严重新冠肺炎患者的疗效。我们已经根据这些发现申请了一项专利，我们正在提交一篇带有我们的结果的论文。重要的是，我们能够证明作用机制不仅适用于SARS-CoV2，也适用于其他病毒感染(如流感)，从而使我们的发现广泛适用于地方性和大流行感染

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