Distinct Time Courses and Pathogenic Contributions of Alveolar Epithelial and Endothelial Injury in Acute Respiratory Distress Syndrome with COVID-19: Evidence from Circulating Biomarkers

Background:  In severe cases of coronavirus disease (COVID-19), acute respiratory distress syndrome (ARDS) with alveolar tissue injury occurs. However, the time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of COVID-19 ARDS remain unclear. Methods:  We evaluated the levels of a circulating alveolar epithelial injury marker (soluble receptor for advanced glycation end-products: sRAGE) and an endothelial injury marker (angiopoietin-2: ANG-2), along with an alveolar permeability indicator (surfactant protein D: SP-D) in 107 serum samples from nine patients with ARDS and eight without ARDS, all with COVID-19. We compared the initial levels of these markers between ARDS and non-ARDS patients, and analysed the temporal changes of these markers in ARDS patients. Findings:  All the initial levels of sRAGE, ANG-2, and SP-D were significantly higher in the ARDS patients than in the non-ARDS patients. The peak sRAGE level in the ARDS patients was observed at the very early phase of disease progression. However, the peaks of ANG-2 and SPD were observed at a later phase. Moreover, the ANG-2 level was significantly correlated with the arterial oxygenation and the SPD level, but the sRAGE level was not.  Interpretation:  Evaluation of circulating markers confirms that COVID-19 ARDS is characterised by severe alveolar tissue injury. Our data indicate that the endothelial injury, which continues for a longer period than the epithelial injury, seems to be the main contributor to alveolar barrier disruption. Targeting the endothelial injury may, thus, be a promising approach to overcome ARDS with COVID-19. Funding: None Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The study protocol was reviewed and approved by the institutional review board of Yokohama City University Hospital (B200700100).