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Preprint in English | medRxiv | ID: ppmedrxiv-22269723


BackgroundAcute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after the peak of viral load has passed; however, its underlying mechanisms remain unclear. Alveolar epithelial injury is reported to be a very early event in ARDS with COVID-19. Herein, we assessed whether necrosis of alveolar epithelial cells and subsequent releases of damage associated molecular patterns (DAMPs) at an early disease stage aggravates ARDS with COVID-19 MethodsWe analyzed the levels of cytokeratin18-M65, an epithelial total cell death marker; CK18-M30, an epithelial apoptosis-specific marker; and HMGB-1, one of the DAMPs released from necrotic cells, in patients with COVID-19 with and without ARDS and healthy adults, in addition to the circulating alveolar epithelial and endothelial injury markers, namely sRAGE, angiopoietin-2, and surfactant protein-D. Molecular mechanisms of alveolar epithelial cell death and effects of neutralization on alveolar tissue injury were assessed using a mouse model mimicking COVID-19-induced ARDS. ResultsCOVID-19-induced ARDS was characterized by the elevation of sRAGE, an epithelial injury marker, at a very early disease stage. Although both serum levels of CK18-M65 and CK18-M30 were elevated in COVID-19-induced ARDS, the median CK18-M30/M65 ratio, an indicator of the fraction of apoptosis among total epithelial cell death, was 31.5% in serum from COVID-19 patients with ARDS, a value significantly lower than that of non-ARDS patients or healthy subjects. Moreover, the median M30/M65 ratio in bronchoalveolar lavage fluid (BALF) in COVID-19-induced ARDS was 27.8%, indicating that alveolar epithelial cell death is mainly caused by necrosis. Serum levels of HMGB-1 were also significantly elevated in ARDS versus non-ARDS patients. In a mouse model mimicking COVID-19-induced ARDS, the ratio of CK18-M30 to a total epithelial cell death marker in BALF was also lower than that in control subjects. Moreover, the alveolar epithelial cell necrosis involved two forms of programmed necrosis: necroptosis and pyroptosis. Finally, neutralization of HMGB-1 attenuated alveolar tissue injury in the mouse model. ConclusionsNecrosis, including necroptosis and pyroptosis, seems to be the primary form of alveolar epithelial cell death and subsequent release of DAMPs is a potential driver of COVID-19-induced ARDS.

Preprint in English | medRxiv | ID: ppmedrxiv-21252061


Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that leads to severe respiratory failure (RF). It is known that host exposure to viral infection triggers an iron-lowering response to mitigate pathogenic load and tissue damage. However, the association between host iron-lowering response and COVID-19 severity is not clear. This two-center observational study of 136 adult hospitalized COVID-19 patients analyzed the association between disease severity and initial serum iron, total iron-binding capacity (TIBC), and transferrin saturation (TSAT) levels. Serum iron levels were significantly lower in patients with mild RF than in the non-RF group; however, there were no significant differences in iron levels between the non-RF and severe RF groups, depicting a U-shaped association between serum iron levels and disease severity. TIBC levels decreased significantly with increasing severity; consequently, TSAT was significantly higher in patients with severe RF than in other patients. Multivariate analysis including only patients with RF adjusted for age and sex demonstrated that higher serum iron and TSAT levels were independently associated with the development of severe RF, indicating that inadequate response to lower serum iron might be an exacerbating factor for COVID-19.

Preprint in English | medRxiv | ID: ppmedrxiv-21249528


The time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of acute respiratory distress syndrome (ARDS) with coronavirus disease (COVID-19) remain unclear. Here, we evaluated the characteristics of circulating markers of alveolar epithelial and endothelial injury in serum samples from eleven ARDS patients and ten non-ARDS patients, all with COVID-19. Our results indicates that the alveolar epithelial injury at the very early disease stage and the endothelial injury which continues to exacerbate during the later disease stage seem to be the hallmarks of ARDS with COVID-19.