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EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-322800


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, admitted to Yokohama City University Hospital from January to July 2020. 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. Results: : All the initial levels of sRAGE (median: 2680 pg/mL, IQR:1522–5076 vs. median 701 pg/mL, IQR:344–1148.0, p=0.0152), ANG-2 (median: 699 pg/mL, IQR: 410-2501 vs. median: 231 pg/mL, IQR: 64-584, p=0.0464), and SP-D (median: 17542 pg/mL, IQR: 7423-22979 vs. 1771 pg/mL, IQR: 458-204, p=0.0274) 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 (median: day 1, IQR: day 1–3.5). However, the peaks of ANG-2 (median: day 4, IQR: day 2.5–6) and SPD (median: day 5, IQR: day 3–7.5) were observed at a later phase. Moreover, the ANG-2 level was significantly correlated with the arterial oxygenation (p=0.030) and the SPD level (p=0.002), but the sRAGE level was not. Conclusion: 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.

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.