Early Alveolar Epithelial Cell Necrosis is a Potential Driver of ARDS with COVID-19 (preprint)

ABSTRACT

Rationale Acute respiratory distress syndrome (ARDS) with COVID-19 is aggravated by hyperinflammatory responses even after passing the peak of viral load. However, the underlying mechanisms remain unclear. Objectives: Here, we assess whether alveolar epithelial cell necrosis and subsequent releases of damage associated molecular patterns (DAMPs) at an early disease stage aggravate ARDS with COVID-19 Methods: In patients with COVID-19 with and without ARDS and healthy adults, serum levels of the following were quantified an epithelial total cell death marker, cytokeratin18-M65; an epithelial apoptosis marker, CK18-M30; HMGB-1; and alveolar epithelial and endothelial injury markers, sRAGE, angiopoietin-2, and surfactant protein-D. Molecular mechanisms of alveolar epithelial cell death and effects of HMGB-1 neutralization on alveolar tissue injury were assessed using a mouse model of COVID-19-induced ARDS. Measurements and main results: The levels of CK18-M65, CK18-M30, and alveolar tissue injury markers were elevated in early stages of ARDS. The median M30/M65 ratio, an epithelial apoptosis indicator, was 31.50% in patients with ARDS, a value significantly lower than that of non-ARDS patients or healthy subjects. Serum levels of HMGB-1, one of DAMPs released from necrotic cells, were also significantly elevated in ARDS versus non-ARDS patients. In a COVID-19-induced ARDS mouse model, 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. Conclusions: Necrosis, 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.