Abstract
COVID-19 ARDS is associated with prolonged ventilator dependence and high mortality, but the underlying mechanisms are unknown. Critical to the pathogenesis of ARDS is injury to the alveolar epithelial cell (AEC) barrier; clinical recovery requires epithelial regeneration. We previously identified a KRT8 hi transitional state that regenerating AEC2s adopt during differentiation into AEC1s, the persistence of which may be pathogenic in pulmonary fibrosis. Here, we hypothesize that ineffectual differentiation of transitional cells into AEC1s without fibrosis may perpetuate barrier permeability and poor clinical outcomes in COVID-19 ARDS. To test this hypothesis, we examined postmortem lung tissue of COVID-19 ARDS patients. We observed extensive AEC1 injury, rare mature AEC2s, and abundant transitional cells. Transitional cells were cuboidal, partially spread or, rarely, flat but did not express AEC1 markers. They formed monolayers on alveolar septa denuded of AEC1s but structurally normal without fibrosis. We conclude that ineffectual AEC1 differentiation from transitional AECs may perpetuate barrier permeability and respiratory failure in COVID-19 ARDS. In contrast to fibrosis, transitional AECs may retain the capacity for physiologic AEC1 regeneration with restoration of normal alveolar architecture and function. Novel therapies to promote AEC1 differentiation from transitional cells may accelerate barrier restitution and clinical recovery in ARDS.
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