ARDS due to COVID-19 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; clinical recovery requires epithelial regeneration. During physiologic regeneration in mice, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; persistence of the transitional state is associated with pulmonary fibrosis in humans. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiologic regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and fatal acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells in organized monolayers on alveolar septa without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or interrogation of scRNAseq datasets revealed that transitional cells in mouse models of physiologic regeneration, ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. Thus, in severe, fatal early ARDS, AEC1 differentiation from transitional cells is incomplete, underlying persistent barrier permeability and respiratory failure, but ongoing without fibrosis; senescence of transitional cells may be associated with pulmonary fibrosis.

中文翻译：

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致命的 COVID-19 和非 COVID-19 急性呼吸窘迫综合征与无纤维化的过渡状态的不完全肺泡 1 型上皮细胞分化有关

由 COVID-19 和其他病因引起的 ARDS 是由于肺泡上皮细胞 (AEC) 屏障受损导致非心源性肺水肿，从而导致急性呼吸衰竭；临床恢复需要上皮再生。在小鼠的生理再生过程中，AEC2s 增殖，退出细胞周期，并在分化为 AEC1s 之前短暂地呈现过渡状态；过渡状态的持续存在与人类肺纤维化有关。尚不清楚在人类 ARDS 中，移行细胞是否出现并分化为无纤维化的 AEC1，以及为什么在生理再生过程中移行细胞分化为 AEC1 但纤维化持续存在。我们假设不完全但持续的 AEC1 从无纤维化的移行细胞分化可能是 ARDS 持续屏障通透性和致命性急性呼吸衰竭的基础。死后 ARDS 肺的免疫染色显示肺泡隔上的有组织的单层中有大量的移行细胞，没有纤维化。它们通常呈立方体或部分散开，有时是扁平的，偶尔表达 AEC1 标记。scRNAseq 数据集的免疫染色和/或询问显示，生理再生、ARDS 和纤维化小鼠模型中的过渡细胞表达细胞周期退出的标志物，但仅在纤维化中表达特定的衰老标志物。因此，在严重、致命的早期 ARDS 中，AEC1 从移行细胞的分化是不完全的，潜在的持续性屏障通透性和呼吸衰竭，但持续无纤维化；移行细胞的衰老可能与肺纤维化有关。