Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis.
Fatal COVID-19 and non-COVID-19 Acute Respiratory Distress Syndrome is Associated with Incomplete Alveolar Type 1 Epithelial Cell Differentiation from the Transitional State Without Fibrosis.
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致命的 COVID-19 和非 COVID-19 急性呼吸窘迫综合征与肺泡 1 型上皮细胞从无纤维化过渡状态的不完全分化有关。
DOI：
10.1101/2021.01.12.426404
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Zemans,RachelL
中科院分区：
文献类型：
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作者：
Ting,Christopher;Aspal,Mohit;Vaishampayan,Neil;Huang,StevenK;Riemondy,KentA;Wang,Fa;Farver,Carol;Zemans,RachelL
由2019冠状病毒病和其他病因引起的急性呼吸窘迫综合征（ARDS）是由肺泡上皮细胞（AEC）屏障损伤引起的，导致非心源性肺水肿，引起急性呼吸衰竭;恢复需要上皮再生。在小鼠的生理再生过程中，2型AEC（AEC 2）增殖，退出细胞周期，短暂地呈现过渡状态，然后分化为1型AEC（AEC 1）;在人类中，过渡状态的持续与肺纤维化有关。目前尚不清楚在人类ARDS中是否有移行细胞出现并分化为AEC 1而不发生纤维化，以及为什么移行细胞在生理再生过程中分化为AEC 1，但在纤维化中持续存在。我们假设，不完全但正在进行的AEC 1分化的过渡细胞无纤维化可能是基础的持续屏障通透性和急性呼吸衰竭的ARDS。免疫组化染色显示，死后ARDS肺组织中有大量的移行细胞，无纤维化。它们通常呈立方形或部分散布，有时是扁平的，偶尔表达AEC 1标记。免疫染色和/或单细胞RNA测序显示，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异性衰老标志物。因此，在严重的、致命的早期ARDS中，从移行细胞分化的AEC 1是不完全的，是持续屏障通透性和呼吸衰竭的基础，但在没有纤维化的情况下持续进行;移行细胞的衰老可能与肺纤维化相关。
Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 and other etiologies results from injury to the alveolar epithelial cell (AEC) barrier resulting in noncardiogenic pulmonary edema, which causes acute respiratory failure; recovery requires epithelial regeneration. During physiological regeneration in mice, type 2 AECs (AEC2s) proliferate, exit the cell cycle, transiently assume a transitional state, then differentiate into type 1 AECs (AEC1s); in humans, persistence of the transitional state is associated with pulmonary fibrosis. It is unknown whether transitional cells emerge and differentiate into AEC1s without fibrosis in human ARDS and why transitional cells differentiate into AEC1s during physiological regeneration but persist in fibrosis. We hypothesized that incomplete but ongoing AEC1 differentiation from transitional cells without fibrosis may underlie persistent barrier permeability and acute respiratory failure in ARDS. Immunostaining of postmortem ARDS lungs revealed abundant transitional cells without fibrosis. They were typically cuboidal or partially spread, sometimes flat, and occasionally expressed AEC1 markers. Immunostaining and/or single-cell RNA sequencing revealed that transitional cells in mouse models of physiological 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.