Ting Christopher, Aspal Mohit, Vaishampayan Neil, Huang Steven K, Riemondy Kent A, Wang Fa, Farver Carol, Zemans Rachel L
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan.
Am J Pathol. 2022 Mar;192(3):454-467. doi: 10.1016/j.ajpath.2021.11.014. Epub 2021 Dec 30.
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.
2019冠状病毒病及其他病因所致的急性呼吸窘迫综合征（ARDS）是由肺泡上皮细胞（AEC）屏障受损导致非心源性肺水肿引起的，进而导致急性呼吸衰竭；恢复需要上皮再生。在小鼠的生理性再生过程中，2型AEC（AEC2）增殖，退出细胞周期，短暂进入过渡状态，然后分化为1型AEC（AEC1）；在人类中，过渡状态的持续存在与肺纤维化有关。在人类ARDS中，过渡细胞是否会出现并在无纤维化的情况下分化为AEC1，以及为什么过渡细胞在生理性再生过程中会分化为AEC1而在纤维化过程中持续存在，目前尚不清楚。我们推测，在ARDS中，过渡细胞向AEC1的不完全但持续的分化且无纤维化，可能是屏障通透性持续存在和急性呼吸衰竭的基础。对ARDS死亡患者的肺组织进行免疫染色发现，有大量无纤维化的过渡细胞。它们通常呈立方形或部分铺展状，有时扁平，偶尔表达AEC1标志物。免疫染色和/或单细胞RNA测序显示，在生理性再生、ARDS和纤维化小鼠模型中的过渡细胞表达细胞周期退出标志物，但仅在纤维化模型中表达特定的衰老标志物。因此，在严重的、致命的早期ARDS中，过渡细胞向AEC1的分化不完全，是屏障通透性持续存在和呼吸衰竭的基础，但该过程在无纤维化的情况下持续进行；过渡细胞的衰老可能与肺纤维化有关。
