Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.

中文翻译：

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致命 COVID-19 中的肺上皮和内皮损伤、组织修复丧失、纤维蛋白溶解抑制和细胞衰老

由严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 引起的 2019 年冠状病毒病 (COVID-19) 的特征是呼吸窘迫、多器官功能障碍，在某些情况下甚至死亡。COVID-19 呼吸窘迫的病理机制以及与加重风险因素的相互作用尚未完全确定。使用 SARS-CoV-2 RNA 的深度测序、多重测序评估了 18 名致命 COVID-19 患者的肺尸检样本，症状发作至死亡时间为 3 至 47 天，其中 6 例患者的生前血浆样本进行了评估血浆蛋白测量，以及肺基因表达和成像分析。该病例系列中突出的组织病理学特征包括进行性弥漫性肺泡损伤，伴有过度血栓形成和迟发性肺组织和血管重塑。肺泡-毛细血管屏障急性损伤的特征是表面活性蛋白表达丧失，肺泡上皮细胞、内皮细胞、呼吸道上皮基底细胞和组织修复过程受损。其他主要发现包括血浆和肺纤溶酶原激活物抑制剂-1浓度增加导致凝块纤维蛋白溶解受损，以及肺上皮细胞和内皮细胞中细胞衰老标志物（包括p21和sirtuin-1）的调节。总之，这些发现进一步确定了肺部对 SARS-CoV-2 感染反应的分子病理学特征，并为可能适合治疗干预的信号通路提供了重要见解。