Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.
Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.
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DOI：
10.1097/cce.0000000000000827
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发表时间：
2023-01
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血管功能障碍和毛细血管渗漏在重症新冠肺炎患者中很常见，但对参与新冠肺炎发病机制的内皮通路的识别一直受到限制。血管生成素样蛋白4(Angiopoietin-like 4，ANGPTL4)是一种在低氧和低营养条件下分泌的蛋白质，具有多种生物学效应，包括血管损伤和毛细血管渗漏。目的：探讨血管生成素受体4在新冠肺炎相关预后中的作用。从2020年4月到2021年5月，225名新冠肺炎重症监护室患者参加了一项前瞻性的多中心队列研究，研究对象来自华盛顿大学、南加州大学和纽约大学三个不同的医学中心。分别于ICU入院后第1、7、14天测定血浆ANGPTL4水平。我们使用先前发表的组织蛋白质组数据和从新冠肺炎患者收集的标本中的肺单个核糖核酸(SNRNA)测序数据来确定产生ANGPTL4的组织和细胞。较高的血浆血管紧张素原受体4浓度与较差的住院死亡率显著相关(调整后的优势比每对数增加，1.53；95%可信区间，1.17-2.00；p=0.002)。较高的ANGPTL4浓度也与静脉血栓栓塞症和急性呼吸窘迫综合征的比例较高有关。随后死亡的患者在住院前2周的纵向血管紧张素Ⅱ受体4浓度与存活患者相比有显著差异(p=8.1ANGPTL4× × 10-5)。蛋白质组学分析表明，与新冠肺炎其他器官相比，肺组织中血管生成素PTL4的表达丰富。新冠肺炎肺组织中ANGPTL4单核基因在肺泡2型上皮细胞和肺成纤维细胞中的表达均显著高于对照组。NGPTL4表达于肺上皮细胞和成纤维细胞，与新冠肺炎危重病患者的临床预后有关。
Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. To assess the role of ANGPTL4 in COVID-19–related outcomes. Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2 increase, 1.53; 95% CI, 1.17–2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10–5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.