First Department of Critical Care Medicine & Pulmonary Services, School of Medicine, National & Kapodistrian University of Athens, "Evangelismos" Hospital, 10676 Athens, Greece.
Center for Pulmonary Vascular Disease, Division of Cardiology, Azrieli Heart Center and Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC H3T 1E2, Canada.
Int J Mol Sci. 2024 Oct 2;25(19):10640. doi: 10.3390/ijms251910640.
Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients ( < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.
内皮素-1（ET-1）是一种由内皮细胞产生的强效血管收缩剂，主要在肺血管中从循环血液中清除。在健康的肺循环中，ET-1 的局部产生速度小于其清除速度。在本研究中，我们旨在研究 COVID-19 引起的急性呼吸窘迫综合征（ARDS）患者的肺循环对 ET-1 的异常处理是否与不良临床结局相关。为此，我们在入住 ICU 后的第 1 天和第 3 天，对机械通气的 COVID-19 合并 ARDS 患者（COVID-19 ARDS，N=18）进行了中心静脉和系统动脉 ET-1 血浆水平的同步测量。我们还在两组不同的 SARS-CoV-2 阴性机械通气危重症患者中测量了中心静脉和系统动脉 ET-1 血浆水平，这些患者在年龄、性别和疾病严重程度方面相匹配，一组患有 ARDS（非 COVID-19 ARDS，N=14），另一组无 ARDS（非 COVID-19 非 ARDS，N=20）。入住 ICU 时，COVID-19 引起的 ARDS 患者的系统动脉和中心静脉 ET-1 水平均高于非 COVID-19 ARDS 和非 COVID-19 非 ARDS 患者（<0.05），但系统动脉：中心静脉（A：V）ET-1 比值正常[0.63（0.49-1.02）]，提示这些患者的肺 ET-1 清除功能正常。另一方面，非 COVID-19 ARDS 患者的 ET-1 处理异常[A：V ET-1 比值 1.06（0.93-1.20）]，而非 COVID-19 非 ARDS 组的 ET-1 处理正常[A：V ET-1 比值 0.79（0.52-1.11）]。在第 3 天，三组的 A：V 比值均<1。当根据 28 天 ICU 死亡率将 COVID-19 ARDS 患者进行分组时，虽然他们的系统动脉和中心静脉水平没有差异，但非幸存者的 ICU 入院时的 A：V ET-1 比值明显更高[0.95（0.78-1.34）]，幸存者[0.57（0.48-0.92）]，=0.027）。我们的结果强调了 ET-1 作为 COVID-19 危重症患者的生物标志物和治疗靶点的潜在重要性。非幸存者的 A：V ET-1 比值升高表明，肺 ET-1 处理的早期破坏可能是预后不良的关键标志物。
