Department of Veterinary Biosciences and.
Department of Immunology and Inflammation, Cleveland Clinic, Cleveland, Ohio; and.
Am J Respir Cell Mol Biol. 2021 Jun;64(6):677-686. doi: 10.1165/rcmb.2020-0465OC.
There is an urgent need for new drugs for patients with acute respiratory distress syndrome (ARDS), including those with coronavirus disease (COVID-19). ARDS in influenza-infected mice is associated with reduced concentrations of liponucleotides (essential precursors for phospholipid synthesis) in alveolar type II (ATII) epithelial cells. Because surfactant phospholipid synthesis is a primary function of ATII cells, we hypothesized that disrupting this process could contribute significantly to the pathogenesis of influenza-induced ARDS. The goal of this study was to determine whether parenteral liponucleotide supplementation can attenuate ARDS. C57BL/6 mice inoculated intranasally with 10,000 plaque-forming units/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP (cytidine 5'-diphospho)-choline (100 μg/mouse i.p.) ± CDP -diacylglycerol 16:0/16:0 (10 μg/mouse i.p.) once daily from 1 to 5 days after inoculation (to model postexposure influenza prophylaxis) or as a single dose on Day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily postexposure prophylaxis with CDP-choline attenuated influenza-induced hypoxemia, pulmonary edema, alterations in lung mechanics, impairment of alveolar fluid clearance, and pulmonary inflammation without altering viral replication. These effects were not recapitulated by the daily administration of CTP (cytidine triphosphate) and/or choline. Daily coadministration of CDP-diacylglycerol significantly enhanced the beneficial effects of CDP-choline and also modified the ATII cell lipidome, reversing the infection-induced decrease in phosphatidylcholine and increasing concentrations of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days after inoculation also attenuated hypoxemia, altered lung mechanics, and inflammation. Overall, our data show that liponucleotides act rapidly to reduce disease severity in mice with severe influenza-induced ARDS.
急性呼吸窘迫综合征（ARDS）患者，包括新型冠状病毒病（COVID-19）患者急需新药。流感感染的小鼠中的 ARDS 与肺泡 II 型（ATII）上皮细胞中脂核苷酸（磷脂合成的必需前体）浓度降低有关。由于表面活性剂磷脂合成是 ATII 细胞的主要功能，我们假设破坏该过程可能会对流感引起的 ARDS 的发病机制产生重大影响。本研究的目的是确定是否可以通过补充脂核苷酸来减轻 ARDS。用 10000 个噬菌斑形成单位/小鼠的 H1N1 流感 A/WSN/33 病毒鼻内接种 C57BL/6 小鼠，在接种后 1 至 5 天内，每天给予 CDP（胞苷 5'-二磷酸）-胆碱（100μg/只腹腔内）和 CDP-二酰基甘油 16:0/16:0（10μg/只腹腔内）一次，以模拟暴露后流感预防，或在第 5 天给予单剂量，以模拟治疗正在发生的流感引起的 ARDS。每日暴露后预防用 CDP-胆碱可减轻流感引起的低氧血症、肺水肿、肺力学改变、肺泡液体清除受损和肺部炎症，而不改变病毒复制。用 CTP（胞苷三磷酸）和/或胆碱每日给药不能再现这些作用。每日联合给予 CDP-二酰基甘油可显著增强 CDP-胆碱的有益作用，还可改变 ATII 细胞脂质组，逆转感染引起的磷脂酰胆碱减少，并增加 ATII 细胞中大多数其他脂质类别的浓度。在接种后 5 天给予两种脂核苷酸的单剂量治疗也可减轻低氧血症、改变肺力学和炎症。总的来说，我们的数据表明，脂核苷酸可迅速作用于感染严重的流感的 ARDS 小鼠，减轻疾病严重程度。
