Am J Respir Cell Mol Biol . Post-exposure Liponucleotide Prophylaxis and Treatment Attenuates ARDS in Influenza-infected Mice

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Am J Respir Cell Mol Biol


. 2021 Feb 19.
doi: 10.1165/rcmb.2020-0465OC. Online ahead of print.
Post-exposure Liponucleotide Prophylaxis and Treatment Attenuates ARDS in Influenza-infected Mice


Lucia E Rosas ¹ , Lauren M Doolittle ² , Lisa M Joseph ¹ , Hasan El-Musa ² , Michael V Novotny ³ , Judy M Hickman-Davis ² , R Duncan Hite ⁴ , Ian C Davis ⁵



Affiliations

• PMID: 33606602
• DOI: 10.1165/rcmb.2020-0465OC

Abstract

There is an urgent need for new drugs for ARDS patients, including those with COVID-19. ARDS in influenza-infected mice is associated with reduced levels of liponucleotides (essential precursors for de novo 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 pfu/mouse of H1N1 influenza A/WSN/33 virus were treated with CDP-choline (100 μg/mouse, i.p.) +/- CDP-diacylglycerol 16:0/16:0 (10 μg/mouse, i.p.) once daily from 1-5 days post-inoculation (to model post-exposure influenza prophylaxis) or as a single dose on day 5 (to model treatment of patients with ongoing influenza-induced ARDS). Daily post-exposure 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 daily administration of CTP and/or choline. Daily co-administration 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 levels of most other lipid classes in ATII cells. Single-dose treatment with both liponucleotides at 5 days post-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.

Keywords: Alveolar type II cell; Influenza; Liponucleotide; Phospholipid; Surfactant.