Mechanisms of exacerbation of COVID-19 pathogenesis in mice expressing human ACE2 by polycyclic aromatic hydrocarbons (PAHs), and its protection by inhibition of soluble epoxide hydrolase (sEH)

多环芳烃 (PAH) 表达人 ACE2 的小鼠中 COVID-19 发病机制恶化，以及通过抑制可溶性环氧化物水解酶 (sEH) 对其进行保护

• 批准号: 10156460
• 负责人: BHAGAVATULA MOORTHY
• 金额: $ 24.07万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156460
• 关键词: 2019-nCoV; ACE2; Acids; Acute Lung Injury; Adult; Adult Respiratory Distress Syndrome; Age; Air; Anti-Inflammatory Agents; Aromatic Polycyclic Hydrocarbons; Attenuated; Autopsy; Benzo(a)pyrene; Body Weight decreased; CCL2 gene; COVID-19; COVID-19 pathogenesis; COVID-19 treatment; CYP11A1 gene; Cell Separation; Cells; Chemosensitization; Clinical Trials; Data; Diesel Exhaust; Disease Outbreaks; Eicosanoids; Eicosatrienoic Acid; Environmental Pollutants; Enzyme-Linked Immunosorbent Assay; Epoxide hydrolase; Experimental Designs; Exposure to; Female; Functional disorder; Future; Gene Expression Profiling; Genes; Histology; Human; Hydration status; Hydroxyeicosatetraenoic Acids; Hyperoxia; IL8 gene; Immune; Individual; Infection; Inflammation; Inflammatory; Injury; Interleukin-1; Interleukin-1 beta; Interleukin-6; K-18 conjugate; Life; Lung; Lung Inflammation; Lung diseases; Measures; Mediating; Modeling; Molecular; Multiple Organ Failure; Mus; Names; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Patients; Phase; Population; Receptor Cell; Risk; Role; SARS coronavirus; Severe Acute Respiratory Syndrome; Smoker; Stromal Cells; Symptoms; Syndrome; TNF gene; Testing; Transgenic Mice; Transgenic Organisms; Urea; Viral; Virus; Virus Diseases; Western Blotting; Wild Type Mouse; betacoronavirus; cigarette smoke; cigarette smoking; cytokine; cytokine release syndrome; drinking water; environmental chemical; experimental study; inhibitor/antagonist; lung injury; macrophage; male; molecular phenotype; neutrophil; non-smoker; novel; pollutant; prevent; receptor; recruit; respiratory; severe COVID-19; single-cell RNA sequencing

Project Summary Severe coronavirus disease (COVID-19) is caused by a novel Beta-coronavirus, now named SARS-CoV-2. COVID-19 is characterized by unresolved systemic hyperinflammation associated with a life-threatening “cytokine storm syndrome”, leading to multi-organ failure dysfunction in some patients. Recent studies have shown that cigarette smoking and other environmental pollutants exacerbate respiratory illness in COVID-19 infected individuals, but the mechanisms responsible for the potentiation of lung disease is not known. Models of lung damage due to environmental chemicals (e.g., cigarette smoking) include the use of polycyclic aromatic hydrocarbons (PAH), especially benzo[a]pyrene (BP), which are present in cigarette smoke, charbroiled steaks, diesel exhausts etc. In these models, additional hyperoxic exposure leads to exacerbation of ARDS-like symptoms. Current data suggests that using a soluble epoxide hydrolase inhibitor (sEHI) protects against lung injury related to ARDS, as they prevent hydration of anti-inflammatory eicosanoids [e.g., epoxy eicasotrienoic acids (EETs). The central hypothesis proposed in this application is that BP would exacerbate lung injury/inflammation during SARS-CoV-2 infection, and subsequent hyperoxia exposure, and that treatment of these mice with sEHI would confer protection against lung injury. Gene expression profiling using single cell RNA-Seq and FACS approaches will be done to determine the molecular pathways of lung injury and inflammation mediated by BP/SARS-CoV- 2/hyperoxia. We propose the following specific aims: 1. To test the hypothesis that transgenic K18-hACE2 mice that are treated with BP prior to infection with SARS-CoV-2 will be more susceptible to lung injury than those that are mock treated prior to infection. We will also test the hypothesis that treatment with the sEHI TPPU will confer protection against lung injury/ARDS in the BP/SARS-COV-2/-exposed mice. Gene expression profiling using single cell RNA-seq will be performed to determine the role of specific lung cells in lung injury mediated by BP/SARS-CoV-2 and its protection by sEHI. 2. To test the hypothesis that exposure of BP/SARS-CoV-2 treated mice to hyperoxia will lead to further exacerbation of lung injury compared to those maintained in room air, and that these mice will display lesser injury if they were exposed to sEHI treatment during the hyperoxia phase. The proposed studies will unravel molecular mechanisms of lung injury mediated by SARS-CoV-2/hyperoxia, and its potentiation by environmental PAHs. Furthermore, if our sEHI studies aimed to protect mice against COVID-19 pathogenesis, it will be a big step towards future clinical trials on the use of sEHs for treatment of COVID019 in humans.

项目概要 严重冠状病毒病（COVID-19）是由一种新型 Beta 冠状病毒引起的，现已命名为 SARS-CoV-2 的特点是尚未解决的全身性过度炎症。 患有危及生命的“细胞因子风暴综合征”，导致多器官衰竭功能障碍 最近的研究表明，一些患者吸烟和其他环境有关。 污染物加剧了 COVID-19 感染者的呼吸道疾病，但其机制 导致肺部疾病加重的原因尚不清楚。 环境化学品（例如吸烟）包括使用多环芳香族化合物 碳氢化合物（PAH），尤其是香烟烟雾中存在的苯并[a]芘（BP）， 炭烤牛排、柴油机尾气等。在这些模型中，额外的高氧暴露会导致 目前的数据表明，使用可溶性环氧化物会加剧ARDS样症状。 水解酶抑制剂 (sEHI) 可防止与 ARDS 相关的肺损伤，因为它们可以防止水合作用 抗炎类二十烷酸 [例如环氧二十三烯酸 (EET)]。 本申请中提出的假设是血压会使肺部恶化 SARS-CoV-2 感染期间的损伤/炎症以及随后的高氧暴露， 并且用 sEHI 治疗这些小鼠可以预防肺损伤。 使用单细胞 RNA-Seq 和 FACS 方法进行基因表达谱分析 确定 BP/SARS-CoV 介导的肺损伤和炎症的分子途径 2/高氧 我们提出以下具体目标： 1. 检验转基因假设。 在感染 SARS-CoV-2 之前接受 BP 治疗的 K18-hACE2 小鼠的死亡率会更高 比感染前接受模拟治疗的患者更容易受到肺损伤。我们还将测试 假设使用 SEHI TPPU 治疗可以预防肺损伤/ARDS 使用单细胞 RNA-seq 对 BP/SARS-COV-2/暴露小鼠进行基因表达谱分析。 旨在确定特定肺细胞在 BP/SARS-CoV-2 介导的肺损伤中的作用 2. 检验接触 BP/SARS-CoV-2 可以治疗的假设。 与维持在高氧环境中的小鼠相比，高氧小鼠将导致肺损伤进一步恶化。 室内空气，并且如果这些小鼠接受 SEHI 治疗，它们的损伤会更轻 拟议的研究将揭示肺的分子机制。 SARS-CoV-2/高氧介导的损伤及其因环境多环芳烃而增强。 此外，如果我们的 sEHI 研究旨在保护小鼠免受 COVID-19 发病机制的影响，那么它将是 朝着未来使用 sEH 治疗人类 COVID019 的临床试验迈出了一大步。