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: 10337295
• 负责人: BHAGAVATULA MOORTHY
• 金额: $ 20.06万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337295
• 关键词: 2019-nCoV; ACE2; Acids; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adult; 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 diseases; Measures; Mediating; Modeling; Molecular; Multiple Organ Failure; Mus; Names; Oxidative Stress; Oxygen; Pathology; Pathway interactions; Patients; Phase; Population; Pulmonary Inflammation; Receptor Cell; Risk; Role; SARS coronavirus; SARS-CoV-2 exposure; SARS-CoV-2 infection; 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; 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.

项目摘要 严重冠状病毒病（COVID-19）是由一种新型β-冠状病毒引起的，现在被命名为 SARS-CoV-2. COVID-19的特征是未解决的全身性炎症过度相关 患有危及生命的“细胞因子风暴综合征”，导致多器官功能衰竭， 一些病人。最近的研究表明，吸烟和其他环境 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。肺损伤模型 环境化学品（例如，吸烟）包括使用多环芳香剂 碳氢化合物（PAH），特别是苯并[a]芘（BP），存在于香烟烟雾中， 在这些模型中，额外的高氧暴露导致 ARDS样症状加重。目前的数据表明，使用可溶性环氧化物 水解酶抑制剂（sEHI）可以防止与ARDS相关的肺损伤，因为它们可以防止水化 抗炎类二十烷酸[例如，环氧二十碳三烯酸（ESTs）。中央 本申请中提出的假设是BP会加重肺 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治疗这些小鼠将赋予针对肺损伤的保护。 将使用单细胞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。为了验证转基因生物 在感染SARS-CoV-2之前用BP治疗的K18-hACE 2小鼠将更多 比那些在感染前接受模拟治疗的人更容易受到肺损伤。我们还将测试 假设用sEHI TPPU治疗将赋予对肺损伤/ARDS的保护， BP/SARS-COV-2/-暴露小鼠。使用单细胞RNA-seq的基因表达谱将是 以确定特定肺细胞在BP/SARS-CoV-2介导的肺损伤中的作用 以及sEHI对其的保护。2.为了检验BP/SARS-CoV-2暴露治疗 小鼠高氧将导致肺损伤的进一步恶化相比， 如果这些小鼠暴露于sEHI治疗，它们将显示出较小的损伤 在高氧阶段。这些研究将揭示肺结核的分子机制。 SARS-CoV-2/高氧介导的损伤以及环境多环芳烃对其的增强作用。 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， 这是未来使用sEH治疗人类COVID 019的临床试验的一大步。