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 严重的冠状病毒病（COVID-19）是由新型β-核纳病毒（如今）引起的 SARS-COV-2。 威胁生命的“细胞因子风暴综合征”，导致多器官故障功能障碍 一些患者。 污染物加剧了COVID-19的感染个体中的呼吸道疾病，但这些机制 负责肺部疾病的增强尚不清楚。 环境化学品（例如，吸烟）包括使用芳香芳香族 碳氢化合物（PAH），尤其是在香烟中存在的苯并[a] pyrene（bp）， charbroiled牛排，柴油排气等 ARDS样症状的加剧表明使用可溶性环氧 水解酶抑制剂（SEHI）可预防与ARDS有关的肺损伤 抗感染的类花生素[ 该应用中所提供的假设是BP WOOLD加剧肺 SARS-COV-2感染期间的损伤/炎症，随后的高氧暴露， 用SEHI对这些处理的治疗将赋予对龙舌兰的保护。 使用单细胞RNA-seq和FACS方法进行基因表达分析将进行 确定BP/SARS-COV介导的肺损伤和炎症的分子途径 2/高氧。我们提出以下特定目的：1。 在感染SARS-COV-2之前用BP处理的K18-HACE2小鼠将更多 容易受到肺部感染之前被模拟治疗的肺部。 假设通过sehi tppu进行针对肺损伤/ARD的会议治疗 BP/SARS-COV-2/暴露的小鼠使用单细胞RNA-Seq进行基因表达分析 进行确定特异性肺细胞在BP/SARS-COV-2介导的肺损伤中的作用 及其通过SEHI 2。测试BP/SARS-COV-2 与维持在 房间空气，如果鼠标接触SEHI治疗，则会显示出较小的受伤 在高氧阶段。 SARS-COV-2/高氧及其潜在的PAH介导的损伤。 此外，如果我们的SEHI研究旨在保护小鼠免受Covid-19发病机理的侵害，那将是 迈出了对人类Covid019治疗的USEHS的未来临床试验迈出的重要一步。