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.

项目总结