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Principal Investigator: BHAGAVATULA MOORTHY
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2021
Award: $240,720
Funding agency: National Institute of Environmental Health Sciences
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.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><21+ years old><3,4-Benzopyrene><3,4-Benzpyrene><3-10C><7-Ethoxyresorufin O-Deethylase><ACE2><AMCF-I><ARDS><Acids><Acute Lung Injury><Acute Pulmonary Injury><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult><Adult ARDS><Adult Human><Adult RDS><Adult Respiratory Distress Syndrome><Age><Air><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Aromatic Polycyclic Hydrocarbons><Attenuated><Autopsy><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Benzo(a)pyrene><Beta Proprotein Interleukin 1><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Weight decreased><CCL2><CCL2 gene><COVID-19><COVID-19 pathogenesis><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 pathogenesis><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><CXCL8><CYP 1A1><CYP11A><CYP11A1><CYP11A1 gene><CYP1A1 Product><CYP1A1 Protein><Cachectin><Carbamide><Cell Body><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Chemokine, CC Motif, Ligand 2><Chemosensitization><Chemosensitization/Potentiation><Clinical Trials><CoV-2><CoV2><Cytochrome P-450 CYP1A1><Cytochrome P450 1A1><Cytochrome P450 IA1><Cytochrome P450, Subfamily I (Aromatic Compound-Inducible), Polypeptide 1><Da Nang Lung><Data><Diesel Exhaust><Dioxin-Inducible Cytochrome P1-450><Disease Outbreaks><Dysfunction><ELISA><EROD><Eicosanoids><Eicosatrienoic Acid><Elaqua XX><Environmental Pollutants><Enzyme-Linked Immunosorbent Assay><Epoxide Hydrases><Epoxide Hydratases><Epoxide hydrolase><Ethoxyresorufin Dealkylase><Ethoxyresorufin O-Deethylase><Ethylresorufin O-Deethylase><Experimental Designs><Exposure to><Female><Functional disorder><Future><GCP1><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genes><HETE><HPGF><Hepatocyte-Stimulating Factor><Histology><Human><Hybridoma Growth Factor><Hydration><Hydration status><Hydroxyeicosatetraenoic Acids><Hyperoxia><IFN-beta 2><IFNB2><IL-1><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL-8><IL1><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><IL8><IL8 gene><Immune><Immunes><Individual><Infection><Inflammation><Inflammatory><Injury><Interleukin 1beta><Interleukin I><Interleukin-1><Interleukin-1 beta><Interleukin-1β><Interleukin-6><K-18><K-18 conjugate><K18><K18 combination><K60><Life><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Lung diseases><Lymphocyte-Stimulating Hormone><MCAF><MCP-1><MCP1><MGI-2><MOF syndrome><Macrophage Cell Factor><Macrophage-Derived TNF><Marrow Neutrophil><Measures><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Myeloid Differentiation-Inducing Protein><Mφ><Names><Neutrophilic Granulocyte><Neutrophilic Leukocyte><O element><O2 element><Outbreaks><Oxidative Stress><Oxygen><P450 Form 6><P450-1A1><P450-P1><P450SCC><Pathology><Pathway interactions><Patients><Phase><Physiopathology><Plasmacytoma Growth Factor><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Potentiation><Preinterleukin 1 Beta><Pulmonary Diseases><Pulmonary Disorder><Receptor Cell><Receptor Protein><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Risk><Role><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCYA2><SCYB8><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Small Inducible Cytokine A2><Smoker><Stiff lung><Stromal Cells><Symptoms><Syndrome><T Helper Factor><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TSG-1><Testing><Transcript Expression Analyses><Transcript Expression Analysis><Transgenic Mice><Transgenic Organisms><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Urea><Urea Carbamide><Ureaphil><Viral><Viral Diseases><Virus><Virus Diseases><Weight Loss><Weight Reduction><Western Blotting><Western Immunoblotting><Wild Type Mouse><Wuhan coronavirus><adulthood><ages><angiotensin converting enzyme 2><angiotensin converting enzyme II><antiinflammatory><b-ENAP><beta CoV><beta coronavirus><betaCoV><betacoronavirus><body weight loss><cell sorting><cigarette smoke><cigarette smoking><cigarette use><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 pathogenesis><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><cytokine><cytokine release syndrome><cytokine storm><disease of the lung><disorder of the lung><drinking water><environmental chemical><experiment><experimental research><experimental study><gene expression analysis><gene expression assay><hCoV19><hyperoxygenation><inhibitor><inhibitor/antagonist><injuries><interferon beta 2><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung disorder><lung injury><lymphocyte activating factor><macrophage><male><molecular phenotype><multiorgan failure><multiple organ system failure><nCoV2><necropsy><neutrophil><non-smoker><nonsmoker><novel><pathophysiology><pathway><pollutant><polyaromatic hydrocarbons><polynuclear aromatic hydrocarbon><postmortem><prevent><preventing><protein blotting><pulmonary><receptor><recruit><respiratory><scRNA-seq><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome-CoV><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><single cell RNA-seq><single cell RNAseq><single-cell RNA sequencing><social role><transcriptional profiling><transgenic><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><viral infection><virus infection><virus-induced disease><wet lung><wildtype mouse><wt-loss><β CoV><β coronavirus><βCoV>