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.
