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Scavenger receptor BI regulates oxidized lipid driven pulmonary and vascular inflammation after ozone exposure

Principal Investigator: 
,

East Carolina University

This New Investigator Award study is evaluating whether injury after exposure to ozone is mediated through changes in the lung and blood of levels of oxidized phospholipids. This will be tested in normal mice and in mice genetically lacking the Scavenger Receptor B1 that binds oxidized phospholipids.

Funded under
Status: 
Ongoing
Abstract
Abstract for the 2016 HEI Annual Conference
 
Alterations in Pulmonary and Systemic Specializing Lipid Mediators Production after Ozone Exposure
K.M. Gowdy1, B.J. Kilburg-Basnyat1, S.W. Reece1, M. Hodge1, M.L. Armstrong2, S. Davies3, and S.R. Shaikh4
1Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC; 2School of Pharmacy, University of Colorado, Denver, Denver, CO; 3Vanderbilt University, Nashville, TN; 4Department of Biochemistry, East Carolina University, Greenville, NC
 
Background Ozone (O3) exposure is associated with an increase in cardiopulmonary-induced morbidity and mortality. O3 reacts with lipids in the lung to generate oxidized products that can induce pulmonary and systemic inflammation.  Specialized pro-resolving mediators (SPMs) are produced in tissue to support resolution of the immune response. The role of SPMs in O3-induced cardiopulmonary inflammation is unknown. We hypothesize that O3 exposure induces pulmonary and systemic inflammation causing an increase in pro-inflammatory lipids (e.g. oxidized phospholipids (oxPL)) as well as a reduction in SPMs, which are critical to resolve the O3-induced pulmonary and cardiovascular inflammation.
 
Methods C57Bl/6J male mice were exposed to filtered air (FA) or 1 ppm O3 for 3h and necropsied 24h post-exposure. Pulmonary and systemic inflammation was determined by bronchoalveolar lavage fluid (BAL), cytokine production, and cellular differentials. Lung and spleen oxPL and SPM concentrations were quantified by liquid chromatography-mass spectrometry (LC-MS).
 
Results 24h post-O3 exposure pulmonary inflammation was significantly increased with pulmonary neutrophilia and protein production in BAL. In the blood, there was a significant decrease in total white blood cells and monocytes 24hrs after O3 exposure. OxPLs were elevated in the BAL after O3 exposure as well as inflammatory cytokines.  However, after O3 exposure there was a significant decrease in lung and spleen levels of SPMs (14 HDHA, 17 HDHA, and Protectin D1).
 
Conclusions These data demonstrate that O3 exposure modulates the lipidome. O3 induced decreases of SPMs as well as increases in inflammatory lipid mediator levels that may contribute to pulmonary and cardiovascular inflammation and dysfunction.  Future studies will elucidate if SPM replacement restores function and decreases pulmonary and systemic inflammation as well as the mechanisms of how O3 can modulate lipid metabolism.
 
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