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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 2018 HEI Annual Conference
 

Sex differences in pulmonary eicosanoid metabolism in response to ozone exposure

Kymberly M. Gowdy1, Sky W. Reece1, Brita J. Kilburg-Basnyat1, Myles Hodge1, Christine Psaltis1, Michael Yaeger2, Bin Luo1, Michael Armstrong3, Nichole Reisdorph3, Espen E. Spangenburg4, Johanna L. Hannan4, Robert M. Tighe5, Saame Raza Shaikh6

1 Department of Pharmacology and Toxicology, Brody School of Medicine, East Carolina University, Greenville, NC; 2 Department of Biomedical Engineering, East Carolina University, Greenville, NC; 3 School of Pharmacy, University of Colorado, Denver, Denver, CO; 4 Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC; 5 Department of Medicine, Duke University Medical Center, Durham, NC; 6 Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Rationale: Epidemiological studies demonstrate that sex impacts the development and progression of several lung diseases. Ozone (O3) is a criteria air pollutant that can trigger sex-biased pulmonary inflammation. Eicosanoids, potent bioactive lipid mediators, play an important role in regulating a diverse set of homeostatic and inflammatory processes. Accumulating evidence suggests there are sex dimorphisms in eicosanoid biology. However, the impact of O3 exposure on sex-based pulmonary eicosanoid metabolism has not been investigated.

Methods: 8-week-old C57BL/6J mice were exposed to filtered air (FA) or 1 ppm O3 for 3h. Bronchoalveolar lavage (BAL) and lung tissue were collected 6h or 24h post exposure. Cell counts and protein were measured in BAL. Eicosanoid levels in the lung tissue were measured by LC-MS/MS. Cytokines, chemokines, and eicosanoid biosynthesis enzyme levels in the lungs were measured by RT-PCR.

Results: Sex differences in BAL cell counts were observed post O3 exposure as evidenced by significant increased BAL neutrophils in female 24h after exposure. BAL protein was significantly higher 24h post O3 exposure in male and female compared to FA exposure with no sex differences observed. The pulmonary levels of prostaglandins (PGD2, PGE2, PGF2a, and PGI2), thromboxanes (TXA2 and TXB2), hydroxyeicosatetraenoic acid (5S-HETE, 8S-HETE, 12S-HETE, 15S-HETE), and leukotriene 4 (LTE4) were significantly increased in females 24h post O3 exposure compared to males. Males displayed significantly higher levels of 11(12)- epoxyeicosatrienoic acid (EET) at 24h post O3 exposure compared to females. The mRNA expression of cyclooxygenase (COX1 and COX2) enzymes in lung tissue showed trends of decreasing post O3 exposure independent of sex.

Conclusion: This study is the first to report that O3 exposure reveals sex differences in pulmonary eicosanoid production. In females, pro-inflammatory eicosanoid (PGs, TXs, etc.) production was increased but not in anti-inflammatory eicosanoid (EETs) production. Our findings reveal that the inflammatory pathologies triggered by O3 exposure are more pronounced in females and associated with increased levels of pro-inflammatory eicosanoids.

 
POSTER
 
 
 
PUBLICATIONS
 

Kilburg-Basnyat B, Reece SW, Crouch MJ, Luo B, Boone AD, Yaeger M, Hodge M, Psaltis C, Hannan JL, Manke J, Armstrong ML, Reisdorph N, Tighe RM, Shaikh SR, Gowdy KM. Specialized Pro-Resolving Lipid Mediators Regulate Ozone-Induced Pulmonary and Systemic Inflammation. Toxicol Sci. 2018 Jun 1;163(2):466-477. doi: 10.1093/toxsci/kfy040.

Tighe RM, Birukova A, Yaeger MJ, Reece SW, Gowdy KM. Euthanasia- and Lavage-mediated Effects on Bronchoalveolar Measures of Lung Injury and Inflammation. Am J Respir Cell Mol Biol. 2018 Aug;59(2):257-266. doi: 10.1165/rcmb.2017-0357OC.