Epidemiological studies consistently show a positive relationship between airborne matter (PM) and increased morbidity and mortality from cardiovascular disease. The mechanisms underlying PM-associated cardiovascular toxicity are largely unknown. We have discovered aromatic chlorinated hydrocarbons combine with metal-containing PM to form surface stabilized, environmentally persistent free radicals (EPFRs). We have shown that EPFRs: 1) are capable of redox cycling and continuously forming reactive oxygen species, 2) produce inflammation and oxidative stress (OS) in the lung, 3) increase the expression of proinflammatory genes in the heart, 4) produce cardiac inflammation, 5) decrease left ventricular function in vivo, and 6) increase OS and the magnitude of cardiac ischemia/reperfusion injury (l/R). These data suggest EPFR mediated OS and inflammation underlies the observed functional deficits and increased vulnerability to l/R injury. Cellular homeostasis in response to OS and inflammation is maintained by the balanced activation of tier 2 antioxidant genes via the transcription factor, Nrf2, and the proinflammatory NfKB pathway. We hypothesize that: EPFR-induced oxidative stress and inflammation enhance cardiac injury and dysfunction by """"""""tipping the balance"""""""" between the antioxidant Nrf2 and the proinflammatory NFKB pathway to favor NFKB. TO test this hypothesis, we propose 3 specific aims.
Aim 1 will determine the dose-response relationship between EPFRs and cardiac function in vivo and will characterize OS and inflammatory responses in the heart and lungs.
Aim 2 will explore the ability of EPFRs to increase infarct size and enhance the deficits in left ventricular function after l/R injury in vivo.
Aim 3 will explore the effect of EPFRs exposure on the activity of the Nrf2 antioxidant and NFkB inflammatory pathways. Project 4 relies on the interdisciplinary strengths of the LSU-SRP. Lung tissue from our studies will be analyzed for OS and inflammation in Project 2. Project 5 will examine P450 expression and function with respect to OS in our cardiac tissue. We will also draw heavily on the expertise and analysis performed by the Oxidative Stress Core, while all of the samples tested will be generated by the Materials Core.

Public Health Relevance

Our observation that EPFRs decrease cardiac function and increase cardiac vulnerability to ischemic injury poses a substantial and virtually unstudied risk factor for individuals having or at risk of developing ischemic heart disease. This increased vulnerability, may explain the causal relationship between exposure to airborne particulates and increased cardiovascular morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
2P42ES013648-03
Application #
8097843
Study Section
Special Emphasis Panel (ZES1-SET-V (04))
Project Start
2009-08-15
Project End
Budget Start
2011-09-01
Budget End
2012-03-31
Support Year
3
Fiscal Year
2011
Total Cost
$141,522
Indirect Cost
Name
Louisiana State University A&M Col Baton Rouge
Department
Type
DUNS #
075050765
City
Baton Rouge
State
LA
Country
United States
Zip Code
70803
Hijano, Diego R; Siefker, David T; Shrestha, Bishwas et al. (2018) Type I Interferon Potentiates IgA Immunity to Respiratory Syncytial Virus Infection During Infancy. Sci Rep 8:11034
Haywood, Benjamin J; White, John R; Cook, Robert L (2018) Investigation of an early season river flood pulse: Carbon cycling in a subtropical estuary. Sci Total Environ 635:867-877
Connick, J Patrick; Reed, James R; Backes, Wayne L (2018) Characterization of Interactions Among CYP1A2, CYP2B4, and NADPH-cytochrome P450 Reductase: Identification of Specific Protein Complexes. Drug Metab Dispos 46:197-203
Potter, Phillip M; Guan, Xia; Lomnicki, Slawomir M (2018) Synergy of iron and copper oxides in the catalytic formation of PCDD/Fs from 2-monochlorophenol. Chemosphere 203:96-103
Harmon, Ashlyn C; Hebert, Valeria Y; Cormier, Stephania A et al. (2018) Particulate matter containing environmentally persistent free radicals induces AhR-dependent cytokine and reactive oxygen species production in human bronchial epithelial cells. PLoS One 13:e0205412
Jaligama, Sridhar; Patel, Vivek S; Wang, Pingli et al. (2018) Radical containing combustion derived particulate matter enhance pulmonary Th17 inflammation via the aryl hydrocarbon receptor. Part Fibre Toxicol 15:20
Dugas, Tammy R (2018) Unraveling mechanisms of toxicant-induced oxidative stress in cardiovascular disease. Curr Opin Toxicol 7:1-8
Patterson, Matthew C; DiTusa, Mark F; McFerrin, Cheri A et al. (2017) Formation of environmentally persistent free radicals (EPFRs) on ZnO at room temperature: Implications for the fundamental model of EPFR generation. Chem Phys Lett 670:5-10
Nganai, Shadrack; Lomnicki, Slawo (2017) Surface catalysed PCDD/F formation from precursors - high PCDF yield does not indicate de novo mechanism! Int J Environ Pollut 61:208-222
Pandey, Amit V; Henderson, Colin J; Ishii, Yuji et al. (2017) Editorial: Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function. Front Pharmacol 8:881

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