2009 Progress Report: Novel Markers of Air Pollution-induced Vascular ToxicityEPA Grant Number: R833990
Title: Novel Markers of Air Pollution-induced Vascular Toxicity
Investigators: Campen, Matthew J. , Lund, Amie K.
Institution: Lovelace Biomedical & Environmental Research Institute
Current Institution: University of New Mexico
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: November 1, 2008 through October 31, 2011 (Extended to October 31, 2012)
Project Period Covered by this Report: November 1, 2008 through October 31,2009
Project Amount: $500,000
RFA: Development of Environmental Health Outcome Indicators (2007) RFA Text | Recipients Lists
Research Category: Health Effects , Health
Efforts to reduce the burden of heart disease and stroke have been hampered by a lack of knowledge in key areas including, but not limited to, environmental factors that may predispose susceptible individuals to plaque rupture as well as detrimental pathological effects associated with already increased levels of factors in the circulation or tissue. The objective of the present project is to characterize the role of known factors associated with progression of atherosclerosis associated with exposure to ubiquitous environmental air pollutants, such as diesel and gasoline engine exhaust. Furthermore, we have examined the role of oxidized low density lipoprotein (oxLDL) acting through the LOX-1 receptor as a mediator of the induction of vascular proteinases associated with plaque instability.
Because we have seen very clearly two predominant outcomes in our toxicological assays (vascular lipid peroxidation and inflammation), we wished to examine (1) whether specific receptors, such as LOX-1, might link these outcomes; and (2) whether other biomarkers might arise from within these pathways that may represent more robust indicators of exposure.
In Specific Aim 1, we proposed to assay hypothesized markers in plasma and aortic tissue from mice exposed to various pollutant atmospheres. These studies will link the plasma markers with their mechanistic origins.
Mouse plasma from 7- and 50-day exposures to diesel emissions, coal combustion, and woodsmoke combustion have been transferred from LRRI to UNM for analysis. We have completed most proposed assays on the 50-day samples. Examples of findings for LOX-1 and osteopontin (OPN) are presented below. Interestingly, the responses of LOX-1 are quite different compared to what we have seen acutely, with a significant downregulation in the diesel exposed mice. OPN showed minimal changes, possibly a reduction in the medium concentration of diesel. We are continuing to analyze the 7-day samples and are also investigating related markers. Over the coming year, data will be finalized and we will integrate our findings with respect to the relative pollutant concentrations within each of the combustion mixtures. Much of the chemistry of the exposure atmospheres has been characterized and reported within the framework of the National Environmental Respiratory Center, and we will be able to consider multivariate analysis of the observed changes in biomarkers.
In Specific Aim 2, we proposed to test the role of LOX-1 scavenger receptors in mediating the vascular effects of inhaled pollutants. We hypothesize that oxidatively modified phospholipids may be a link between the lung and systemic circulation; scavenger receptors are the likely mediating intermediary.
We have completed Aim 2, treating mice with an antibody to LOX-1, to selectively block the function of this pathway during exposures. As predicted, we observed a complete blockade of the systemic vascular lipid peroxidation caused by exposure to vehicular emissions (in this case, a combination of diesel and gasoline emissions). Similarly, reductions in intravascular accumulation of macrophages, along with mRNA induction of a number of markers were observed due to the LOX-1 blockade. Thus, Aim 2 confirms the importance of the LOX-1 pathway in driving the systemic vascular effects of inhaled emissions.
This study has been prepared for communication and tentatively accepted to the American Journal of Respiratory and Critical Care Medicine, pending major revisions. A second manuscript, detailing the changes in LOX-1 in a more chronic rat model exposed to ozone with/without diesel particles, also has been published in the past year (Kodavanti et al., 2010).
In Specific Aim 3, we proposed to use the information obtained in Specific Aims 1 and 2 to develop hypotheses for protein or biochemical markers to test in human plasma. We have confirmed that relative levels of soluble LOX-1 in the plasma of human subjects become elevated following controlled exposure to diesel exhaust. We are currently analyzing similar samples from humans exposed to a number of related pollutants, including nitrogen dioxide, particulate matter and ozone.
Thus, over the final year of this project we will round out the assays and integration of data for Aims 1 and 3. Although certain followup activities are planned related to the mechanistic findings of a role for LOX-1 in lipid peroxidation, those will be outside the scope of the current project.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
|Other project views:||All 9 publications||6 publications in selected types||All 6 journal articles|
||Kodavanti UP, Thomas R, Ledbetter AD, Schladweiler MC, Shannahan JH, Wallenborn JG, Lund AK, Campen MJ, Butler EO, Gottipolu RR, Nyska A, Richards JE, Andrews D, Jaskot RH, McKee J, Kotha SR, Patel RB, Parinandi NL. Vascular and cardiac Impairments in rats inhaling ozone and diesel exhaust particles. Environmental Health Perspectives 2011;119(3):312-318.||
||Lund AK, Lucero J, Harman M, Madden MC, McDonald JD, Seagrave JC, Campen MJ. The oxidized low-density lipoprotein receptor mediates vascular effects of inhaled vehicle emissions. American Journal of Respiratory and Critical Care Medicine 2011;184(1):82-91.||