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INHALED COMPLEX COMBUSTION EMISSIONS UPREGULATE TRANSCRIPTION AND ACTIVITY OF SYSTEMATIC MATRIX METALLOPROTEINASE-9 (MMP9): EVIDENCE IN MURINE AND HUMAN MODELS
Citation:
MADDEN, M. C., M. J. CAMPEN, A. K. LUND, J. LUCERO, S. LUCAS, T. KNUCKLES, M. DOYLE, S. ALLEN, M. D. REED, J. C. SEAGRAVE, AND J. MAUDERLY. INHALED COMPLEX COMBUSTION EMISSIONS UPREGULATE TRANSCRIPTION AND ACTIVITY OF SYSTEMATIC MATRIX METALLOPROTEINASE-9 (MMP9): EVIDENCE IN MURINE AND HUMAN MODELS. Presented at Society of Toxicology 47th Annual Meeting, Seattle, WA, March 16 - 20, 2008.
Impact/Purpose:
To expolore the cumulative impact of whole exhaust constituents.
Description:
Air pollution is associated with acute and chronic adverse human health effects related to atherosclerotic pathologies. MMP9 has a crucial role in the progression and ultimate degradation of vascular lesions and polymorphisms of MMP9 are highly associated with increased incidence of myocardial infarction. Following evidence that gasoline exhaust emissions induce transcription of MMP9 in the aortas of apolipoprotein E knockout mice, we sought to test the integrity and translational validity of this marker across varying pollutant atmospheres and also in human samples. ApoE mice were exposed by inhalation to primary gaseous components of gasoline engine emissions, namely carbon monoxide (CO; 8 and 80 ppm), nitrogen dioxide (NO2; 0.2 and 2.0 ppm) and nitric oxide (NO; 17 ppm). Other groups of mice were also exposed to secondary organic aerosols, coal emissions, and diesel exhaust. Results of MMP9 mRNA changes, as assessed by real time PCR, indicate a strong role for freely-diffusible components such as CO and NO, but also some degree of induction by pollutant components that do not penetrate the lung in meaningful levels (PM, NO2). However, no single component produced effects as great as the whole exhausts, suggesting that systemic vascular effects are driven by the sum of components. We then assayed plasma MMP9 protein in mice and humans (n=10) and found a significant upregulation of MMP9 (p=0.0003) following diesel exhaust exposure compared to air control exposures. These results strongly suggest that systemic effects are not initiated by any one pollutant component and imply that accurate assessment of air pollution health effects must consider the cumulative impact of whole exhaust constituents. [This abstract may not represent official US EPA policy.]