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Mechanistic Insights into the Relationship between Lung and Vascular Response to Ambient Particulate Matter (PM)
Citation:
THOMAS, R. F., A. DE VIZCAYA-RUIZ, A. OSORNIO-VARGAS, M. SCHLADWEILER, J. K. MCGEE, AND U. P. KODAVANTI. Mechanistic Insights into the Relationship between Lung and Vascular Response to Ambient Particulate Matter (PM). Presented at Annual Society of Toxicology meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
This abstract characterizes the relationship between lung and vascular injury following Mexico City ambient air particle samples exposure in rats and shows that vascular effects do occur but are delayed.
Description:
The mechanisms by which pulmonary-encountered ambient PM induces vascular response are not well understood. We examined lung and aortic response of rats following intratracheal instillation of three ambient PM. Chemically characterized PM10 and PM2.5 from the north and PM10 from the south of Mexico City were tested for their in vivo acute lung and vascular toxicity. Male Wistar Kyoto rats (14 weeks) were intratracheally instilled with either saline or one of three PM at 3 mg/ml (3 mg/kg). All three PM induced inflammation (day 1>day 3) as evidenced by the increases in bronchoalveolar lavage fluid (BALF) protein and neutrophils with small differences between PM types. There were no effects on circulating inflammatory cells or hematological parameters. Gene expression for biomarkers of inflammation, oxidative stress, vasoconstriction, thrombosis, metalloproteases, and receptors which recognize oxidatively modified proteins and lipids (RAGE and Oldlr-1) were analyzed in the lung and the aorta at days 1 and 3 post instillation. Pulmonary HO-1, TNF-α, and MIP-2 expressions increased several fold along with marked upregulation of tissue factor and PAI-1 mRNA with all three PM but no upregulation of tPA was noted. Maximum response occurred at day 1 but diminished by day 3. Endothelin-1 mRNA was induced only slightly at day 3 while no increase in MMP-2 occurred in the lung. The most remarkable induction occurred of iNOS in the lung at day 1 (>70-fold). RAGE expression decreased in the lung at day 1, while Oldlr-1 increased slightly at day 3. Although the effects on the aorta were milder than what is observed in the lung, the response was significant and occurred at a later time point of day 3 with most markers. Aorta MMP-2, HO-1, endothelin-1, iNOS and eNOS were induced up to 3-fold by all three PM at day 3. PAI-1 and tPA were not induced consistently or significantly. Unlike lung, both Oldlr1 and RAGE expressions were increased in the aorta. We provide the evidence of delayed vascular effects from ambient PM exposure that are reflective of oxidative stress, vasoconstriction, matrix abnormalities and increased thrombosis likely mediated via upregulation of RAGE and Oldlr-1. (Does not reflect US EPA policy). Supported in part by EPA SEE Program, and EPA/UNC co-op #CR83346301).