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LUNG

Pulmonary Expression of PreproET-1 and PreproET-3 mRNAs Is Altered Reciprocally in Rats After Inhalation of Air Pollutants

Errol Thomson^*,, Prem Kumarathasan^* and Renaud Vincent^*,,1

^* Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9; and Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada K1N 6N5

To whom requests for reprints should be addressed at ¹ Inhalation Toxicology and Aerobiology Section, Health Canada, 0803C Tunney’s Pasture, Ottawa, Ontario K1A 0K9, Canada. E-mail: Renaud_Vincent{at}hc-sc.gc.ca

Abstract

Perturbation of vascular homeostasis is an important mechanism related to the acute health effects of inhaled pollutants. Inhalation of urban particulate matter and ozone by rats has been shown to result in increased synthesis of the potent vasoactive peptide endothelin (ET)-1 in the lungs, with spillover into the circulation. In the present work, we have analyzed the interrelationships between responses of the three major endothelin isoforms, ET-1_[1–21], ET-2_[1–21], and ET-3_[1–21], to inhaled pollutants at the peptide and gene expression levels. Fisher-344 rats were exposed for 4 hrs by nose-only route to clean air, urban particles EHC-93 (0, 50 mg/m³), ozone (0, 0.8 ppm), or ozone and particles together. Circulating levels of both the ET-1 _[1–21] and ET-3_[1–21] peptides were increased immediately after exposure to particulate matter or ozone. While expression of preproET-1 mRNA in the lungs increased, expression of preproET-3 mRNA decreased immediately after exposure. PreproET-2 mRNA was not detected in the lungs, and exposure to either pollutant did not affect plasma ET-2 levels. Co-exposure to ozone and particles, while altering lung preproET-1 and preproET-3 mRNA levels in a fashion similar to ozone alone, did not cause changes in the circulating levels of the two corresponding peptides. Thus, de novo synthesis of ET-3 in the lungs is not responsible for the increase of circulating plasma ET-3 after inhalation of pollutants, which implies regulation of preproET-3 at a remote site and, hence, systemic impacts of the pollutants. Upregulation of preproET-1 coupled with down-regulation of preproET-3 in the lungs of animals exposed to air pollutants implies a mismatch of local ET-1/ET_A receptor–mediated vasoconstriction and ET-3/ET_B receptor–mediated vasodilation.

Key Words: endothelin (ET)-1 • ET-2 • ET-3 • lung • gene expression • real-time polymerase chain reaction (PCR) • particulate matter • ozone • air pollution