title: Differential regulation of the lung endothelin system by urban particulate matter and ozone.
abstract: Periodic elevation of ambient particulate matter and ozone levels is linked to acute cardiac morbidity and mortality. Increased plasma levels of the potent vasoconstrictor endothelin (ET)-1, a prognostic indicator of cardiac mortality, have been detected in both animal models and humans after exposure to air pollutants. The lungs are the primary source of circulating ET-1, but the direct effects of individual air pollutants and their interaction in modulating the pulmonary endothelin system are unknown. Fischer-344 rats were exposed to particles (0, 5, 50 mg/m3 EHC-93), ozone (0, 0.4, 0.8 ppm), or combinations of particles and ozone for 4 h. Changes in gene expression were measured using real-time reverse transcription polymerase chain reaction immediately after exposure and following 24 h recovery in clean air. Both pollutants individually increased preproET-1, endothelin converting enzyme-1, and endothelial nitric oxide synthase mRNA levels in the lungs shortly after exposure, consistent with the concomitant increase in plasma of the 21 amino acid ET-1[1-21] peptide measured by HPLC-fluorescence. PreproET-1 mRNA remained elevated 24 h after exposure to particles but not after ozone, in line with previously documented changes of the peptide in plasma. Both pollutants transiently increased endothelin-B receptor mRNA expression, while ozone decreased endothelin-A receptor mRNA levels. Coexposure to particles plus ozone increased lung preproET-1 mRNA but not plasma ET-1[1-21], suggesting alternative processing or degradation of endothelins. This coincided with an increase in the lungs of matrix metalloproteinase-2 (MMP-2), an enzyme that cleaves bigET-1 to ET-1[1-32]. Taken together, our data indicate that ozone and particulate matter independently regulate the expression of lung endothelin system genes, but show complex toxicological interaction with respect to plasma ET-1.
authors.affiliation: Healthy Environments and Consumer Safety Branch, and Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada, K1A 0K9.
authors.forename: Errol
authors.initials: E
authors.lastname: Thomson
authors.forename: Prem
authors.initials: P
authors.lastname: Kumarathasan
authors.forename: Patrick
authors.initials: P
authors.lastname: Goegan
authors.forename: Rémy A
authors.initials: RA
authors.lastname: Aubin
authors.forename: Renaud
authors.initials: R
authors.lastname: Vincent
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004784:Environmental Monitoring / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D019570:Inhalation Exposure / Q000009:adverse effects*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010126:Ozone / Q000633:toxicity*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms
chemical_list: D000393:Air Pollutants; D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C119962:endothelin-1 (1-21), (Cys,Acm(1,15),Aib(3,11),Leu(7))-; D010126:Ozone; D019001:Nitric Oxide Synthase; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes