Differential regulation of the lung endothelin system by urban particulate matter and ozone.
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.
Thomson
Errol
E
Healthy Environments and Consumer Safety Branch, and Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada, K1A 0K9.
Kumarathasan
Prem
P
Goegan
Patrick
P
Aubin
Rémy A
RA
Vincent
Renaud
R
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
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