Ozone effects on blood biomarkers of systemic inflammation, oxidative stress, endothelial function, and thrombosis: The Multicenter Ozone Study in oldEr Subjects (MOSES)

Autoři: John R. Balmes aff001;  Mehrdad Arjomandi aff001;  Philip A. Bromberg aff004;  Maria G. Costantini aff006;  Nicholas Dagincourt aff007;  Milan J. Hazucha aff004;  Danielle Hollenbeck-Pringle aff008;  David Q. Rich aff009;  Paul Stark aff007;  Mark W. Frampton aff010
Působiště autorů: Department of Medicine, University of California at San Francisco, San Francisco, CA, United States of America aff001;  Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, United States of America aff002;  San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States of America aff003;  Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America aff004;  Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina, Chapel Hill, NC, United States of America aff005;  Health Effects Institute, Boston, MA, United States of America aff006;  New England Research Institute, Watertown, MA, United States of America aff007;  Alpert Medical School, Brown University, Providence, RI, United States of America aff008;  Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY, United States of America aff009;  Department of Medicine, University of Rochester Medical Center, Rochester, NY, United States of America aff010;  Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, United States of America aff011
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222601


The evidence that exposure to ozone air pollution causes acute cardiovascular effects is mixed. We postulated that exposure to ambient levels of ozone would increase blood markers of systemic inflammation, prothrombotic state, oxidative stress, and vascular dysfunction in healthy older subjects, and that absence of the glutathione S-transferase Mu 1 (GSTM1) gene would confer increased susceptibility. This double-blind, randomized, crossover study of 87 healthy volunteers 55–70 years of age was conducted at three sites using a common protocol. Subjects were exposed for 3 h in random order to 0 parts per billion (ppb) (filtered air), 70 ppb, and 120 ppb ozone, alternating 15 min of moderate exercise and rest. Blood was obtained the day before, approximately 4 h after, and approximately 22 h after each exposure. Linear mixed effect and logistic regression models evaluated the impact of exposure to ozone on pre-specified primary and secondary outcomes. The definition of statistical significance was p<0.01. There were no effects of ozone on the three primary markers of systemic inflammation and a prothrombotic state: C-reactive protein, monocyte-platelet conjugates, and microparticle-associated tissue factor activity. However, among the secondary endpoints, endothelin-1, a potent vasoconstrictor, increased from pre- to post-exposure with ozone concentration (120 vs 0 ppb: 0.07 pg/mL, 95% confidence interval [CI] 0.01, 0.14; 70 vs 0 ppb: -0.03 pg/mL, CI -0.09, 0.04; p = 0.008). Nitrotyrosine, a marker of oxidative and nitrosative stress, decreased with increasing ozone concentrations, with marginal significance (120 vs 0 ppb: -41.5, CI -70.1, -12.8; 70 vs 0 ppb: -14.2, CI -42.7, 14.2; p = 0.017). GSTM1 status did not modify the effect of ozone exposure on any of the outcomes. These findings from healthy older adults fail to identify any mechanistic basis for the epidemiologically described cardiovascular effects of exposure to ozone. The findings, however, may not be applicable to adults with cardiovascular disease.

Klíčová slova:

Biomarkers – Blood – Inflammation – Oxidative stress – Platelet activation – Platelets – Ozone – Fibrinogen


1. Sun Q, Hong X, Wold LE. Cardiovascular effects of ambient particulate air pollution exposure. Circulation. 2010;121(25): 2755–2765. doi: 10.1161/CIRCULATIONAHA.109.893461 20585020

2. Schelegle ES, Morales CA, Walby WF, Marion S, Allen RP. 6.6-hour inhalation of ozone concentrations from 60 to 87 parts per billion in healthy humans. Am J Respir Crit Care Med. 2009;180(3): 265–272. doi: 10.1164/rccm.200809-1484OC 19447899

3. Adams WC. Comparison of chamber 6.6-h exposures to 0.04–0.08 PPM ozone via square-wave and triangular profiles on pulmonary responses. Inhal Toxicol. 2006;18(2): 127–136. doi: 10.1080/08958370500306107 16393927

4. Kim CS, Alexis NE, Rappold AG, Kehrl H, Hazucha MJ, Lay JC, et al. Lung function and inflammatory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 hours. Am J Resp Crit Care Med. 2011;183: 1215–1221. doi: 10.1164/rccm.201011-1813OC 21216881

5. Bell ML, McDermott A, Zeger SL, Samet JM, Dominici F. Ozone and short-term mortality in 95 US urban communities, 1987–2000. JAMA. 2004;292(19): 2372–2378. doi: 10.1001/jama.292.19.2372 15547165

6. Bravo MA, Son J, de Freitas CU, Gouveia N, Bell ML. Air pollution and mortality in Sao Paulo, Brazil: Effects of multiple pollutants and analysis of susceptible populations. J Expo Sci Environ Epidemiol. 2016;26(2): 150–161. doi: 10.1038/jes.2014.90 25586330

7. Ballester F, Rodriguez P, Iniguez C, Saez M, Daponte A, Galan I, et al. Air pollution and cardiovascular admissions association in Spain: results within the EMECAS project. J Epidemiol Community Health. 2006;60: 328–336. doi: 10.1136/jech.2005.037978 16537350

8. Chan CC, Chuang KJ, Chien LC, Chen WJ, Chang WT. Urban air pollution and emergency admissions for cerebrovascular diseases in Taipei, Taiwan. Eur Heart J. 2006;27: 1238–1244. doi: 10.1093/eurheartj/ehi835 16537554

9. Chang CC, Tsai SS, Ho SC, Yang CH. Air pollution and hospital admissions for cardiovascular disease in Taipei, Taiwan. Environ Res. 2005;98: 114–119. doi: 10.1016/j.envres.2004.07.005 15721891

10. Halonen JI, Lanki T, Tiittanen P, Niemi JV, Loh M, Pekkanen J. Ozone and cause-specific cardiorespiratory morbidity and mortality. J Epidemiol Community Health. 2010;64(9): 814–820. doi: 10.1136/jech.2009.087106 19854743

11. Lee JT, Kim H, Cho YS, Hong YC, Ha EH, Park H. Air pollution and hospital admissions for ischemic heart diseases among individuals 64+ years of age residing in Seoul, Korea. Arch Environ Health. 2003;58(10): 617–623. doi: 10.3200/AEOH.58.10.617-623 15562633

12. Szyszkowicz M. Ambient air pollution and daily emergency department visits for ischemic stroke in Edmonton, Canada. Int J Occup Med Environ Health. 2008;21(14): 295–300.

13. Rodopoulou S, Chalbot MC, Samoli E, Dubois DW, San Filippo BD, Kavouras IG. Air pollution and hospital emergency room and admissions for cardiovascular and respiratory diseases in Dona Ana County, New Mexico. Environ Res. 2014;129: 39–46. doi: 10.1016/j.envres.2013.12.006 24529001

14. Barnett AG, Williams GM, Schwartz J, Best TL, Neller AH, Petroeschevsky AL, et al. The effects of air pollution on hospitalizations for cardiovascular disease in elderly people in Australian and New Zealand cities. Environ Health Perspect. 2006;114(7): 1018–1023. doi: 10.1289/ehp.8674 16835053

15. Corea F, Silvestrelli G, Baccarelli A, Giua A, Previdi P, Siliprandi G, et al. Airborne pollutants and lacunar stroke: a case cross-over analysis on stroke unit admissions. Neurol Int. 2012;4(2): e11. doi: 10.4081/ni.2012.e11 23139849

16. Franck U, Leitte AM, Suppan P. Multiple exposures to airborne pollutants and hospital admissions due to diseases of the circulatory system in Santiago de Chile. Sci Total Environ. 2014;468–469: 746–756. doi: 10.1016/j.scitotenv.2013.08.088 24064344

17. Fung KY, Luginaah I, Gorey KM, Webster G. Air pollution and daily hospital admissions for cardiovascular diseases in Windsor, Ontario. Can J Public Health. 2005;96(1): 29–33. 15682690

18. Goldberg MS, Giannetti N, Burnett RT, Mayo NE, Valois MF, Brophy JM. A panel study in congestive heart failure to estimate the short-term effects from personal factors and environmental conditions on oxygen saturation and pulse rate. Occup Environ Med. 2008;65(10): 659–666. doi: 10.1136/oem.2007.034934 18801926

19. Symons JM, Wang L, Guallar E, Howell E, Dominici F, Schwab M, et al. A case-crossover study of fine particulate matter air pollution and onset of congestive heart failure symptom exacerbation leading to hospitalization. Am J Epidemiol. 2006;164(5): 421–433. doi: 10.1093/aje/kwj206 16793862

20. Tolbert PE, Klein M, Peel JL, Sarnat SE, Sarnat JA. Multipollutant modeling issues in a study of ambient air quality and emergency department visits in Atlanta. J Expo Anal Environ Epidemiol. 2007;17: S29–S35.

21. Zanobetti A, Schwartz J. Air pollution and emergency admissions in Boston, MA. J Epidemiol Community Health. 2006;60: 890–895. doi: 10.1136/jech.2005.039834 16973538

22. Sarnat SE, Winquist A, Schauer JJ, Turner JR, Sarnat JA. Fine particulate matter components and emergency department visits for cardiovascular and respiratory diseases in the St. Louis, Missouri-Illinois, metropolitan area. Environ Health Perspect. 2015;123(5): 437–444. doi: 10.1289/ehp.1307776 25575028

23. Shah ASV, Lee KK, McAllister DA, Hunter A, Nair H, Whiteley W, et al. Short term exposure to air pollution and stroke: systematic review and meta-analysis. BMJ. 2015;350: h1295. doi: 10.1136/bmj.h1295 25810496

24. Mustafic H, Jabre P, Caussin C, Murad M, Escolano S, Tafflet M, et al. Main air pollutants and myocardial infarction: a systematic review and meta-analysis. JAMA. 2012;307(7): 713–721. doi: 10.1001/jama.2012.126 22337682

25. Shah ASV, Langrish JP, Nair H, McAllister DA, Hunter AL, Donaldson K, et al. Global association of air pollution and heart failure: a systematic review and meta-analysis. The Lancet. 2013;382(9897): 1039–1048.

26. U.S. EPA. Integrated Science Assessment for ozone and related photochemical oxidants. Research Triangle Park (NC): U.S. Environmental Protection Agency; 2013, Feb. EPA 600/R-10/076F.

27. Arjomandi M, Wong H, Donde A, Frelinger J, Dalton S, Ching W, et al. Exposure to medium and high ambient levels of ozone causes adverse systemic inflammatory and cardiac autonomic effects. Am J Physiol Heart Circ Physiol. 2015;308(12): H1499–H1509. doi: 10.1152/ajpheart.00849.2014 25862833

28. Devlin RB, Duncan KE, Jardim M, Schmitt MT, Rappold AG, Diaz-Sanchez D. Controlled exposure of healthy young volunteers to ozone causes cardiovascular effects. Circulation. 2012;126(1): 104–111. doi: 10.1161/CIRCULATIONAHA.112.094359 22732313

29. Frampton M, Pietropaoli A, Dentler M, Chalupa D, Little E, Stewart J, et al. Cardiovascular effects of ozone in healthy subjects with and without deletion of glutathione-S-transferase M1. Inhal Toxicol. 2015;27: 113–119. doi: 10.3109/08958378.2014.996272 25600221

30. Wu W, Peden D, McConnell R, Fruin S, Diaz-Sanchez D. Glutathione-S-transferase M1 regulation of diesel exhaust particle-induced pro-inflammatory mediator expression in normal human bronchial epithelial cells. Particle and Fibre Toxicology. 2012;9(1): 31. doi: 10.1186/1743-8977-9-31 22867088

31. Alexis NE, Zhou H, Lay JC, Harris B, Hernandez ML, Lu T-S, et al. The glutathione-S-transferase Mu 1 null genotype modulates ozone-induced airway inflammation in human subjects. J Allergy Clin Immunol. 2009;124(6): 1222–1228. doi: 10.1016/j.jaci.2009.07.036 19796798

32. Alexis NE, Lay JC, Zhou H, Kim CS, Hernandez ML, Kehrl H, et al. The glutathione-S-transferase mu 1 (GSTM1) null genotype and increased neutrophil response to low-level ozone (0.06 ppm). J Allergy Clin Immunol. 2013;131(2): 610–612. doi: 10.1016/j.jaci.2012.07.005 22921799

33. Shumake KL, Sacks JD, Lee JS, Johns DO. Susceptibility of older adults to health effects induced by ambient air pollutants regulated by the European Union and the United States. Aging Clin Exp Res. 2013;25(1): 3–8. doi: 10.1007/s40520-013-0001-5 23740627

34. Arjomandi M, Balmes JR, Frampton MW, Bromberg P, Stark P, Alexis NE, et al. Respiratory Responses to Ozone Exposure: The Multicenter Ozone Study in oldEr Subjects (MOSES). Am J Respir Crit Care Med. 2018;197: 1319–1327. doi: 10.1164/rccm.201708-1613OC 29232153

35. Rich D, Balmes J, Frampton M, Zareba W, Stark P, Arjomandi M, et al. Cardiovascular function and ozone exposure: The Multicenter Ozone Study in oldEr Subjects (MOSES). Environ Int. 2018;119: 193–202. doi: 10.1016/j.envint.2018.06.014 29980042

36. Frampton M, Balmes J, Bromberg P, Stark P, Arjomandi M, Hazucha M, et al. Multicenter Ozone Study in oldEr Subjects (MOSES). Part 1. Effects of exposure to low concentrations of ozone on respiratory and cardiovascular outcomes. Boston (MA): Health Effects Institute; 2017. Research Report No. 192, Pt. 1.

37. Wang JC, Kobie JJ, Zhang L, Cochran M, Mosmann TR, Ritchlin CT, et al. An 11-color flow cytometric assay for identifying, phenotyping, and assessing endocytic ability of peripheral blood dendritic cell subsets in a single platform. J Immunol Methods. 2009;341(1–2): 106–116. doi: 10.1016/j.jim.2008.11.002 19049809

38. Khorana AA, Francis CW, Menzies KE, Wang JG, Hyrien O, Hathcock J, et al. Plasma tissue factor may be predictive of venous thromboembolism in pancreatic cancer. J Thromb Haemost. 2008;6(11): 1983–1985. doi: 10.1111/j.1538-7836.2008.03156.x 18795992

39. Stewart JC, Chalupa DC, Devlin RB, Frasier LM, Huang L-S, Little EL, et al. Vascular effects of ultrafine particles in persons with type 2 diabetes. Environ Health Perspect. 2010;118: 1692–1698. doi: 10.1289/ehp.1002237 20822968

40. Li N, Goodall AH, Hjemdahl P. Efficient flow cytometric assay for platelet-leukocyte aggregates in whole blood using fluorescence signal triggering. Cytometry. 1999;35(2): 154–161. 10554171

41. Jimenez JJ, Wenche J, Mauro LM, Horstman LL, Bidot CJ, Ahn YS. Endothelial microparticles (DMP) as vascular disease markers. Adv Clin Chem. 2005;39: 131–153. 16013670

42. Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151(7): 483–495. doi: 10.7326/0003-4819-151-7-200910060-00009 19805771

43. Devlin RB, McDonnell WF, Mann R, Becker S, House DE, Schreinemachers D, et al. Exposure of humans to ambient levels of ozone for 6.6 hours causes cellular and biochemical changes in the lung. Am J Respir Cell Mol Biol. 1991;4: 72–81. doi: 10.1165/ajrcmb/4.1.72 1846079

44. Thompson AMS, Zanobetti A, Silverman F, Schwartz J, Coull B, Urch B, et al. Baseline repeated measures from controlled human exposure studies: Associations between ambient air pollution exposure and the systemic inflammatory biomarkers IL-6 and fibrinogen. Environ Health Perspect. 2010;118: 120–124. doi: 10.1289/ehp.0900550 20056584

45. Schnabel R, Blankenberg S. Oxidative stress in cardiovascular disease: successful translation from bench to bedside? Circulation. 2007;116(12): 1338–1340. doi: 10.1161/CIRCULATIONAHA.107.728394 17875978

46. Chen C, Arjomandi M, Balmes J, Tager I, Holland N. Effects of chronic and acute ozone exposure on lipid peroxidation and antioxidant capacity in healthy young adults. Environ Health Perspect. 2007;115(12): 1732–1737. doi: 10.1289/ehp.10294 18087591

47. Chuang KJ, Chan CC, Su TC, Lee CT, Tang CS. The effect of urban air pollution on inflammation, oxidative stress, coagulation, and autonomic dysfunction in young adults. Am J Resp Crit Care Med. 2007;176(4): 370–376. doi: 10.1164/rccm.200611-1627OC 17463411

48. Patrignani P, Tacconelli S. Isoprostanes and other markers of peroxidation in atherosclerosis. Biomarkers. 2005;10 Suppl 1: S24–S29.

49. Morrow JD. The isoprostanes—unique products of arachidonate peroxidation: their role as mediators of oxidant stress. Curr Pharm Des. 2006;12(8): 895–902. doi: 10.2174/138161206776055985 16533158

50. Laskin DL, Fakhrzadeh L, Laskin JD. Nitric oxide and peroxynitrite in ozone-induced lung injury. Adv Exp Med Biol. 2001;500: 183–190. doi: 10.1007/978-1-4615-0667-6_24 11764933

51. Yu AP, Tam BT, Yau WY, Chan KS, Yu SS, Chung TL, et al. Association of endothelin-1 and matrix metallopeptidase-9 with metabolic syndrome in middle-aged and older adults. Diabetol Metab Syndr. 2015;7: 111. doi: 10.1186/s13098-015-0108-2 26692905

52. Calderon-Garciduenas L, Vincent R, Mora-Tiscareno A, Franco-Lira M, Henriquez-Roldan C, Barragan-Mejia G, et al. Elevated plasma endothelin-1 and pulmonary arterial pressure in children exposed to air pollution. Environ Health Perspect. 2007;115(8): 1248–1253. doi: 10.1289/ehp.9641 17687455

53. Bossard M, Pumpol K, van der Lely S, Aeschbacher S, Schoen T, Krisai P, et al. Plasma endothelin-1 and cardiovascular risk among young and healthy adults. Atherosclerosis. 2015;239(1): 186–191. doi: 10.1016/j.atherosclerosis.2014.12.061 25617859

54. Bohm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 2007;76(1): 8–18. doi: 10.1016/j.cardiores.2007.06.004 17617392

55. Pernow J, Shemyakin A, Bohm F. New perspectives on endothelin-1 in atherosclerosis and diabetes mellitus. Life Sci. 2012;91(13–14): 507–516. doi: 10.1016/j.lfs.2012.03.029 22483688

56. Barath S, Langrish JP, Lundbäck M, Bosson JA, Goudie C, Newby DE, et al. Ozone exposure does not impair vascular function or affect heart rate variability in humans. Toxicol Sci. 2013;135: 292–299. doi: 10.1093/toxsci/kft157 23872581

57. Kahle JJ, Neas LM, Devlin RB, Case MW, Schmitt MT, Madden MC, et al. Interaction effects of temperature and ozone on lung function and markers of systemic inflammation, coagulation, and fibrinolysis: a crossover study of healthy young volunteers. Environ Health Perspect. 2015;123(4): 310–316. doi: 10.1289/ehp.1307986 25514459

58. Strak M, Hoek G, Steenhof M, Kilinc E, Godri KJ, Gosens I, et al. Components of ambient air pollution affect thrombin generation in healthy humans: the RAPTES project. Occup Environ Med. 2013;70(5): 332–340. doi: 10.1136/oemed-2012-100992 23378445

59. Liao D, Heiss G, Chinchilli VM, Duan Y, Folsom AR, Lin HM, et al. Association of criteria pollutants with plasma hemostatic/inflammatory markers: a population-based study. J Expo Anal Environ Epidemiol. 2005;15(4): 319–328. doi: 10.1038/sj.jea.7500408 15536489

60. Goodman JE, Prueitt RL, Sax SN, Pizzurro DM, Lynch HN, Zu K, et al. Ozone exposure and systemic biomarkers: Evaluation of evidence for adverse cardiovascular health impacts. Crit Rev Toxicol. 2015;45(5): 412–452. doi: 10.3109/10408444.2015.1031371 25959700

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