Thromb Haemost 2012; 108(04): 756-768
DOI: 10.1160/TH12-03-0161
Animal Models
Schattauer GmbH

Thrombogenic changes in young and old mice upon subchronic exposure to air pollution in an urban roadside tunnel

Jan Emmerechts
1   Center for Molecular and Vascular Biology, University of Leuven, Belgium
,
Vanessa De Vooght
2   Occupational & Environmental Medicine, Unit of lung toxicology, University of Leuven, Belgium
,
Steven Haenen
2   Occupational & Environmental Medicine, Unit of lung toxicology, University of Leuven, Belgium
,
Serena Loyen
1   Center for Molecular and Vascular Biology, University of Leuven, Belgium
,
Soetkin Van kerckhoven
1   Center for Molecular and Vascular Biology, University of Leuven, Belgium
,
Bianca Hemmeryckx
1   Center for Molecular and Vascular Biology, University of Leuven, Belgium
,
Jeroen A. J. Vanoirbeek
2   Occupational & Environmental Medicine, Unit of lung toxicology, University of Leuven, Belgium
,
Peter H. Hoet
2   Occupational & Environmental Medicine, Unit of lung toxicology, University of Leuven, Belgium
,
Ben Nemery
2   Occupational & Environmental Medicine, Unit of lung toxicology, University of Leuven, Belgium
,
Marc F. Hoylaerts
1   Center for Molecular and Vascular Biology, University of Leuven, Belgium
› Author Affiliations
Further Information

Publication History

Received: 12 March 2012

Accepted after major revision: 31 July 2012

Publication Date:
29 November 2017 (online)

Summary

Epidemiological studies indicate that elderly persons are particularly susceptible to the cardiovascular health complications of air pollution, but pathophysiological mechanisms behind the increased susceptibility remain unclear. Therefore, we investigated how continuous traffic-related air pollution exposure affects haemostasis parameters in young and old mice. Young (10 weeks) and old (20 months) mice were placed in an urban roadside tunnel or in a clean environment for 25 or 26 days and markers of inflammation and endothelial cells or blood platelet activation were measured, respectively. Plasma microvesicles and pro/ anticoagulant factors were analysed, and thrombin generation analysis was performed. Despite elevated macrophage carbon load, tunnel mice showed no overt pulmonary or systemic inflammation, yet manifested reduced pulmonary thrombomudulin expression and elevated endothelial von Willebrand factor (VWF) expression in lung capillaries. In young mice, soluble P-selectin (sP-sel) increased with exposure and correlated with soluble E-selectin and VWF. Baseline plasma factor VIII (FVIII), sP-sel and VWF were higher in old mice, but did not pronouncedly increase further with exposure. Traffic-related air pollution markedly raised red blood cell and blood platelet numbers in young and old mice and procoagulant blood platelet-derived microvesicle numbers in old animals. Changes in coagulation factors and thrombin generation were mild or absent. Hence, continuous traffic-related air pollution did not trigger overt lung inflammation, yet modified pulmonary endothelial cell function and enhanced platelet activity. In old mice, subchronic exposure to polluted air raised platelet numbers, VWF, sP-sel and microvesicles to the highest values presently recorded, collectively substantiating a further elevation of thrombogenicity, already high at old age.

 
  • References

  • 1 Baccarelli A, Martinelli I, Zanobetti A. et al. Exposure to particulate air pollution and risk of deep vein thrombosis. Arch Intern Med 2008; 168: 920-927.
  • 2 Dominici F, McDermott A, Daniels M. et al. Mortality among residents of 90 cities. In Revised Analyses of Time-Series Studies of Air Pollution and Health. Boston, MA: Health Effects Institute; 2003: 9-24.
  • 3 Hoek G, Brunekreef B, Goldbohm S. et al. Association between mortality and indicators of traffic-related air pollution in the Netherlands: a cohort study. Lancet 2002; 360: 1203-1209.
  • 4 Katsouyanni K, Touloumi G, Samoli E. et al. Confounding and effect modification in the short-term effects of ambient particles on total mortality: results from 29 European cities within the APHEA2 project. Epidemiology 2001; 12: 521-531.
  • 5 Pope 3rd CA, Burnett RT, Thurston GD. et al. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004; 109: 71-77.
  • 6 Samet JM, Rappold A, Graff D. et al. Concentrated ambient ultrafine particle exposure induces cardiac changes in young healthy volunteers. Am J Respir Crit Care Med 2009; 179: 1034-1042.
  • 7 Samoli E, Peng R, Ramsay T. et al. Acute effects of ambient particulate matter on mortality in Europe and North America: results from the APHENA study. Environ Health Perspect 2008; 116: 1480-1486.
  • 8 Rudez G, Janssen NA, Kilinc E. et al. Effects of ambient air pollution on hemostasis and inflammation. Environ Health Perspect 2009; 117: 995-1001.
  • 9 Brook RD, Rajagopalan S, Pope 3rd CA. et al. Particulate matter air pollution and cardiovascular disease: An update to the scientific statement from the American Heart Association. Circulation 2010; 121: 2331-2378.
  • 10 Peters A, Dockery DW, Muller JE. et al. Increased particulate air pollution and the triggering of myocardial infarction. Circulation 2001; 103: 2810-2815.
  • 11 Lucking AJ, Lundback M, Mills NL. et al. Diesel exhaust inhalation increases thrombus formation in man. Eur Heart J 2008; 29: 3043-3051.
  • 12 Mills NL, Tornqvist H, Gonzalez MC. et al. Ischemic and thrombotic effects of dilute dieselexhaust inhalation in men with coronary heart disease. N Engl J Med 2007; 357: 1075-1082.
  • 13 Hoffmann B, Moebus S, Mohlenkamp S. et al. Residential exposure to traffic is associated with coronary atherosclerosis. Circulation 2007; 116: 489-496.
  • 14 Baccarelli A, Martinelli I, Pegoraro V. et al. Living near major traffic roads and risk of deep vein thrombosis. Circulation 2009; 119: 3118-3124.
  • 15 Sacks JD, Stanek LW, Luben TJ, Johns DO, Buckley BJ, Brown JS. et al. Particulate matter-induced health effects: who is susceptible?. Environ Health Perspect 2011; 119: 446-454.
  • 16 Goldberg MS, Burnett RT, Bailar 3rd JC. et al. The association between daily mortality and ambient air particle pollution in Montreal, Quebec. 2. Cause-specific mortality. Environ Res 2001; 86: 26-36.
  • 17 Pope 3rd CA, Renlund DG, Kfoury AG. et al. Relation of heart failure hospitalization to exposure to fine particulate air pollution. Am J Cardiol 2008; 102: 1230-1234.
  • 18 Larrieu S, Jusot JF, Blanchard M. et al. Short term effects of air pollution on hospitalizations for cardiovascular diseases in eight French cities: the PSAS program. Sci Total Environ 2007; 387: 105-112.
  • 19 Anderson HR, Atkinson RW, Bremner SA. et al. Particulate air pollution and hospital admissions for cardiorespiratory diseases: are the elderly at greater risk?. Eur Respir J Suppl 2003; 40: 39s-46s.
  • 20 Lloyd-Jones DM, Larson MG, Beiser A. et al. Lifetime risk of developing coronary heart disease. Lancet 1999; 353: 89-92.
  • 21 Naess IA, Christiansen SC, Romundstad P. et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 05: 692-699.
  • 22 Emmerechts J, Loyen S, Hoylaerts MF. Microparticle number or procoagulant activity are not upregulated in healthy elderly persons. Thromb Res 2012; 129: 98-100.
  • 23 Emmerechts J, Alfaro-Moreno E, Vanaudenaerde BM. et al. Short-term exposure to particulate matter induces arterial but not venous thrombosis in healthy mice. J Thromb Haemost 2010; 08: 2651-2661.
  • 24 Morel O, Toti F, Hugel B. et al. Procoagulant microparticles: disrupting the vascular homeostasis equation?. Arterioscler Thromb Vasc Biol 2006; 26: 2594-2604.
  • 25 Emmerechts J, Jacobs L, Van Kerckhoven S. et al. Air Pollution-Associated Procoagulant Changes: role of Circulating Microvesicles. J Thromb Haemost 2012; 10: 96-106.
  • 26 Kulkarni NS, Prudon B, Panditi SL. et al. Carbon loading of alveolar macrophages in adults and children exposed to biomass smoke particles. Sci Total Environ 2005; 345: 23-30.
  • 27 Jacobs L, Emmerechts J, Mathieu C. et al. Air pollution related prothrombotic changes in persons with diabetes. Environ Health Perspect 2010; 118: 191-196.
  • 28 Hemmeryckx B, Emmerechts J, Bovill EG. et al. Effect of ageing on the murine venous circulation. Histochem Cell Biol 2012; 137: 537-546.
  • 29 Moura R, Tjwa M, Vandervoort P. et al. Thrombospondin-1 deficiency accelerates atherosclerotic plaque maturation in ApoE-/- mice. Circ Res 2008; 103: 1181-1189.
  • 30 Hemmeryckx B, Van Hove CE, Fransen P. et al. Progression of the prothrombotic state in aging Bmal1-deficient mice. Arterioscler Thromb Vasc Biol 2011; 31: 2552-2559.
  • 31 Peters LL, Cheever EM, Ellis HR. et al. Large-scale, high-throughput screening for coagulation and hematologic phenotypes in mice. Physiol Genomics 2002; 11: 185-193.
  • 32 Wu Z, Liu MC, Liang M. et al. Sirt1 protects against thrombomodulin downregulation and lung coagulation following particulate matter exposure. Blood 2012; 119: 2422-2429.
  • 33 Poursafa P, Kelishadi R, Lahijanzadeh A. et al. The relationship of air pollution and surrogate markers of endothelial dysfunction in a population-based sample of children. BMC Public Health 2011; 11: 115.
  • 34 Mills NL, Tornqvist H, Robinson SD. et al. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation 2005; 112: 3930-3936.
  • 35 Tornqvist H, Mills NL, Gonzalez M. et al. Persistent endothelial dysfunction in humans after diesel exhaust inhalation. Am J Respir Crit Care Med 2007; 176: 395-400.
  • 36 Mills NL, Miller MR, Lucking AJ. et al. Combustion-derived nanoparticulate induces the adverse vascular effects of diesel exhaust inhalation. Eur Heart J 2011; 32: 2660-2671.
  • 37 Theilmeier G, Michiels C, Spaepen E. et al. Endothelial von Willebrand factor recruits platelets to atherosclerosis-prone sites in response to hypercholesterolemia. Blood 2002; 99: 4486-4493.
  • 38 Nemmar A, Hoet PH, Vandervoort P. et al. Enhanced peripheral thrombogenicity after lung inflammation is mediated by platelet-leukocyte activation: role of P-selectin. J Thromb Haemost 2007; 05: 1217-1226.
  • 39 Nemmar A, Hoet PH, Dinsdale D. et al. Diesel exhaust particles in lung acutely enhance experimental peripheral thrombosis. Circulation 2003; 107: 1202-1208.
  • 40 Nemmar A, Hoet PH, Vanquickenborne B. et al. Passage of inhaled particles into the blood circulation in humans. Circulation 2002; 105: 411-414.
  • 41 Chirinos JA, Heresi GA, Velasquez H. et al. Elevation of endothelial microparticles, platelets, and leukocyte activation in patients with venous thromboembolism. J Am Coll Cardiol 2005; 45: 1467-1471.
  • 42 Gerlofs-Nijland ME, Totlandsdal AI, Kilinc E. et al. Pulmonary and cardiovascular effects of traffic-related particulate matter: 4-week exposure of rats to roadside and diesel engine exhaust particles. Inhal Toxicol 2010; 22: 1162-1173.
  • 43 Motohashi H, Kimura M, Fujita R. et al. NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation. Blood 2010; 115: 677-686.
  • 44 Baskurt OK, Levi E, Caglayan S. et al. Hematological and hemorheological effects of air pollution. Arch Environ Health 1990; 45: 224-228.
  • 45 Chen KC, Lee EW, McGrath JJ. Effect of intermittent carbon monoxide inhalation on erythropoiesis and organ weights in rats. J Appl Toxicol 1984; 04: 145-149.
  • 46 Saadat M, Bahaoddini A. Hematological changes due to chronic exposure to natural gas leakage in polluted areas of Masjid-i-Sulaiman (Khozestan province, Iran). Ecotoxicol Environ Saf 2004; 58: 273-276.
  • 47 Goldberg ED, Dygai AM, Zakharova O. et al. The modulating influence of enkephalins on the bone marrow haemopoiesis in stress. Folia Biol 1990; 36: 319-331.
  • 48 Ratajczak MZ, Kuczynski WI, Onodera K. et al. A reappraisal of the role of insulin-like growth factor I in the regulation of human hematopoiesis. J Clin Invest 1994; 94: 320-327.
  • 49 Seaton A, Soutar A, Crawford V. et al. Particulate air pollution and the blood. Thorax 1999; 54: 1027-1032.
  • 50 Ziaei S, Nouri K, Kazemnejad A. Effects of carbon monoxide air pollution in pregnancy on neonatal nucleated red blood cells. Paediatr Perinat Epidemiol 2005; 19: 27-30.
  • 51 Mutlu GM, Green D, Bellmeyer A. et al. Ambient particulate matter accelerates coagulation via an IL-6-dependent pathway. J Clin Invest 2007; 117: 2952-2961.
  • 52 Budinger GR, McKell JL, Urich D. et al. Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms. PLoS One 2011; 06: e18525.
  • 53 Kilinc E, Van Oerle R, Borissoff JI. et al. Factor XII activation is essential to sustain the procoagulant effects of particulate matter. J Thromb Haemost 2011; 09: 1359-1367.