Exposure to diesel exhaust nanoparticles does not induce blood hypercoagulability in an at-risk population
Article first published online: 11 AUG 2005
Journal of Thrombosis and Haemostasis
Volume 3, Issue 9, pages 2103–2105, September 2005
How to Cite
BLOMBERG, A., TÖRNQVIST, H., DESMYTER, L., DENEYS, V. and HERMANS, C. (2005), Exposure to diesel exhaust nanoparticles does not induce blood hypercoagulability in an at-risk population. Journal of Thrombosis and Haemostasis, 3: 2103–2105. doi: 10.1111/j.1538-7836.2005.01559.x
- Issue published online: 11 AUG 2005
- Article first published online: 11 AUG 2005
- Received 24 May 2005, accepted 16 June 2005
The respiratory tract is regarded as the main target for air pollutants. Epidemiological studies have reported that exposure to ambient air pollution, especially particulate matter (PM) pollutants, is associated with increased cardiovascular morbidity and mortality, mainly in elderly individuals with pre-existing chronic heart or lung diseases . However, the biological mechanisms linking cardiovascular diseases to PM air pollution remain to be elucidated.
Diesel exhaust (DE) is a major contributor to ambient PM pollution and contains a great number of ultra-fine, nanometer-sized particles. In a previous Lancet publication by Seaton and collaborators , it was suggested that alveolar inflammation provoked by inhalation of ultra-fine particles, in addition to promoting exacerbations of respiratory disease, has an additional effect on coagulability of the blood and, hence, increased the susceptibility of individuals to acute episodes of cardiovascular disease. Therefore, the aim of the present study was to investigate whether acute exposure to diesel exhaust nanoparticles would result in extra-pulmonary adverse effects including activation of blood coagulation, systemic inflammation, endothelial damage or alteration of the pulmonary epithelium integrity.
Fifteen ex-smoking individuals (mean age 66 years; range: 56–72) with mild to moderate chronic obstructive pulmonary disease (COPD) according to GOLD-criteria (FEV1 ranging from 50 to 80 of predicted value and FEV% <70%) participated. None of the subjects suffered from diabetes mellitus, acute respiratory infection, or clinically significant ischemic coronary heart disease. The subjects were exposed to diesel exhaust at a PM concentration of 300 μg m−3 and filtered air for 1 h on two separate occasions in a single-blinded randomized manner, according to a standard protocol . During the exposures, the subjects alternated rest and mild exercise (VE = 10–15 L min−1 m−2) on a bicycle ergometer. The study was approved by the local ethics committee and subjects gave their written informed consent. Peripheral blood samples were drawn at three time-points: before, 6 and 24 h after the end of each exposure. Systemic inflammation was estimated by C-reactive protein and fibrinogen. von Willebrand factor (VWF) activity was measured as a surrogate of endothelial damage. D-dimer and prothrombin fragment 1–2 were determined in order to detect activation of blood coagulation. Finally, Clara cell protein (CC16) was measured as a sensitive peripheral indicator of the integrity of the lung–blood barrier.
Data are presented as medians and interquartile range. Differences between DE and air exposures (value after DE − value after air) for each marker at the three time-points were compared using Friedman test. A P-value of <0.05 was considered significant. No significant diesel exhaust-induced changes were seen in either of the determined markers (Fig. 1).
Even if the biological mechanisms responsible for the cardiovascular effects are largely unknown, several hypothetical patho-physiological pathways have been suggested among which altered cardiac autonomic function, endothelial damage, systemic inflammation, and blood hypercoagulability . However, none of these mechanisms has so far been clearly validated.
In the present study, individuals with COPD, as a susceptible subgroup with respect to air pollution, were exposed to diesel exhaust at a PM concentration that could be encountered in occupational settings, cities with congested streets and in enclosed spaces such as tunnel and garages. The particles generated as a consequence of diesel combustion are extremely small (mainly <100 nm) and are considered the most deleterious fraction of PM air pollution because of their ability to reach the deep lung. Based on previous human data, it is well known that exposure to DE induces oxidative stress, and inflammation in the airways of healthy humans [3,4]. However, it has been suggested that these nanoparticles are rapidly removed from the airways through a combination of phagocytosis, lymphatic flow towards hilar nodes, and capillary blood flow . Furthermore, it has been shown that ultra fine carbon particles can be detected in peripheral blood in humans within minutes after inhalation .
In order to address the aim of the present study, very sensitive systemic markers were selected. C-reactive protein, and fibrinogen are two acute-phase proteins, which increase as a consequence of inflammation and are considered as cardiovascular risk factors. D-dimer, and prothrombin fragment 1 + 2 are indicators of a low-grade activation of blood coagulation. As they are released at the end of the coagulation cascade, an increase of these markers would indicate the activation of the whole coagulation process. The vascular endothelium plays a pivotal role in regulating hemostasis and produces many important substances involved in cardiovascular patho-physiology. Such a substance is VWF, the activity of which is proposed as a sensitive marker of endothelial function and integrity, which plays an important role in hemostasis by mediating platelet aggregation and adhesion on the injured vessel. Finally, CC16 in plasma is considered a sensitive marker of integrity of the lung–blood barrier.
The present findings do not support the hypothesis of diesel exhaust nanoparticle-induced systemic effects in a susceptible group of individuals with COPD. Neither was, in contrast to studies after ozone exposure , any sign of DE-induced injury on the lung epithelium present, as CC16 plasma levels remained unchanged. It cannot be excluded that this study has certain limitations. First, the exposure duration is short, although performed at a high ambient PM concentration. However, studies in healthy individuals using a similar protocol have revealed airway as well as systemic inflammation in terms of increased white blood cell counts 6 h postexposure . Secondly, the time frame for sampling in the present study was limited, although based on previous data [3,4]. Thus it cannot be excluded that the chosen time-points could be too early or too late to detect a signal. Thirdly, it remains possible that other markers of inflammation and blood hypercoagulability would have been more sensitive in a diesel exhaust-induced response.
In conclusion, this study gives no support to the hypothesis that short-term exposure to diesel nanoparticles is associated with systemic inflammation, activation of blood coagulation, endothelial dysfunction or lung epithelial injury in at-risk individuals with COPD. Additional studies employing other susceptible populations and endpoints are pending.
This work was supported by grants from the Swedish Heart-Lung Foundation, the Umeå University, Sweden, the European Commission HELIOS project (QLK4–1308), and the Salus Sanguinis Foundation of the Cliniques Universitaires Saint-Luc, Belgium. The authors are grateful to Professors Pierre Wallemacq and Alfred Bernard for their assistance in the assays of CC16 and CRP.