Elsevier

Toxicology Letters

Volume 149, Issues 1–3, 1 April 2004, Pages 243-253
Toxicology Letters

Possible mechanisms of the cardiovascular effects of inhaled particles: systemic translocation and prothrombotic effects

https://doi.org/10.1016/j.toxlet.2003.12.061Get rights and content

Abstract

Particulate air pollution is associated with cardiovascular morbidity and mortality. Fine particles with a diameter <2.5 μm (PM2.5) have an important role in triggering biological responses. These particles, and particularly the ultrafine fraction (<100 nm) penetrate deeply into the respiratory tract. Recently, we have demonstrated that ultrafine particles are able to translocate from the lung into the systemic circulation in hamsters and humans. In urban areas, diesel engines are considered to be the major source of PM2.5. We therefore evaluated the acute effect (1 h) of diesel exhaust particles (DEP) in a hamster model of peripheral vascular thrombosis induced by free-radical mediated endothelial injury, using intravenous Rose Bengal and local illumination. Intratracheal doses of 5–500 μg of DEP per animal induced inflammation with elevation of neutrophils, total proteins and histamine in bronchoalveolar lavage. DEP enhanced experimental arterial and venous platelet rich-thrombus formation in vivo. Blood samples taken from hamsters 30 and 60 min after instillation of DEP caused platelet activation, when analyzed in the Platelet Function Analyser (PFA-100). The direct addition of DEP to untreated hamster blood also caused platelet aggregation. These effects persisted up to 24 h after instillation. Our results provide plausible mechanistic explanations for the epidemiologically established link between air pollution and acute cardiovascular effects.

Introduction

Air pollution is one of the major public health concerns in industrialized cities throughout the world. This issue is continuing to attract more and more attention and interest within the scientific and regulatory communities as well as the general public.

It is well known from historical data that episodes of air pollution could be responsible for increases in morbidity and mortality, the majority of which occurred among elderly individuals and people with known pre-existing cardiovascular and respiratory diseases (Anderson, 1999, Nemery et al., 2001).

Although it is clear that urban air pollution consists of a highly complex and variable mixture of gaseous and particulate agents, there is a consensus among scientists that while gaseous pollutants, such as ozone, play an important role, the unifying element in most studies of the adverse health effects of urban air pollution consists of respirable particles (Brunekreef and Holgate, 2002, Dockery et al., 1992, Samet et al., 2000, Schwartz, 1997. Indeed, epidemiological investigations have reported close associations between levels of particulate matter with a diameter ≤10 μm (PM10) and morbidity and mortality attributable to respiratory and cardiovascular complications (Samet et al., 2000, Schwartz, 1994, Wordley et al., 1997). More recently, Pope et al. (2002) concluded from mortality data on 500,000 individuals throughout the United States between 1979 and 2000 that for every 10 μg/m3 increase in fine particles (PM2.5), all-cause mortality increased by 6% annually and cardiopulmonary mortality by 9%.

One of the important findings of these epidemiological observations is that peaks of air pollution not only have respiratory effects, but they also increase cardiovascular morbidity and mortality (Peters et al., 1999). In fact, more people seem to die from cardiovascular than from pulmonary diseases during episodes of urban air pollution (Pope et al., 1999). Moreover, a number of recent epidemiological studies support that parameters of cardiovascular function are affected by particulate air pollutants (Gold et al., 2000, Liao et al., 1999). In addition, short-term effects of exposure to particles have been recently described. For instance, it has been reported that exposure to particulate air pollution increased the susceptibility to ischemia (Pekkanen et al., 2002) and the occurrence of myocardial infarction (Peters et al., 2001).

Although most studies have mainly investigated the link with PM10 (or PM2.5), recent evidence (essentially from experimental studies) suggests that the so-called ultrafine fraction of these particles (UFPs), i.e. particles with diameter below 0.1 μm, could be of greatest concern. These particles deposit in greater numbers and deeper into the lungs, than larger particles. In addition, they have a larger surface area than larger-sized particles, thus having greater potential for interactions with biological targets and causing a greater inflammatory response (Nemmar et al., 1999, Oberdorster et al., 1996). UFPs are mainly emitted from combustion engines (e.g. diesel-powered engines) and other high-temperature processes in the form of fractal-like aggregates composed of solid nanoparticles (Xiong and Friedlander, 2001). Because of the large increase in vehicle traffic, these ultrafine particles are now probably more frequent than in the past, when other sources of energy, such as coal or other fuels were used. Thus, more than 100,000 particles per cubic centimeter may be found in the vicinity of a busy road (Shi et al., 2000).

However, the underlying pathophysiological mechanisms linking particulate air pollution and cardiovascular morbidity and mortality remain to be elucidated. One of the reasons why it is important to improve our understanding of how pollutant particles may impact on cardiovascular endpoints, is that the hitherto relative absence of biological plausibility for the epidemiological associations has led some people to question the causality between these observations and urban air pollution.

Therefore, the main purpose of this article is to report our contribution in the understanding of how inhaled particles may affect the cardiovascular system. Thus, our starting hypothesis of this mechanistic approach was to assess whether and to what extent ultrafine particles might: (1) translocate from the lungs into the systemic circulation and thus (2) influence, directly or indirectly hemostasis and relevant cardiovascular endpoints such as thrombosis. All the results described here have been previously published (Nemmar et al., 2002a, Nemmar et al., 2002b, Nemmar et al., 2003a, Nemmar et al., 2003b).

Section snippets

Materials and methods

The studies described below were reviewed and approved by the Institutional Review Board of the University of Leuven.

Systemic translocation experiments in humans (Nemmar et al., 2002a)

Radioactivity was detected in blood already after 1 min, reached a maximum between 10 and 20 min and remained at this level up to 60 min (Fig. 3).

At all time points, TLC of blood showed a peak of radioactivity at the application point and another peak that moved with the solvent front. The TLC after the direct addition to blood of Technegas particles (collected on a filter, at the mouth) or 99mTc-pertechnetate (TcO4) showed that the bound radioactivity stays at the origin whilst the free

Discussion

Our study was initiated in order to find biological plausibility for the intriguing and consistent epidemiological association between particulate air pollution and cardiovascular mortality and morbidity.

Acknowledgements

The authors are grateful to Prof. Vermylen (Center of Molecular and Vascular Biology, K.U. Leuven), Prof. Mortelmans (Nuclear Medicine, K.U. Leuven) and all other co-authors of the cited articles. This work was supported by grants from the Katholieke Universiteit Leuven (F/00/058 and OT/02/45) and from the Fund for Scientific Research Flanders (G.0165.03).

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