Abstract
The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2–200 nm primary diameter), with translocation markedly greater for particles <10 nm diameter. Gold nanoparticles preferentially accumulated in inflammation-rich vascular lesions of fat-fed apolipoproteinE-deficient mice. Furthermore, following inhalation, gold particles could be detected in surgical specimens of carotid artery disease from patients at risk of stroke. Translocation of inhaled nanoparticles into the systemic circulation and accumulation at sites of vascular inflammation provides a direct mechanism that can explain the link between environmental nanoparticles and cardiovascular disease and has major implications for risk management in the use of engineered nanomaterials.
Highlights
The manufacture of nanomaterials is growing exponentially and with this so is the potential for human exposure
While these observations are important, a major area of uncertainty remains: How do inhaled particles influence the pathogenesis of systemic cardiovascular disease? Are inhaled nanoparticles able to translocate into the circulation and directly contribute to cardiovascular disease?
Fourteen healthy male volunteers were exposed to gold nanoparticles (median primary particle size of 3.8 nm, present in loose agglomerates of 18.7 nm by inhalation (116 ± 12 μg/m3; 5.8 ± 0.3 × 106 particles/cm3) for 2 h during intermittent exercise (Supplementary Figure S1)
Summary
The manufacture of nanomaterials is growing exponentially and with this so is the potential for human exposure. Pollution, such as that derived from vehicle exhaust, remains a major public health concern.[10,11] We have previously demonstrated that acute exposure to diesel exhaust causes vascular dysfunction, thrombosis, and myocardial ischemia in healthy individuals and in patients with coronary heart disease.[12,13] Chronic exposure to particulate air pollution is associated with the development and progression of the vascular disease atherosclerosis in animals and man.[14,15] While these observations are important, a major area of uncertainty remains: How do inhaled particles influence the pathogenesis of systemic cardiovascular disease? An alternative hypothesis is that inhaled nanoparticles penetrate the alveolar epithelium and translocate into the circulation and directly contribute to cardiovascular disease.[19,20] It has been speculated that these processes may be accelerated by inflammation, through increased permeability of the alveolar wall or through assisted translocation within macrophages.[21−23]
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