Miller MR, Raftis JB, Langrish JP, et al. Inhaled nanoparticles accumulate at sites of vascular disease. ACS Nano. 2017;11(5):4542-4552.
To determine if inhaled nanoparticles cause cardiovascular disease (CVD) directly, by translocating across the lung, or simply trigger systemic inflammatory reactions.
This paper reports results of a series of clinical and animal experiments, each designed to answer a specific question regarding how nanoparticles contribute to cardiovascular disease. In each trial, participants were exposed to gold nanoparticles by either inhalation (humans), or instillation directly through the trachea (mice), followed by blood, urine, or tissue sampling.
The first (N=14 men) and second (N=19) trials involved healthy human volunteers; participants in the third human trial were patients who had recently had cardiovascular accidents and were scheduled for carotid endarterectomy (N=12). The first rodent experiment involved normal mice; the second involved apolipoprotein E knockout mice (ApoE-/-) who had been fed a high-fat diet to accelerate development of atherosclerotic lesions.
In all experiments participants were exposed to gold nanoparticles, but particle size and exposure duration varied. Participants in the first human trial were exposed to 3.8 nm particle average for 2 hours; in the second human trial, 10 were exposed to small (~4 nm) particles and 9 to large (34 nm) particles. In the first animal trial, mice were exposed to varying sizes, from 2 to 200 nm; in the second animal trial, mice were exposed to 5 nm particles over 5 weeks. In the third human trial, 3 of the 12 patients were exposed to inhaled gold nanoparticles (5 nm) for 4 hours prior to surgery.
Knowledge from this study may help us avert an increase in morbidity by encouraging implementation of safe manufacturing and handling practices to reduce accidental exposures.
Gold nanoparticles were used because they are similar in size to combustion-derived nanoparticles but have low biological activity; they are also easier to measure. Because endogenous levels of gold in the blood are low, investigators could assume that any detected material was derived experimentally.
Levels of gold nanoparticles in blood, urine, and carotid plaque tissue (animal trial 2 and human trial 3). Levels of gold were determined using high-resolution inductively coupled plasma mass spectroscopy (HR-ICPMS) and Raman microscopy.
Gold was detected in the blood of healthy volunteers exposed to inhaled nanoparticles within 15 minutes and was still present 3 months after exposure. Levels were significantly greater following inhalation of smaller (4-5 nm) particles compared to larger (30+ nm) particles. In mice, accumulation was markedly greater in the smaller (<10 nm) particles than in the larger (10-200 nm) range.
In both human and animal trials, gold nanoparticles preferentially accumulated in areas of greater inflammation, in particular vascular lesions. The authors conclude that inhaled gold nanoparticles rapidly translocate into systemic circulation and accumulate at sites of vascular inflammation. This provides a direct mechanism that explains the link between environmental nanoparticles and cardiovascular disease.
In recent years various studies have reported significant associations between inhaled nanoparticle exposure derived from vehicular exhaust and morbidity and mortality risk. We now have a decent explanation for why and how this happens. In addition, the rapid growth of nanomaterial manufacture and utilization has the potential to greatly increase human exposure. Knowledge from this study may help us avert an increase in morbidity by encouraging implementation of safe manufacturing and handling practices to reduce accidental exposures. Until now our understanding of a mechanism of action that would explain the cardiovascular disease association has been rudimentary. This paper advances our understanding and certainly suggests caution.
The authors demonstrated that inhaled nanoparticles translocate from the lung into the circulation in man, and the particles accumulate at sites of vascular inflammation. Particle translocation appears to be size-dependent, with greater translocation and accumulation of smaller nanoparticles.
Prior research shows that acute exposure to diesel exhaust causes vascular dysfunction, thrombosis, and myocardial ischemia in healthy individuals and in patients with coronary heart disease.1 Chronic exposure to particulate air pollution is associated with development and progression of atherosclerosis in both animals and humans.2
But it has not been clear how this happens. Inhaled particles are known to deposit deep in the lungs and trigger oxidative stress and inflammation.3 One theory suggests that the inflammatory mediators triggered by these particles pass into general circulation and influence disease risk. Others believe that the nanoparticles themselves penetrate the alveolar epithelium and translocate into the circulation and directly contribute to disease.4 This paper strongly suggests that the latter mechanism is more likely. It is probably not this simple a choice. In the end we will likely come to understand that the nanoparticles trigger tissue inflammation, which increases the translocation of particles.5
While the results of this present study provide a convincing explanation for how CVD risk may be linked to environmental nanoparticle exposure, it only hints toward a possible explanation for the results observed by Bakian et al, which positively associated air pollution levels to suicide rates in Salt Lake City,6 or the results of an observational study by Power et al, which found an association between air pollution and anxiety.7 These 2 papers suggest that nanoparticles not only pass into general circulation but also cross the blood-brain barrier, triggering psychological morbidities as well.
This study does not prove a causative association. The data only show that nanoparticles accumulate at sites of vascular disease; they do not prove that nanoparticles cause or aggravate CVD.
The findings of this paper and similar studies should raise concern for our patients who have, or who are at risk for, CVD. Limiting exposure to obvious sources of inhaled nanoparticles, in particular diesel exhaust, may help limit disease progression. However, less obvious sources of nanoparticle exposures also pose risks. The number of nanoparticles in our everyday environment continues to escalate. For example, few would recognize toner inks used in home and office printing as hazards for CVD, but they release nanomaterials (used to improve toner performance) and have been associated with respiratory problems.8 Also, food pigments contain titanium dioxide nanoparticles, which can enter the body and cause oxidative stress.9
This paper further advances our understanding of the problems posed by diesel and other fossil fuel combustion byproducts. The size and number of airborne particulates may eventually be of greater concern than absolute mass as smaller particles may pose greater threat. This paper also alerts us to the potential danger posed by a wide variety of nanosubstances considered benign, not because of their chemical constituents but because of their size and ability to translocate and then accumulate at sites of inflammation.
- Lucking AJ, Lundback M, Mills NL, et al. Diesel exhaust inhalation increases thrombus formation in man. Eur Heart J. 2008;29(24):3043-3051.
- Brook RD. Cardiovascular effects of air pollution. Clin Sci (Lond). 2008;115(6):175-187.
- Miller MR, Shaw CA, Langrish JP. From particles to patients: oxidative stress and cardiovascular effects of air pollution. Future Cardiol. 2012;8(4):577-602.
- Hussain M, Wu D, Saber AT, et al. Intratracheally instilled titanium dioxide nanoparticles translocate to heart and liver and activate complement cascade in the heart of C57BL/6 mice. Nanotoxicology. 2015;9(8):1013-1022.
- Meiring JJ, Borm PJ, Bagatelle K, et al. The influence of hydrogen peroxide and histamine on lung permeability and translocation of iridum nanoparticles in the isolated rat lung. Part Fibre Toxicol. 2005;2:3.
- Bakian AV, Huber RS, Coon H, et al. Acute air pollution exposure and risk of suicide completion. Am J Epidemiol. 2015;181(5):295-303.
- Power MC, Kioumourtzoglou MA, Hart JE, Okereke OI, Laden F, Weisskopf MG. The relation between past exposure to fine particulate air pollution and prevalent anxiety: observational cohort study. BMJ. 2015;350:h1111.
- Pirela SV, Martin J, Bello D, Demokritou P. Nanoparticle exposures from nano-enabled toner-based printing equipment and human health: state of science and future research needs [published online ahead of print May 19, 2017]. Crit Rev Toxicol.
- Jayaram DT, Runa S, Kemp ML, Payne CK. Nanoparticle-induced oxidation of corona proteins initiates an oxidative stress response in cells. Nanoscale. 2017;9(22):7595-7601.