How inhaled nanoparticles contribute to vascular disease

Relation

Miller MR, Raftis JB, Langrish JP, et al. Inhaled nanoparticles accumulate at sites of vascular disease.ACS Nano. 2017;11(5):4542-4552.

Objective

To determine whether inhaled nanoparticles directly cause cardiovascular disease (CVD) by moving across the lungs or simply trigger systemic inflammatory responses.

Draft

This paper reports the results of a series of clinical and animal studies, each designed to answer a specific question about how nanoparticles contribute to cardiovascular disease. In each study, participants were exposed to gold nanoparticles either through inhalation (humans) or direct instillation through the trachea (mice), followed by blood, urine, or tissue samples.

Participant

The first (N=14 men) and second (N=19) studies involved healthy human volunteers; Participants in the third human study were patients who had recently suffered a cardiovascular accident and were scheduled to undergo carotid endarterectomy (N=12). The first rodent experiment included normal mice; the second involved apolipoprotein E knockout mice (ApoE-/-) that were fed a high-fat diet to accelerate the development of atherosclerotic lesions.

Interventions

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 an average of 3.8 nm particles for 2 hours; In the second human study, 10 were exposed to small (~4 nm) particles and 9 to large (34 nm) particles. In the first animal experiment, mice were exposed to different sizes from 2 to 200 nm; In the second animal experiment, mice were exposed to 5 nm particles for 5 weeks. In the third human study, 3 of the 12 patients were exposed to inhaled gold nanoparticles (5 nm) for 4 hours before surgery.

Knowledge from this study may help us avert increases in morbidity by encouraging the 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 gold levels in blood are low, investigators could assume that any material detected was obtained experimentally.

Target parameters

Concentrations of gold nanoparticles in blood, urine and carotid plaque tissue (animal experiment 2 and human experiment 3). Gold contents were determined using high-resolution inductively coupled plasma mass spectroscopy (HR-ICPMS) and Raman microscopy.

Results

Gold was detected in the blood of healthy volunteers exposed to inhaled nanoparticles within 15 minutes and was still present 3 months after exposure. Concentrations were significantly higher after inhalation of smaller (4–5 nm) particles compared to larger (30+ nm) particles. In mice, accumulation was significantly greater in the smaller (<10 nm) particles than in the larger (10–200 nm) range.

In both human and animal studies, gold nanoparticles preferentially accumulated in areas of greater inflammation, particularly in vascular lesions. The authors conclude that inhaled gold nanoparticles rapidly enter the systemic circulation and accumulate at sites of vascular inflammation. This provides a direct mechanism explaining the association between environmental nanoparticles and cardiovascular disease.

Clinical implications

In recent years, various studies have reported significant associations between inhalational exposure to nanoparticles from vehicle exhaust and the risk of morbidity and mortality. We now have a decent explanation as to why and how this happens. Furthermore, the rapid growth in the production and use of nanomaterials has the potential to greatly increase human exposure. Knowledge from this study may help us avert increases in morbidity by encouraging the implementation of safe manufacturing and handling practices to reduce accidental exposures. To date, our understanding of a mechanism of action that would explain the association with cardiovascular disease has been rudimentary. This paper advances our understanding and certainly urges caution.

The authors showed that inhaled nanoparticles pass from the lungs into the circulation in humans and that the particles accumulate at sites of vascular inflammation. Particle translocation appears to be size dependent, with greater translocation and accumulation of smaller nanoparticles.

Previous research shows that acute exposure to diesel exhaust causes vascular dysfunction, thrombosis, and myocardial ischemia in healthy individuals and in patients with coronary artery disease.¹Chronic exposure to particulate air pollution is associated with the development and progression of atherosclerosis in both animals and humans.²

But it wasn't clear how this happens. Inhaled particles are known to lodge deep in the lungs and trigger oxidative stress and inflammation.³One theory is that the inflammatory mediators triggered by these particles enter the general circulation and influence disease risk. Others believe that the nanoparticles themselves penetrate the alveolar epithelium and enter the circulation, contributing directly to disease.⁴This paper strongly suggests that the latter mechanism is more likely. It's probably not such an easy choice. In the end, we will probably understand that the nanoparticles trigger tissue inflammation, which increases the translocation of particles.⁵

While the results of this present study provide a compelling explanation for how CVD risk may be related to exposure to nanoparticles in the environment, it only suggests one possible explanation for the findings reported by Bakian et al Seestadt,⁶or the results of an observational study by Power et al., which found a connection between air pollution and anxiety.⁷These 2 publications suggest that nanoparticles not only enter the general circulation, but also cross the blood-brain barrier and also trigger mental illnesses.

This study does not prove a causal relationship. The data only shows that nanoparticles accumulate at sites of vascular disease; they do not prove that nanoparticles cause or worsen CVD.

The results of this paper and similar studies should be of concern to our patients suffering from or at risk of CVD. Limiting exposure to obvious sources of inhaled nanoparticles, particularly diesel exhaust, may help limit disease progression. However, less obvious sources of exposure to nanoparticles also pose risks. The number of nanoparticles in our everyday environment continues to increase. For example, few would recognize toner inks used in home and office printing as risks for CVD, but they release nanomaterials (used to improve toner performance) and have been linked to respiratory problems.⁸Food dyes also contain titanium dioxide nanoparticles, which can enter the body and cause oxidative stress.⁹

This paper expands our understanding of the problems caused by diesel and other byproducts of fossil fuel combustion. The size and number of particles in the air may ultimately be of greater importance than absolute mass, as smaller particles can pose a greater threat. This paper also alerts us to the potential danger posed by a variety of nanosubstances that are considered benign, not because of their chemical components, but because of their size and ability to move and then accumulate at sites of inflammation.