Manufactured and airborne nanoparticle cardiopulmonary interactions: a review of mechanisms and the possible contribution of mast cells

Abstract

Human inhalation exposures to manufactured nanoparticles (NP) and airborne ultrafine particles (UFP) continues to increase in both occupational and environmental settings. UFP exposures have been associated with increased cardiovascular mortality and morbidity, while ongoing research supports adverse systemic and cardiovascular health effects after NP exposures. Adverse cardiovascular health effects include alterations in heart rate variability, hypertension, thrombosis, arrhythmias, increased myocardial infarction, and atherosclerosis. Exactly how UFP and NP cause these negative cardiovascular effects is poorly understood, however a variety of mediators and mechanisms have been proposed. UFP and NP, as well as their soluble components, are known to systemically translocate from the lung. Translocated particles could mediate cardiovascular toxicity through direct interactions with the vasculature, blood, and heart. Recent study suggests that sensory nerve stimulation within the lung may also contribute to UFP- and NP-induced acute cardiovascular alterations. Activation of sensory nerves, such as C-fibers, within the lung may result in altered cardiac rhythm and function. Lastly, release of pulmonary-derived mediators into systemic circulation has been proposed to facilitate cardiovascular effects. In general, these proposed pulmonary-derived mediators include proinflammatory cytokines, oxidatively modified macromolecules, vasoactive proteins, and prothrombotic factors. These pulmonary-derived mediators have been postulated to contribute to the subsequent prothrombotic, atherogenic, and inflammatory effects after exposure. This review will evaluate the potential contribution of individual mediators and mechanisms in facilitating cardiopulmonary toxicity following inhalation of UFP and NP. Lastly, we will appraise the literature and propose a hypothesis regarding the possible role of mast cells in contributing to these systemic effects.

Figure 1

Possible mediators and mechanisms of cardiovascular toxicity following NP and UFP inhalation exposure. After inhalation, NP and UFP may translocate and induce cardiovascular toxicity, while particles remaining within the lung may alter cardiac function via autonomic nervous system dysfunction. Pulmonary inflammation and oxidative stress may lead to increases in systemic levels of oxidized-macromolecules, cytokines, and vasoactive and prothrombotic factors which can systemically result in adverse cardiovascular health effects.

Figure 2

Potential mechanism by which IL-33 release could lead to the activation of mast cells and mediate the systemic effects of inhaled NP and UFP. Inhalation of NP and UFP can stimulate the production of IL-33 from alveolar epithelial cells and macrophages resulting in activation of pulmonary mast cells. This activation causes the released causes the released of variety of mast cell-derived mediators resulting in pulmonary inflammation and injury. These mast cell-derived mediators could also leak into the circulation and mediate the cardiovascular effects of NP and UFP. The IL-33 produced within the lung could also reach the circulation and activate systemic mast cells, thereby mediating the cardiovascular effects of NP and UFP.