The effects and underlying mechanisms by which engineered and combustion derived nanoparticles impact platelet function

Abstract

Combustion-derived nanoparticles (diameter ≤ 100 nm) present in air pollution are thought to be associated with the onset of platelet-driven thrombotic events such as myocardial infarction. In addition, the emergence of nanotechnology has led to increased human exposure to engineered nanoscale structures. My first aim was to establish whether engineered nanoparticles could influence platelet function and whether this was dictated by their size and surface charge. The second aim was to evaluate if combustion-derived nanoparticles could modulate platelet aggregation in-vivo and determine the underlying mechanisms. 50 nm and 100 nm carboxyl, amine and unmodified model engineered polystyrene nanoparticles as well as diesel exhaust particles (DEP) and carbon black (CB) were intratracheal (i.t.) or intravenously (i.v.) administered into mice and in-vitro and in-vivo platelet aggregation, markers of pulmonary and systemic inflammation and plasma nitrate levels were measured. All model engineered nanoparticles induced concentration-dependent platelet aggregation which was inhibited by conventional platelet inhibitors and endogenous vascular regulators. In contrast, amine-modified 50 nm particles enhanced agonist-induced platelet aggregation in-vitro and in-vivo. DEP increased agonist-induced platelet aggregation in-vivo that was not associated with inflammation or altered plasma nitrite levels. In contrast, CB did not increase platelet aggregation but did appear to initiate inflammation. All nanoparticles investigated induced platelet aggregation with potencies and mechanisms that were dependent upon a distinct combination of size and surface chemistry. 50 nm cationic particles may present the largest risk to human health by exacerbating thrombotic events, as they can enhance the effects of platelet agonists at low concentrations. Additionally, exposure to DEP can enhance platelet aggregation in-vivo suggesting that the thrombotic incidents triggered by acute exposure to particulate pollutants may be platelet driven although the underlying mechanism does not appear to involve systemic inflammation or alterations in NO bioavailability.