The acute pulmonary and thrombotic effects of cerium oxide nanoparticles after intratracheal instillation in mice

Abstract

Cerium oxide nanoparticles (CeO 2 NPs), used as a diesel fuel catalyst, can be emitted into the ambient air, resulting in exposure to humans by inhalation. Recent studies have reported the development of lung toxicity after pulmonary exposure to CeO 2 NPs. However, little is known about the possible thrombotic effects of these NPs. The present study investigated the acute (24 hours) effect of intratracheal (IT) instillation of either CeO 2 NPs (0.1 or 0.5 mg/kg) or saline (control) on pulmonary and systemic inflammation and oxidative stress and thrombosis in mice. CeO 2 NPs induced a significant increase of neutrophils into the bronchoalveolar lavage (BAL) fluid with an elevation of tumor necrosis factor α (TNFα) and a decrease in the activity of the antioxidant catalase. Lung sections of mice exposed to CeO 2 NPs showed a dose-dependent infiltration of inflammatory cells consisting of macrophages and neutrophils. Similarly, the plasma levels of C-reactive protein and TNFα were significantly increased, whereas the activities of catalase and total antioxidant were significantly decreased. Interestingly, CeO 2 NPs significantly and dose dependently induced a shortening of the thrombotic occlusion time in pial arterioles and venules. Moreover, the plasma concentrations of fibrinogen and plasminogen activator inhibitor-1 were significantly elevated by CeO 2 NPs. The direct addition of CeO 2 NPs (1, 5, or 25 μg/mL) to mouse whole blood, collected from the inferior vena cava, in vitro neither caused significant platelet aggregation nor affected prothrombin time or partial thromboplastin time, suggesting that the thrombotic events observed in vivo may have resulted from systemic inflammation and/or oxidative stress induced by CeO 2 NPs. This study concludes that acute pulmonary exposure to CeO 2 NPs induces pulmonary and systemic inflammation and oxidative stress and promotes thrombosis in vivo.

Effects of cerium oxide nanoparticles on hemostasis: Coagulation, platelets, and vascular endothelial cells

“…Although there are studies on NC compatibility in cell and animal models, no data exist about the effects of NC on human hemostatic system. A recent study, performed in mice, showed that intratracheal instillation of NC promoted thrombosis in vivo , probably as consequence of increased oxidative stress and inflammation . Hemostasis is a complex process orchestrated by endothelial cells, the coagulation cascade, and platelets and, as shown, NPs can act on every single player .…”

“…A recent study, performed in mice, showed that intratracheal instillation of NC promoted thrombosis in vivo, probably as consequence of increased oxidative stress and inflammation. 32 Hemostasis is a complex process orchestrated by endothelial cells, the coagulation cascade, and platelets and, as shown, NPs can act on every single player. 33 In fact, the contact between NPs and blood components can result into blood clotting, platelet aggregation, and endothelial activation, leading to a hypercoagulable state that characterizes common diseases, such as diabetes mellitus, arteriosclerosis, cancer, and obstructive pulmonary disease.…”

<p>Plasma protein adsorption on Fe₃O₄-PEG nanoparticles activates the complement system and induces an inflammatory response</p>

“…On the other hand, IONP-PVP adsorbed proteins related to regulation of proteolysis (associated with blood coagulation) and the Fc receptor-mediated stimulatory signaling pathway, which could potentially modify the risk of intravascular coagulation or incidents of vascular thrombosis. 48 Moreover, nanomedicines could exacerbate some pathologies by impairment or depletion of plasma proteins. For example, the adsorption of lipoproteins is related to hypercholesterolemia and a higher risk of atherosclerosis.…”

Targeting Nanotechnologies for the Treatment of Thrombosis and Cardiovascular Disease

“…Nemmar et al recently published findings that highlighted the acute pulmonary and thrombotic effects of cerium oxide (CeO 2 ) nanoparticles. 82 These authors emphasized that upon the pulmonary exposure of CeO 2 nanoparticles in mice, prothrombotic effects were observed in addition to oxidative stress and proinflammatory physiological responses. 82 In an earlier study, Nemmar et al presented research findings where amorphous silica nanoparticles induced an impaired hemostasis as well as an elevated proinflammatory response, both in vitro and in vivo.…”

“…82 These authors emphasized that upon the pulmonary exposure of CeO 2 nanoparticles in mice, prothrombotic effects were observed in addition to oxidative stress and proinflammatory physiological responses. 82 In an earlier study, Nemmar et al presented research findings where amorphous silica nanoparticles induced an impaired hemostasis as well as an elevated proinflammatory response, both in vitro and in vivo. 83 Such studies confirm the importance of thoroughly investigating the various different nanoparticle materials in the preclinical setting to ensure that any eventual clinical application is free from adverse consequences.…”