Pulmonary exposure to diesel exhaust particles promotes cerebral microvessel thrombosis: protective effect of a cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid.
ABSTRACT Inhaled particulate matter is associated with increased cerebro- and cardiovascular events. However, the systemic mechanisms underlying these effects remain unclear. In the present study, we investigated the mechanisms underlying the relationship between airway and systemic inflammation and pial cerebral venular thrombosis, 24h after intratracheal (i.t.) instillation of diesel exhaust particles (DEP; 15 or 30 microg/mouse) or saline (control). Doses of 15 and 30 microg/mouse induced a dose-dependent macrophage and neutrophil influx into the bronchoalveolar lavage (BAL) fluid with elevation of total proteins and Trolox equivalent antioxidant capacity (TEAC), but without IL-6 release. Similarly, in plasma, IL-6 concentrations did not increase but the TEAC was significantly and dose-dependently decreased. The number of platelets and the tail bleeding time were both significantly reduced after exposure to DEP (30 microg). Interestingly, the same dose showed platelet proaggregatory effect in mouse pial cerebral venules. Pretreatment with the cysteine prodrug l-2-oxothiazolidine-4-carboxylic acid (OTC, 80 mg/kg) 24 and 1h before i.t. DEP (30 microg), abolished the DEP-induced macrophage and neutrophil influx, and the increase of TEAC in BAL. Lung histopathology confirmed the protective effect of OTC on DEP-induced lung inflammation. OTC also reversed the decrease of TEAC concentrations in plasma, the shortening of the bleeding time, and the thrombotic effect of DEP in pial cerebral venules. We conclude that pulmonary exposure to DEP cause oxidative stress responsible, at least partially, for the pulmonary and systemic inflammation and thrombotic events in the pial cerebral microvessels of mice. OTC pretreatment abrogated these effects through its ability to balance oxidant-antioxidant status.
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ABSTRACT: Several epidemiological and clinical studies have shown that exposure to particulate air pollution is associated with increases in morbidity and mortality, and this is more evident in patients with renal diseases. However, the basis of the possible exacerbating effect of particulate air pollution on animal model of renal injury has received scant attention. Here, we assessed the effect of repeated exposure to diesel exhaust particles (DEP) on cisplatin (CP)-induced nephrotoxicity in rats. DEP (0.5 m/kg) was intratracheally (i.t.) instilled every second day for eight days (a total of five exposures). CP, 6 mg/kg was given 1 h before the third exposure to DEP. Two days following the last exposure to either DEP or saline (control), various renal endpoints were measured. Water intake, urine volume, and relative kidney weight were significantly increased in CP + DEP versus DEP and CP + saline versus saline. Plasma creatinine increased and creatinine clearance decreased in CP + DEP versus DEP and CP + saline versus saline. Interestingly, blood urea nitrogen, albumin concentrations, and gamma-glutamyl transpeptidase (GGT) activity in urine were significantly increased in DEP + CP compared with either DEP or saline + CP. The combination of DEP and CP enhanced kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, 8-isoprostane and total nitric oxide in the kidney compared with either saline + CP or DEP. Similarly, systolic blood pressure was increased in CP + DEP versus CP + saline or DEP. The renal tubular necrosis observed in kidneys of CP-treated rats was aggravated by the combination of CP + DEP. We conclude that repeated exposure to DEP potentiated CP-induced nephrotoxicity. Our data provide experimental evidence that patients with kidney injury could be at higher risk than the general population.Experimental Biology and Medicine 04/2014; · 2.80 Impact Factor
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ABSTRACT: Amorphous silica nanoparticles (SiNPs) are being used in biomedical, pharmaceutical, and many other industrial applications entailing human exposure. However, their potential vascular and systemic pathophysiologic effects are not fully understood. Here, we investigated the acute (24 hours) systemic toxicity of intraperitoneally administered 50 nm and 500 nm SiNPs in mice (0.5 mg/kg). Both sizes of SiNPs induced a platelet proaggregatory effect in pial venules and increased plasma concentration of plasminogen activator inhibitor-1. Elevated plasma levels of von Willebrand factor and fibrinogen and a decrease in the number of circulating platelets were only seen following the administration of 50 nm SiNPs. The direct addition of SiNPs to untreated mouse blood significantly induced in vitro platelet aggregation in a dose-dependent fashion, and these effects were more pronounced with 50 nm SiNPs. Both sizes of SiNPs increased lactate dehydrogenase activity and interleukin 1β concentration. However, tumor necrosis factor α concentration was only increased after the administration of 50 nm SiNPs. Nevertheless, plasma markers of oxidative stress, including 8-isoprostane, thiobarbituric acid reactive substances, catalase, and glutathione S-transferase, were not affected by SiNPs. The in vitro exposure of human umbilical vein endothelial cells to SiNPs showed a reduced cellular viability, and more potency was seen with 50 nm SiNPs. Both sizes of SiNPs caused a decrease in endothelium-dependent relaxation of isolated small mesenteric arteries. We conclude that amorphous SiNPs cause systemic inflammation and coagulation events, and alter vascular reactivity. Overall, the effects observed with 50 nm SiNPs were more pronounced than those with 500 nm SiNPs. These findings provide new insight into the deleterious effect of amorphous SiNPs on vascular homeostasis.International Journal of Nanomedicine 06/2014; 9(1):2779 - 2789. · 4.20 Impact Factor
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ABSTRACT: Air pollution has been estimated to be responsible for several millions of deaths worldwide per year, the majority of which have been attributed to cardiovascular causes. The particulate matter in air pollution has been shown impair vascular function, increase blood pressure, promote thrombosis and impair fibrinolysis, accelerate the development of atherosclerosis, increase the extent of myocardial ischaemia, and increase susceptibility to myocardial infarction. The pathways underlying these effects are complex and poorly understood; however, particulate-induced oxidative stress repeatedly emerges as a potential mechanism in all of these detrimental cardiovascular actions. The present mini-review will use diesel exhaust as an example of a pollutant rich in combustion-derived nanoparticles, to describe the potential by which oxidative stress could drive the cardiovascular effects of air pollution.Biochemical Society Transactions 08/2014; 42(4):1006-11. · 2.59 Impact Factor