Article

Pulmonary exposure to diesel exhaust particles promotes cerebral microvessel thrombosis: Protective effect of a cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid

Department of Physiology, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates.
Toxicology (Impact Factor: 3.62). 07/2009; 263(2-3):84-92. DOI: 10.1016/j.tox.2009.06.017
Source: PubMed

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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    • "It is possible that the increase in oxidative stress induced by SiNP may have been accompanied by increased antioxidant enzymes , indicating that SiNP could trigger adaptive responses that counterbalance the potentially damaging activity of oxygen radicals. An increase of total antioxidants in bronchoalveolar lavage has been observed following the pulmonary exposure to particulate air pollution in mice [22]. It has been reported that amorphous SiNP penetrate the platelet plasma membrane and stimulate a rapid and prolonged NO release leading to eNOS uncoupling, ONOO - over-production and eventually, a low [NO]/[ONOO - ] ratio and high nitroxidative/oxidative stress [8]. "

    Full-text · Dataset · Aug 2015
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    • "It is possible that the increase in oxidative stress induced by SiNP may have been accompanied by increased antioxidant enzymes , indicating that SiNP could trigger adaptive responses that counterbalance the potentially damaging activity of oxygen radicals. An increase of total antioxidants in bronchoalveolar lavage has been observed following the pulmonary exposure to particulate air pollution in mice [22]. It has been reported that amorphous SiNP penetrate the platelet plasma membrane and stimulate a rapid and prolonged NO release leading to eNOS uncoupling, ONOO - over-production and eventually, a low [NO]/[ONOO - ] ratio and high nitroxidative/oxidative stress [8]. "

    Full-text · Dataset · Jul 2015
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    • "It is possible that the increase in oxidative stress induced by SiNP may have been accompanied by increased antioxidant enzymes , indicating that SiNP could trigger adaptive responses that counterbalance the potentially damaging activity of oxygen radicals. An increase of total antioxidants in bronchoalveolar lavage has been observed following the pulmonary exposure to particulate air pollution in mice [22]. It has been reported that amorphous SiNP penetrate the platelet plasma membrane and stimulate a rapid and prolonged NO release leading to eNOS uncoupling, ONOO -over-production and eventually, a low [NO]/[ONOO -] ratio and high nitroxidative/oxidative stress [8]. "
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    ABSTRACT: Amorphous silica nanoparticles (SiNP) are being investigated for their potential use in various industrial and medical fields. Therefore, the assessment of their possible pathophysiological effect on circulating cells such as platelets is essential. We recently showed that intraperitoneal administration of SiNP causes proinflammatory and prothrombotic responses in vivo. However, little is known about the interaction of amorphous SiNP with platelets in vitro. Presently, we investigated the in vitro effects of SiNP (1, 5 and 25 μg/ml) on platelet aggregation, oxidative stress and intracellular calcium in mouse platelets. Incubation of platelets with SiNP caused a significant and dose-dependent platelet aggregation. Similarly, the activity of lactate dehydrogenase (as a marker of cell membrane integrity) was significantly increased by SiNP. Total antioxidant activity and lipid platelets vulnerability to in vitro peroxidation (measured by malondialdehyde production) were significantly increased after SiNP exposure. Additionally, SiNP exposure significantly increased the cytosolic calcium concentration. In conclusion, our in vitro data show that incubation of platelets with SiNP caused platelet aggregation, oxidative stress and increased intracellular calcium. This finding provides evidence on the toxicity of SiNP on platelet physiology.
    Full-text · Article · Jun 2015 · International Journal of Physiology, Pathophysiology and Pharmacology
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