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: Diesel exhaust and its particles (DEP) have been under scrutiny for health effects in humans. In the development of these effects inflammation is regarded as a key process. Overall, in vitro studies report similar DEP-induced changes in markers of inflammation, including cytokines and chemokines, as studies in vivo. In vitro studies suggest that soluble extracts of DEP have the greatest impact on the expression and release of proinflammatory markers. Main DEP mediators of effects have still not been identified and are difficult to find, as fuel and engine technology developments lead to continuously altered characteristics of emissions. Involved mechanisms remain somewhat unclear. DEP extracts appear to comprise components that are able to activate various membrane and cytosolic receptors. Through interactions with receptors, ion channels, and phosphorylation enzymes, molecules in the particle extract will trigger various cell signaling pathways that may lead to the release of inflammatory markers directly or indirectly by causing cell death. In vitro studies represent a fast and convenient system which may have implications for technology development. Furthermore, knowledge regarding how particles elicit their effects may contribute to understanding of DEP-induced health effects in vivo, with possible implications for identifying susceptible groups of people and effect biomarkers.02/2013; 2013:685142. DOI:10.1155/2013/685142
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ABSTRACT: Epidemiological and clinical studies have linked exposure to particulate matter (PM) to adverse health effects, which may be registered as increased mortality and morbidity from various cardiopulmonary diseases. Despite the evidence relating PM to health effects, the physiological, cellular, and molecular mechanisms causing such effects are still not fully characterized. Two main approaches are used to elucidate the mechanisms of toxicity. One is the use of in vivo experimental models, where various effects of PM on respiratory, cardiovascular, and nervous systems can be evaluated. To more closely examine the molecular and cellular mechanisms behind the different physiological effects, the use of various in vitro models has proven to be valuable. In the present review, we discuss the current advances on the toxicology of particulate matter and nanoparticles based on these techniques.01/2013; 2013:279371. DOI:10.1155/2013/279371
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ABSTRACT: Earlier studies have suggested an important role of glutathione (GSH) in cytoprotection against free radicals induced oxidative damage. This study reports gastroprotective effects of a cysteine precursor, L-2-oxothiazolidine-4-carboxylate (OTC), in experimental models of gastric secretion and ulceration. Acid secretion studies (volume and acidity) were undertaken in pylorus-ligated rats whereas the gastric lesions were induced by ethanol. Different groups of animals were treated with OTC (0, 100, 200 and 400 mg/kg). The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were measured in the glandular stomach of rats following ethanol-induced gastric lesions. Both medium and high doses of OTC significantly reduced the volume and acidity of gastric secretion in pylorus-ligated rats. Pretreatment with OTC significantly and dose-dependently attenuated the formation of ethanol-induced gastric lesion. OTC significantly protected the gastric mucosa against ethanol-induced depletion of gastric wall mucus, NP-SH and MPO. The gastroprotective effects of OTC may be attributed to its ability to inhibit neutrophils activity and replenish GSH demand.Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 03/2012; 64(3):233-7. DOI:10.1016/j.etp.2010.08.012 · 2.01 Impact Factor