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: To test for a significant association between air pollution and emergency hospital admissions for circulatory diseases (international classification of diseases-9 390-459) in London, England, that would be consistent with a causal effect of pollution on the previous day. Long term concurrent trends, temperature, humidity, day of the week, influenza epidemic of 1989, and cyclical covariations with periodicity > 20 days in daily measures of pollution and admissions for 1987-94 were allowed for. There were 373556 admissions. No association was found between O3 and circulatory diseases. Four other pollutants were associated with acute myocardial infarction and circulatory diseases combined. P values and attributable cases (95% confidence intervals) for acute myocardial infarction were: black smoke P = 0.003, 2.5% (0.8% to 4.3%); NO2 P = 0.002, 2.7% (0.8% to 4.6%); CO P = 0.001, 2.1% (0.7% to 3.5%); and SO2 P = 0.0006, 1.7% (0.7% to 2.6%). There were also associations between black smoke and angina (P = 0.02), NO2 and arrhythmia (P = 0.04), and CO and other circulatory diseases (P = 0.004), but none with heart failure. Acute myocardial infarction was the only diagnosis for which there were significant associations with and without adjustment for cyclical terms. The associations with acute myocardial infarction were significant only in the cool season. Population data were consistent with 1 in 50 heart attacks currently presenting at London hospitals being triggered by outdoor air pollution. Further research is now needed to investigate whether background concentrations of black smoke, NO2, CO, and SO2 are a preventable cause of myocardial infarction. These results, if applied to all myocardial infarctions in the United Kingdom, indicate a potential saving of 6000 heart attacks a year.Occupational and Environmental Medicine 08/1997; 54(8):535-40. · 3.22 Impact Factor
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ABSTRACT: Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.European Respiratory Journal 03/2006; 27(2):359-65. · 6.36 Impact Factor
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ABSTRACT: Recently, it has been demonstrated that ultrafine particles (UFPs) are able to translocate from the lung into the systemic circulation. Precise mechanisms of the anatomical translocation (crossing the air-blood barrier) of inhaled UFPs at the alveolar wall are not fully understood. In this study, we examined the translocation pathway of the intratracheally instilled ultrafine carbon black (UFCB) from the lung into the blood circulation in mouse. Electron microscopy demonstrated accumulation of intratracheally instilled UFCB in the large-sized gaps developing between the cytoplasmic processes of the alveolar epithelial cells, possibly as a result of shrinkage of cytoplasm, by receiving stimulus/signals generated and released following UFCB attachment on the alveolar epithelial cells. Occasional penetration of the accumulated UFCB into the alveolar basement membrane, exposing to the air space, was observed at the gap. These results suggest that inhaled UFPs may, in part, pass the air-blood barrier through the large-sized gap formed between the alveolar epithelial cells.Toxicologic Pathology 02/2006; 34(7):949-57. · 2.06 Impact Factor