Inhalation of diesel exhaust increases ex vivo thrombus formation and causes in vivo platelet activation in man. These findings provide a potential mechanism linking exposure to combustion-derived air pollution with the triggering of acute MI.

We have previously demonstrated that short-term exposure to diesel exhaust (DE) for 1 h induced a marked leukocytic infiltration in the airways of healthy human volunteers involving neutrophils, lymphocytes, and mast cells along with increases in several inflammatory mediators. We hypothesized that the leukocyte infiltration and the various inflammatory responses induced by DE were mediated by enhanced chemokine and cytokine production by resident cells of the airway tissue and lumen. To investigate this, 15 healthy human volunteers were exposed to diluted DE and air on two separate occasions for 1 h each in an exposure chamber. Fiberoptic bronchoscopy was performed 6 h after each exposure to obtain endobronchial biopsies and bronchial wash (BW) cells. Using reverse transcriptase/polymerase chain reaction enzyme-linked immunosorbent assay (RT-PCR ELISA), a novel and sensitive technique to quantify relative amounts of cytokine mRNA gene transcripts, and immunohistochemical staining with computer-assisted image analysis to quantify expression of cytokine protein in the bronchial tissue, we have demonstrated that DE enhanced gene transcription of interleukin-8 (IL-8) in the bronchial tissue and BW cells along with increases in IL-8 and growth-regulated oncogene-alpha (GRO-alpha) protein expression in the bronchial epithelium, and an accompanying trend toward an increase in IL-5 mRNA gene transcripts in the bronchial tissue. There were no significant changes in the gene transcript levels of interleukin-1B (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interferon gamma (IFN-gamma), and granulocyte macrophage colony-stimulating factor (GM-CSF) either in the bronchial tissue or BW cells after DE exposure at this time point. These observations suggest an underlying mechanism for DE-induced airway leukocyte infiltration and offer a possible explanation for the association observed between ambient levels of particulate matter and various respiratory health outcome indices noted in epidemiological studies.

Background-In controlled human exposure studies, diesel engine exhaust inhalation impairs vascular function and enhances thrombus formation. The aim of the present study was to establish whether an exhaust particle trap could prevent these adverse cardiovascular effects in men. Methods and Results-Nineteen healthy volunteers (mean age, 25Ϯ3 years) were exposed to filtered air and diesel exhaust in the presence or absence of a particle trap for 1 hour in a randomized, double-blind, 3-way crossover trial. Bilateral forearm blood flow and plasma fibrinolytic factors were assessed with venous occlusion plethysmography and blood sampling during intra-arterial infusion of acetylcholine, bradykinin, sodium nitroprusside, and verapamil. Ex vivo thrombus formation was determined with the use of the Badimon chamber. Compared with filtered air, diesel exhaust inhalation was associated with reduced vasodilatation and increased ex vivo thrombus formation under both low-and high-shear conditions. The particle trap markedly reduced diesel exhaust particulate number (from 150 000 to 300 000/cm 3 to 30 to 300/cm 3 ; PϽ0.001) and mass (320Ϯ10 to 7.2Ϯ2.0 g/m 3 ; PϽ0.001), and was associated with increased vasodilatation, reduced thrombus formation, and an increase in tissue-type plasminogen activator release. Conclusions-Exhaust particle traps are a highly efficient method of reducing particle emissions from diesel engines. With a range of surrogate measures, the use of a particle trap prevents several adverse cardiovascular effects of exhaust inhalation in men. Given these beneficial effects on biomarkers of cardiovascular health, the widespread use of particle traps on diesel-powered vehicles may have substantial public health benefits and reduce the burden of cardiovascular disease. Clinical Trial Registration-http://www.clinicaltrials.gov. Unique identifier: NCT00745446. (Circulation. 2011;123:1721-1728.) Key Words: air pollution Ⅲ endothelium Ⅲ thrombosis T here is a robust and consistent association between air pollution and cardiorespiratory morbidity and mortality. [1][2][3][4] These harmful effects are most strongly associated with exposure to traffic-derived fine particles (particulate matter [PM] with a mean diameter Ͻ2.5 m [PM 2.5 ]) that originate predominantly from diesel engine exhaust emissions. 5 Diesel engines are popular because of their reliability, efficiency, and relatively low running costs. However, they generate up to 100 times more fine particles than petroleum engines of a similar size and contribute substantially to the global burden of PM air pollution. Editorial see p 1705 Clinical Perspective on p 1728According to the World Health Organization, air pollution is responsible for at least 800 000 premature deaths worldwide each year, with an average loss of life of 1 year. 6 The long-term risk of cardiovascular death rises by 76% for each 10-g/m 3 increase in PM 2.5 . 7,8 Short-term exposure has been linked to the triggering of acute myocardial infarction, 9 with patients 3 times more likely to be expo...

In previous studies we have described the acute inflammatory response of the human airway to inhaled DE. This was characterized by neutrophil, mast cell, and lymphocyte infiltration into the bronchial mucosa with enhanced epithelial expression of IL-8, Gro-␣, and IL-13. In the present study, we investigated whether redox-sensitive transcription factors were activated as a consequence of DE exposure, consistent with oxidative stress triggering airway inflammation. In archived biopsies from 15 healthy subjects exposed to DE [particulates with a mass median diameter of Ͻ10 m, 300 g/m 3 ] and air, immunohistochemical staining was used to quantify the expression of the transcription factors NF-B (p65) and AP-1 (c-jun and c-fos), as well their upstream MAPKs, p38 and JNK, in the bronchial epithelium. In addition, phosphorylation of tyrosine residues was examined. DE induced a significant increase in the nuclear translocation of NF-B (P ϭ 0.02), AP-1 (P ϭ 0.02), phosphorylated JNK (P ϭ 0.04), and phosphorylated p38 (P ϭ 0.01), as well as an increase in total (cytoplasmic ϩ nuclear) immunostaining of phosphorylated p38 (P ϭ 0.03). A significant increase in nuclear phosphorylated tyrosine was also observed (P Ͻ0.05). These observations demonstrate that DE activates redox-sensitive transcription factors in vivo consistent with oxidative stress triggering the increased synthesis of proinflammatory cytokines.particulate matter EPIDEMIOLOGICAL STUDIES HAVE DEMONSTRATED a consistent association between the exacerbations of respiratory disease and concentrations of airborne particulate matter, especially with fine particles with an aerodynamic diameter of Ͻ2.5 m (PM 2.5 ) (22, 23). Particles derived from diesel engines are considered to comprise a significant proportion of PM 2.5 in urban areas, and both in vitro and in vivo studies have demonstrated that they have potent effects on the lung (20, 36). Exposure of human subjects to whole diesel exhaust (DE) (particulates and the associated gas phase) results in an acute inflammatory response characterized by neutrophil, lymphocyte, and mast cell influx into the airways. These cellular changes are associated with upregulation of vascular endothelial adhesion molecules as well as enhanced expression of IL-8, IL-6, Gro-␣, and IL-13 in the bronchial epithelium (24, 30, 31). Instillation of DE particle (DEP) extracts into the nose has also been shown to increase the production of mucosal T helper type 2 (Th2)-related cytokines in atopic volunteers (10). Similarly, bronchial epithelial and macrophage cell lines, as well as primary cultures of bronchial epithelial cells, have been shown to release a variety of chemokines and cytokines when treated with DEP or their organic extracts (2,4,6,7,14,15,18,26,37). The cellular and molecular mechanisms underlying these inflammatory responses remain unresolved.DE-induced cytokine release requires upregulation of signaling pathways modulating cytokine gene expression. Much attention has focused on the capacity of DEP to elicit oxidative stress ...

Every breath we take contains potentially harmful pathogens or allergens. Dendritic cells (DCs), monocytes, and macrophages are essential in maintaining a delicate balance of initiating immunity without causing collateral damage to the lungs because of an exaggerated inflammatory response. To document the diversity of lung mononuclear phagocytes at steady-state, we performed bronchoscopies on 20 healthy subjects, sampling the proximal and distal airways (bronchial wash and bronchoalveolar lavage, respectively), as well as mucosal tissue (endobronchial biopsies). In addition to a substantial population of alveolar macrophages, we identified subpopulations of monocytes, myeloid DCs (MDCs), and plasmacytoid DCs in the lung mucosa. Intermediate monocytes and MDCs were highly frequent in the airways compared with peripheral blood. Strikingly, the density of mononuclear phagocytes increased upon descending the airways. Monocytes from blood and airways produced 10-fold more proinflammatory cytokines than MDCs upon ex vivo stimulation. However, airway monocytes were less inflammatory than blood monocytes, suggesting a more tolerant nature. The findings of this study establish how to identify human lung mononuclear phagocytes and how they function in normal conditions, so that dysregulations in patients with respiratory diseases can be detected to elucidate their contribution to immunity or pathogenesis.

Particulate matter (PM) pollution has been associated with negative health effects, including exacerbations of asthma following exposure to PM peaks. The aim of the present study was to investigate the effects of short-term exposure to diesel exhaust (DE) in asthmatics, by specifically addressing the effects on airway hyperresponsiveness, lung function and airway inflammation.Fourteen nonsmoking, atopic asthmatics with stable disease, on continuous treatment with inhaled corticosteroids, were included. All were hyperresponsive to methacholine. Each subject was exposed to DE (particles with a 50% cut-off aerodynamic diameter of 10 mm (PM10) 300 mg?m -3 ) and air during 1 h on two separate occasions. Lung function was measured before and immediately after the exposures. Sputum induction was performed 6 h, and methacholine inhalation test 24 h, after each exposure.Exposure to DE was associated with a significant increase in the degree of hyperresponsiveness, as compared to after air, of 0.97 doubling concentrations at 24 h after exposure (pv0.001). DE also induced a significant increase in airway resistance (p~0.004) and in sputum levels of interleukin (IL)-6 (p~0.048). No changes were detected in sputum levels of methyl-histamine, eosinophil cationic protein, myeloperoxidase and IL-8.This study indicated that short-term exposure to diesel exhaust, equal to high ambient levels of particulate matter, is associated with adverse effects in asthmatic airways, even in the presence of inhaled corticosteroid therapy. The increase in airway responsiveness may provide an important link to epidemiological findings of exacerbations of asthma following exposure to particulate matter. Eur Respir J 2001; 17: 909-915.

The adverse health effects of particulate matter pollution are of increasing concern. In a recent bronchoscopic study in healthy volunteers, pronounced airway inflammation was detected following exposure to diesel exhaust (DE). The present study was conducted in order to evaluate the time kinetics of the inflammatory response following exposure to DE using induced sputum from healthy volunteers.Fifteen healthy nonsmoking volunteers were exposed to DE particles with a 50% cut-off aerodynamic diameter of 10 mm 300 mg . m -3 and air for 1 h on two separate occasions. Sputum induction with hypertonic saline was performed 6 and 24 h after each exposure. Analyses of sputum differential cell counts and soluble protein concentrations were performed.Six hours after exposure to DE, a significant increase was found in the percentage of sputum neutrophils (37.7 versus 26.2% p=0.002) together with increases in the concentrations of interleukin-6 (12.0 versus 6.3 pg . mL -1 , p=0.006) and methylhistamine (0.11 versus 0.12 mg . L -1 , p=0.024). Irrespective of exposure, a significant increase was found in the percentage of sputum neutrophils at 24 as compared to 6 h, indicating that the procedure of sputum induction itself may change the composition of sputum.This study demonstrates that exposure to diesel exhaust induces inflammatory response in healthy human airways, represented by an early increase in interleukin -6 and methylhistamine concentration and the percentage of neutrophils. Induced sputum provides a safe tool for the investigation of the inflammatory effects of diesel exhaust, but care must be taken when interpreting results from repeated sputum inductions. Eur Respir J 2000; 15: 1046±1051. The adverse health effects of particulate matter (PM) pollution are of increasing concern as several epidemiological studies have revealed an association between elevations in ground level PM concentrations and increased morbidity and mortality from cardiovascular and respiratory causes [1±7].Recently, attention has been directed towards the particulate air pollution emitted from diesel engines. The number of diesel-powered cars is rising and diesel engines emit up to 100 times more particles than petrol engines [8,9]. Diesel exhaust (DE) particles contain a carbonaceous core, which adsorbs various metals and organic compounds on its surface. Consequently, the biological effects of DE may be explained by not only the gases and pure particles but also by these surface components.The number of studies investigating the effects of DE has increased during recent years. In working environments, exposure to DE has been associated with various symptoms related to the eyes and airways [10±12]. In experimental chamber studies, DE has been shown to cause airway symptoms [13] and to induce an acute inflammatory response in human airways as reflected in bronchoalveolar lavage [14,15] and bronchial biopsy [16] samples. Further, local nasal challenge with DE particles has been reported to enhance immunoglobulin E production in the ...

BackgroundSmoke from combustion of biomass fuels is a major risk factor for respiratory disease, but the underlying mechanisms are poorly understood. The aim of this study was to determine whether exposure to wood smoke from incomplete combustion would elicit airway inflammation in humans.MethodsFourteen healthy subjects underwent controlled exposures on two separate occasions to filtered air and wood smoke from incomplete combustion with PM1 concentration at 314 μg/m3 for 3 h in a chamber. Bronchoscopy with bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial mucosal biopsies was performed after 24 h. Differential cell counts and soluble components were analyzed, with biopsies stained for inflammatory markers using immunohistochemistry. In parallel experiments, the toxicity of the particulate matter (PM) generated during the chamber exposures was investigated in vitro using the RAW264.7 macrophage cell line.ResultsSignificant reductions in macrophage, neutrophil and lymphocyte numbers were observed in BW (p < 0.01, <0.05, <0.05, respectively) following the wood smoke exposure, with a reduction in lymphocytes numbers in BAL fluid (<0.01. This unexpected cellular response was accompanied by decreased levels of sICAM-1, MPO and MMP-9 (p < 0.05, <0.05 and <0.01). In contrast, significant increases in submucosal and epithelial CD3+ cells, epithelial CD8+ cells and submucosal mast cells (p < 0.01, <0.05, <0.05 and <0.05, respectively), were observed after wood smoke exposure. The in vitro data demonstrated that wood smoke particles generated under these incomplete combustion conditions induced cell death and DNA damage, with only minor inflammatory responses.ConclusionsShort-term exposure to sooty PAH rich wood smoke did not induce an acute neutrophilic inflammation, a classic hallmark of air pollution exposure in humans. While minor proinflammatory lymphocytic and mast cells effects were observed in the bronchial biopsies, significant reductions in BW and BAL cells and soluble components were noted. This unexpected observation, combined with the in vitro data, suggests that wood smoke particles from incomplete combustion could be potentially cytotoxic. Additional research is required to establish the mechanism of this dramatic reduction in airway leukocytes and to clarify how this acute response contributes to the adverse health effects attributed to wood smoke exposure.Trial registrationNCT01488500Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-015-0111-7) contains supplementary material, which is available to authorized users.