| 41. |
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| 42. |
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| 43. |
- Mills, Nicholas L, et al.
(författare)
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Adverse cardiovascular effects of air pollution
- 2009
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Ingår i: Nature Clinical Practice Cardiovascular Medicine. - : Springer Science and Business Media LLC. - 1743-4297 .- 1743-4300. ; 6:1, s. 36-44
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Tidskriftsartikel (refereegranskat)abstract
- Air pollution is increasingly recognized as an important and modifiable determinant of cardiovascular disease in urban communities. Acute exposure has been linked to a range of adverse cardiovascular events including hospital admissions with angina, myocardial infarction, and heart failure. Long-term exposure increases an individual's lifetime risk of death from coronary heart disease. The main arbiter of these adverse health effects seems to be combustion-derived nanoparticles that incorporate reactive organic and transition metal components. Inhalation of this particulate matter leads to pulmonary inflammation with secondary systemic effects or, after translocation from the lung into the circulation, to direct toxic cardiovascular effects. Through the induction of cellular oxidative stress and proinflammatory pathways, particulate matter augments the development and progression of atherosclerosis via detrimental effects on platelets, vascular tissue, and the myocardium. These effects seem to underpin the atherothrombotic consequences of acute and chronic exposure to air pollution. An increased understanding of the mediators and mechanisms of these processes is necessary if we are to develop strategies to protect individuals at risk and reduce the effect of air pollution on cardiovascular disease.
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| 44. |
- Mills, Nicholas L, et al.
(författare)
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Air pollution and atherothrombosis.
- 2007
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Ingår i: Inhal Toxicol. - : Informa UK Limited. - 1091-7691. ; 19 Suppl 1, s. 81-9
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Tidskriftsartikel (refereegranskat)
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| 45. |
- Mills, Nicholas L, et al.
(författare)
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Exposure to concentrated ambient particles does not affect vascular function in patients with coronary heart disease
- 2008
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Ingår i: Journal of Environmental Health Perspectives. - : National Institute of Environmental Health Sciences. - 0091-6765 .- 1552-9924. ; 116:6, s. 709-715
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exposure to fine particulate air pollution is associated with increased cardiovascular morbidity and mortality. We previously demonstrated that exposure to dilute diesel exhaust causes vascular dysfunction in humans.OBJECTIVES: We conducted a study to determine whether exposure to ambient particulate matter causes vascular dysfunction. METHODS: Twelve male patients with stable coronary heart disease and 12 age-matched volunteers were exposed to concentrated ambient fine and ultrafine particles (CAPs) or filtered air for 2 hr using a randomized, double-blind cross-over study design. We measured peripheral vascular vasomotor and fibrinolytic function, and inflammatory variables-including circulating leukocytes, serum C-reactive protein, and exhaled breath 8-isoprostane and nitrotyrosine-6-8 hr after both exposures.RESULTS: Particulate concentrations (mean +/- SE) in the exposure chamber (190+/-37 microg/m(3)) were higher than ambient levels (31+/-8 microg/m(3)) and levels in filtered air (0.5+/-0.4 microg/m(3); p<0.001). Chemical analysis of CAPs identified low levels of elemental carbon. Exhaled breath 8-isoprostane concentrations increased after exposure to CAPs (16.9+/-8.5 vs. 4.9+/-1.2 pg/mL, p<0.05), but markers of systemic inflammation were largely unchanged. Although there was a dose-dependent increase in blood flow and plasma tissue plasminogen activator release (p<0.001 for all), CAPs exposure had no effect on vascular function in either group.CONCLUSIONS: Despite achieving marked increases in particulate matter, exposure to CAPs--low in combustion-derived particles--did not affect vasomotor or fibrinolytic function in either middle-aged healthy volunteers or patients with coronary heart disease. These findings contrast with previous exposures to dilute diesel exhaust and highlight the importance of particle composition in determining the vascular effects of particulate matter in humans.
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| 46. |
- Mills, Nicholas L, et al.
(författare)
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Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease
- 2007
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 357:11, s. 1075-1082
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exposure to air pollution from traffic is associated with adverse cardiovascular events. The mechanisms for this association are unknown. We conducted a controlled exposure to dilute diesel exhaust in patients with stable coronary heart disease to determine the direct effect of air pollution on myocardial, vascular, and fibrinolytic function.METHODS: In a double-blind, randomized, crossover study, 20 men with prior myocardial infarction were exposed, in two separate sessions, to dilute diesel exhaust (300 mug per cubic meter) or filtered air for 1 hour during periods of rest and moderate exercise in a controlled-exposure facility. During the exposure, myocardial ischemia was quantified by ST-segment analysis using continuous 12-lead electrocardiography. Six hours after exposure, vasomotor and fibrinolytic function were assessed by means of intraarterial agonist infusions.RESULTS: During both exposure sessions, the heart rate increased with exercise (P<0.001); the increase was similar during exposure to diesel exhaust and exposure to filtered air (P=0.67). Exercise-induced ST-segment depression was present in all patients, but there was a greater increase in the ischemic burden during exposure to diesel exhaust (-22+/-4 vs. -8+/-6 millivolt seconds, P<0.001). Exposure to diesel exhaust did not aggravate preexisting vasomotor dysfunction, but it did reduce the acute release of endothelial tissue plasminogen activator (P=0.009; 35% decrease in the area under the curve).CONCLUSIONS: Brief exposure to dilute diesel exhaust promotes myocardial ischemia and inhibits endogenous fibrinolytic capacity in men with stable coronary heart disease. Our findings point to ischemic and thrombotic mechanisms that may explain in part the observation that exposure to combustion-derived air pollution is associated with adverse cardiovascular events.
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| 47. |
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| 48. |
- Pourazar, Jamshid, 1953-
(författare)
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Activation of epithelial signal transduction pathways, cytokine production and airway inflammation following diesel exhaust exposure
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adverse health effects of ambient air pollution are well recognised and include increased morbidity and mortality in respiratory and cardiovascular diseases. Diesel engines are major contributors to ambient particulate matter pollution and diesel particles have been shown to have strong toxicological and oxidative properties.Mechanistic aspects of diesel engine exhaust exposure have been investigated in bronchial mucosal biopsies sampled during bronchoscopy of human subjects exposed in a validated experimental exposure set-up. Two exposure series were performed. Two separate groups of 15 healthy subjects each were exposed to filtered air and diesel exhaust during 1 hour in random order. The first exposure series was performed with the engine at idling with a PM10 concentration of 300µg/m3 and the second was carried out during urban cycle (European Transient Cycle) running conditions with 270 µg particles/m3. Bronchoscopies with sampling of bronchial mucosal biopsies were performed 6 hours after exposure. Biopsies fixed in acetone were bedded in glycolmethacrylate (GMA) resin and were stained for immunohistochemistry. Readings were done with light microscopy as well as image analyser with digital stainings processing of.Diesel exhaust enhanced the expression of the cytokines IL-8 and GRO-α in the bronchial epithelium suggesting that the epithelium plays a major role in mediating the neutrophil-dominated airway mucosal inflammation. The bronchial expression of Th1 and Th2 cytokines was evaluated, addressing the hypothesis that diesel exhaust would induce a Th2 airway response. Diesel exhaust enhanced the expression of Th2 related cytokine IL-13 whereas the expression of Th1 cytokines was unaffected.The investigation of epithelial signal transduction pathways, by means of newly developed and validated cytoplasmic and nuclear stainings for key transcription factors and kinases, demonstrated that exposure to diesel exhaust increased the nuclear translocation of redox sensitive signal transduction components including phosphorylated (p)-p38-MAPK, p-JNK, p-c-jun (AP-1) and p65 (NFκB). These findings indicate novel mechanistic aspects to be involved in the airway response to particulate air pollution.The expression of epidermal growth factor receptor (EGFR) as well as phosphorylated C-terminal Tyr 1173 increased significantly following DE exposure. The findings are consistent with the upregulation of p38 and JNK MAPkinases as well as increased NFκB expression. The MEK-ERK pathway was not affected and Src related phosphorylation was absent.Diesel exposure at urban European transient cycle running conditions resulted in upregulation of the vascular adhesion molecule expression in the bronchial mucosa as signs of an early inflammatory response, while infiltration of inflammatory cells had not yet occurred. Differences in organic composition and particle concentration in the exhaust compared to idling situation may have influenced the outcome.This thesis has added a mechanistic basis for the diesel exhaust induced airway inflammation in-vivo in humans. It is concluded that activation of epithelial signal transduction pathways, cytokine production and increased endothelial adhesion molecule expression play important roles in the airway inflammatory response to diesel exhaust.
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| 49. |
- Pourazar, Jamshid, et al.
(författare)
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Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways
- 2005
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Ingår i: American Journal of Physiology - Lung cellular and Molecular Physiology. - : American Physiological Society. - 1040-0605 .- 1522-1504. ; 289:5, s. L724-L730
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Tidskriftsartikel (refereegranskat)abstract
- Diesel exhaust (DE) is a major component of airborne particulate matter. 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-alpha, 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 <10 mum, 300 microg/m3] and air, immunohistochemical staining was used to quantify the expression of the transcription factors NF-kappaB (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-kappaB (P = 0.02), AP-1 (P = 0.02), phosphorylated JNK (P = 0.04), and phosphorylated p38 (P = 0.01), as well as an increase in total (cytoplasmic + nuclear) immunostaining of phosphorylated p38 (P = 0.03). A significant increase in nuclear phosphorylated tyrosine was also observed (P < 0.05). These observations demonstrate that DE activates redox-sensitive transcription factors in vivo consistent with oxidative stress triggering the increased synthesis of proinflammatory cytokines.
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| 50. |
- Pourazar, Jamshid, et al.
(författare)
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Diesel exhaust increases EGFR and phosphorylated C-terminal Tyr 1173 in the bronchial epithelium
- 2008
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Ingår i: Particle and Fibre Toxicology. - London : BioMed Central (BMC). - 1743-8977. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epidemiological studies have demonstrated adverse health effects of environmental pollution. Diesel exhaust (DE) is a major contributor to particulate matter pollution. DE exposure has been shown to induce a pronounced inflammatory response in the airways, together with an enhanced epithelial expression of cytokines such as IL-8, Gro-alpha, IL-13 and activation of redox sensitive transcription factors (NFkappaB, AP-1), and MAP kinases (p38, JNK). The aim of the present investigation was to elucidate the involvement of the epidermal growth factor receptor (EGFR) signalling pathway in the epithelial response to DE in-vivo.RESULTS: Immunohistochemical staining was used to quantify the expression of the EGFR, phosphorylated Tyrosine residues, MEK and ERK in the bronchial epithelium of archived biopsies from 15 healthy subjects following exposure to DE (PM10, 300 mug/m3) and air. DE induced a significant increases in the expression of EGFR (p = 0.004) and phosphorylated C-terminal Tyr 1173 (p = 0.02). Other investigated EGFR tyrosine residues, Src related tyrosine (Tyr 416), MEK and ERK pathway were not changed significantly by DE.CONCLUSION: Exposure to DE (PM10, 300 mug/m3) caused enhanced EGFR expression and phosphorylation of the tyrosine residue (Tyr 1173) which is in accordance with the previously demonstrated activation of the JNK, AP-1, p38 MAPK and NFkB pathways and associated downstream signalling and cytokine production. No effects were seen on the MEK and ERK pathway suggesting that at the investigated time point (6 hours post exposure) there was no proliferative/differentiation signalling in the bronchial epithelium. The present findings suggest a key role for EGFR in the bronchial response to diesel exhaust.
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