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Airway inflammatory response to diesel exhaust generated at urban cycle running conditions
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics, Energy Technology and Thermal Process Chemistry.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
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2010 (English)In: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 22, no 14, 1144-1150 p.Article in journal (Refereed) Published
Abstract [en]

DE generated under urban running conditions increased bronchial adhesion molecule expressions, together with the novel finding of bronchoalveolar eosinophilia, which has not been shown after exposure to DE at idling. Variations in airway inflammatory response to DE generated under diverse running condition may be related to differences in exhaust composition.

Place, publisher, year, edition, pages
2010. Vol. 22, no 14, 1144-1150 p.
Keyword [en]
Air pollution, adhesion molecules, airway inflammation, particulate matter.
Identifiers
URN: urn:nbn:se:umu:diva-5164DOI: 10.3109/08958378.2010.529181ISI: 000284889300002PubMedID: 21110774OAI: oai:DiVA.org:umu-5164DiVA: diva2:144568
Available from: 2006-05-11 Created: 2006-05-11 Last updated: 2011-02-04Bibliographically approved
In thesis
1. Activation of epithelial signal transduction pathways, cytokine production and airway inflammation following diesel exhaust exposure
Open this publication in new window or tab >>Activation of epithelial signal transduction pathways, cytokine production and airway inflammation following diesel exhaust exposure
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Folkhälsa och klinisk medicin, 2006
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1033
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-795 (URN)91-7264-102-9 (ISBN)
Public defence
2006-06-02, Sal 9B, Tandläkarhögskolan, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2006-05-11 Created: 2006-05-11 Last updated: 2016-08-17Bibliographically approved
2. Respiratory effects of particulate matter air pollution: studies on diesel exhaust, road tunnel, subway and wood smoke exposure in human subjects
Open this publication in new window or tab >>Respiratory effects of particulate matter air pollution: studies on diesel exhaust, road tunnel, subway and wood smoke exposure in human subjects
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background:

Ambient air pollution is associated with adverse health effects, but the sources and components, which cause these effects is still incompletely understood. The aim of this thesis was to investigate the pulmonary effects of a variety of common air pollutants, including diesel exhaust, biomass smoke, and road tunnel and subway station environments. Healthy non-smoking volunteers were exposed in random order to the specific air pollutants and air/control, during intermittent exercise, followed by bronchoscopy.

Methods and results:

In study I, exposures were performed with diesel exhaust (DE) generated at transient engine load and air for 1 hour with bronchoscopy at 6 hours post-exposure. Immunohistochemical analyses of bronchial mucosal biopsies showed that DE exposure significantly increased the endothelial adhesion molecule expression of p-selectin and VCAM-1, together with increased bronchoalveolar lavage (BAL) eosinophils.

In study II, the subjects were exposed for 1 hour to DE generated during idling with bronchoscopy at 6 hours. The bronchial mucosal biopsies showed significant increases in neutrophils, mast cells and lymphocytes together with bronchial wash neutrophils. Additionally, DE exposure significantly increased the nuclear translocation of the aryl hydrocarbon receptor (AhR) and phosphorylated c-jun in the bronchial epithelium. In contrast, the phase II enzyme NAD(P)H-quinone oxidoreductase 1 (NQO1) decreased after DE.

In study III, the 2-hour exposures took place in a road tunnel with bronchoscopy 14 hours later. The road tunnel exposure significantly increased the total numbers of lymphocytes and alveolar macrophages in BAL, whereas NK cell and CD56+/T cell numbers significantly decreased. Additionally, the nuclear expression of phosphorylated c-jun in the bronchial epithelium was significantly increased after road tunnel exposure.

In study IV, the subjects were exposed to metal-rich particulate aerosol for 2 hours at a subway station with bronchial biopsy and BAL sampling at 14 hours. The subway exposure significantly increased the concentration of glutathione disulphide (GSSG) in BAL, with no airway inflammatory responses. In contrast, the number of neutrophils in the bronchial mucosa and the nuclear expression of phosphorylated c-jun in the bronchial epithelium tended to decrease after the subway exposure.

In study V, the exposure to biomass smoke lasted 3 hours. Bronchoscopy was conducted 24 hours post exposure. The investigated biomass combustion emissions resulted in a significant increase in total glutathione and reduced glutathione in BAL, without any evident acute airway inflammatory responses.

 

 

Conclusion:

The present thesis presents data from exposures of healthy subjects to a variety of common air pollutants, as compared with an air reference. Oxidative as well as bronchial mucosal and bronchoalveolar responses differed between these air pollutants, with the most pronounced airway effects seen after exposure to diesel exhaust. This may be due to differences in pulmonary deposition, physicochemical characteristics, toxicological pathways and potency. Additional studies will assist in addressing dose-response and time kinetic aspects of the airway responses.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2011. 110 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1394
Keyword
Airway inflammation, antioxidant, bronchoscopy, detoxification, immunohistochemistry, particulate matter
National Category
Environmental Health and Occupational Health
Identifiers
urn:nbn:se:umu:diva-39568 (URN)978-91-7459-130-9 (ISBN)
Public defence
2011-02-24, E04, Byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-02-04 Created: 2011-02-01 Last updated: 2011-02-04Bibliographically approved

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Sehlstedt, MariaBehndig, AnnelieBoman, ChristofferBlomberg, AndersSandström, ThomasPourazar, Jamshid

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