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Acute exposure to diesel exhaust increases IL-8 and Gro-alpha production in healthy human airways
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
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2000 (English)In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 161, no 2, 550-557 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2000. Vol. 161, no 2, 550-557 p.
URN: urn:nbn:se:umu:diva-5160PubMedID: 10673199OAI: diva2:144564
Available from: 2006-05-11 Created: 2006-05-11 Last updated: 2015-04-17Bibliographically 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
Umeå University medical dissertations, ISSN 0346-6612 ; 1033
National Category
Medical and Health Sciences
urn:nbn:se:umu:diva-795 (URN)91-7264-102-9 (ISBN)
Public defence
2006-06-02, Sal 9B, Tandläkarhögskolan, Umeå, 13:00 (English)
Available from: 2006-05-11 Created: 2006-05-11 Last updated: 2016-08-17Bibliographically approved
2. Airway effects of diesel exhaust in healthy and asthmatic subjects
Open this publication in new window or tab >>Airway effects of diesel exhaust in healthy and asthmatic subjects
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several epidemiological studies have revealed an association between particulate matter (PM) pollution and various health effects. Importantly, there is evidence to suggest that individuals with pre-existing respiratory disease, such as asthma, are more sensitive to elevated ground levels of particulate matter as compared to healthy subjects. Among the various sources of PM pollution, diesel powered vehicles have been identified as important contributors.

The aim of this thesis was to investigate the airway effects of experimental chamber exposure to diesel exhaust (DE) in healthy and asthmatic subjects, focusing on airway responsiveness, airway inflammation and lung function. To achieve a comprehensive picture of the airway responses to DE, a number of different methods were used, including lung function measurements, methacholine inhalation tests, induced sputum and bronchoscopy. Each subject acted as his/her own control by being exposed both to filtered air and DE in a crossover design.

Short term exposure to DE, at a particle concentration (PMi0) of 300 ug/m3, was associated with a clinically significant increase in bronchial hyperresponsiveness in asthmatic subjects. In accordance with the epidemiological data suggesting a 1-4 day lag effect for most health outcomes to PM pollution, the increase was detected one day after DE exposure, indicating a long lasting response to DE in asthmatic airways.

Diesel exhaust induced a range of airway inflammatory changes as reflected in induced sputum, bronchoalveolar lavage and bronchial mucosal biopsies. In healthy subjects, DE exposure was associated with an increase in neutrophils and IL-6 in sputum, elevated levels of IL-8 and IL-6 in bronchial wash (BW), enhanced expression of IL-8 and GRO-a in the bronchial epithelium and with increases in P-selectin and VCAM-1 in the airway mucosa. In contrast, asthmatics responded with an increase in IL-6 in sputum and an enhanced expression of IL-10 in the bronchial epithelium following exposure DE. Thus, clear differences were identified between healthy and asthmatic subjects in the inflammatory response to DE.

Airway epithelial cells constitute the first line of cellular defence towards inhaled air pollutants and increasing evidence suggests that these cells contribute markedly to the initiation of airway inflammatory responses. The bronchial epithelium was identified to have an important regulatory role in response to diesel exhaust, including the capacity to produce chemoattractant and immunoregulatory proteins associated with development of airway inflammation and bronchial hyperresponsiveness.

Lung function measurements revealed that short-term exposure to DE induces an immediate bronchoconstrictive response in both healthy and asthmatic individuals, with significant increases in airway resistance (Raw) following DE exposure.

This thesis also investigated the effects of a lower concentration of DE (PMio 100 ug/m3) than previously studied. It was shown that exposure to DE at a concentration corresponding to a PM level that may be encountered in busy traffic situations, was still associated with potentially adverse airway responses in healthy and asthmatic subjects.

In summary, the results presented here indicate that short term exposure to diesel exhaust, at high ambient concentrations, has the potential to induce a range of biological events in the airways of healthy and asthmatic subjects.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2002. 60 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 750
air pollution, diesel exhaust, airway responsiveness, airway inflammation, lung function, asthmatics, immunohistochemistry, bronchial epithelium
National Category
Respiratory Medicine and Allergy
urn:nbn:se:umu:diva-96901 (URN)91-7305-172-1 (ISBN)
Public defence
2002-02-16, Sal B, 9 trappor, Byggnad ID (Tandläkarhögskolan), Norrlands Universitetssjukhus i Umeå, Umeå universitet, Umeå, 12:00

Diss. (sammanfattning) Umeå : Umeå universitet, 2002, härtill 4 uppsatser.

Available from: 2015-01-26 Created: 2014-12-05 Last updated: 2015-04-10Bibliographically approved

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