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Activation of epithelial signal transduction pathways, cytokine production and airway inflammation following diesel exhaust exposure
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
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: urn:nbn:se:umu:diva-795ISBN: 91-7264-102-9 (print)OAI: oai:DiVA.org:umu-795DiVA: diva2:144569
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
List of papers
1. Acute exposure to diesel exhaust increases IL-8 and Gro-alpha production in healthy human airways
Open this publication in new window or tab >>Acute exposure to diesel exhaust increases IL-8 and Gro-alpha production in healthy human airways
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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
Identifiers
urn:nbn:se:umu:diva-5160 (URN)10673199 (PubMedID)
Available from: 2006-05-11 Created: 2006-05-11 Last updated: 2015-04-17Bibliographically approved
2. Diesel exhaust exposure enhances the expression of IL-13 in the bronchial epithelium of healthy subjects.
Open this publication in new window or tab >>Diesel exhaust exposure enhances the expression of IL-13 in the bronchial epithelium of healthy subjects.
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2004 (English)In: Respiratory Medicine, ISSN 0954-6111, Vol. 98, no 9, 821-825 p.Article in journal (Refereed) Published
Abstract [en]

Epidemiological studies have demonstrated adverse health effects of environmental pollution. Diesel exhaust (DE) is an important contributor to ambient particulate matter pollution. DE exposure has been shown to induce a pronounced inflammatory response in the airways, with an enhanced epithelial expression of IL-8, and Gro-α in healthy subjects. The present investigation was aimed to further characterise the epithelial response to DE in vivo, with particular reference to possible TH2 response, in non-atopic healthy subjects. To determine this response, 15 healthy, non-atopic non-smoking subjects with normal lung function were exposed to DE (PM10 300 μg/m3) and filtered air during 1 h on two separate randomised occasions. Bronchoscopy sampling of bronchial mucosal biopsies was performed 6 h after exposure. Immunohistochemical staining were performed using mAb for IL-10, IL-13 and IL-18 expression. DE exposure induced a significant increase in the expression of IL-13 in the bronchial epithelium cells, 2.1 (1.35–4.88) Md (Q1–Q3) vs. air 0.94 (0.53–1.23); P=0.009. No significant changes were seen in IL-10 and IL-18 expression. This finding suggests an TH2-inflammatory response in the airways of non-atopic healthy individuals.

Keyword
Adult, Air Pollutants/*toxicity, Bronchi/*immunology, Environmental Exposure/adverse effects, Epithelium/immunology, Female, Humans, Immunohistochemistry/methods, Interleukin-13/*analysis, Male, Respiratory Mucosa/immunology, T-Lymphocytes; Helper-Inducer/immunology, Vehicle Emissions/*toxicity
Identifiers
urn:nbn:se:umu:diva-13124 (URN)10.1016/j.rmed.2004.02.025 (DOI)15338792 (PubMedID)
Available from: 2007-05-02 Created: 2007-05-02 Last updated: 2009-10-28Bibliographically approved
3. Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways
Open this publication in new window or tab >>Diesel exhaust activates redox-sensitive transcription factors and kinases in human airways
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2005 (Swedish)In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, Vol. 289, no 5, L724-L730 p.Article in journal (Refereed) Published
Abstract [en]

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.

Identifiers
urn:nbn:se:umu:diva-16057 (URN)doi:10.1152/ajplung.00055.2005 (DOI)15749742 (PubMedID)
Available from: 2007-08-16 Created: 2007-08-16 Last updated: 2009-10-29Bibliographically approved
4. Diesel exhaust increases EGFR and phosphorylated C-terminal Tyr 1173 in the bronchial epithelium
Open this publication in new window or tab >>Diesel exhaust increases EGFR and phosphorylated C-terminal Tyr 1173 in the bronchial epithelium
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2008 (English)In: Particle and Fibre Toxicology, ISSN 1743-8977, E-ISSN 1743-8977, Vol. 5, 8Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
London: BioMed Central, 2008
Keyword
epidermal growth factor, protein-tyrosine phosphorylation, receptor signaling pathway, MEK kinase 1, inflammatory responses, particulate matter, asthmatic subjects, healthy subjects, ERBB receptors, RAS activation
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-19105 (URN)10.1186/1743-8977-5-8 (DOI)000267400700001 ()18460189 (PubMedID)
Available from: 2009-03-04 Created: 2009-03-04 Last updated: 2016-08-17Bibliographically approved
5. Airway inflammatory response to diesel exhaust generated at urban cycle running conditions
Open this publication in new window or tab >>Airway inflammatory response to diesel exhaust generated at urban cycle running conditions
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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.

Keyword
Air pollution, adhesion molecules, airway inflammation, particulate matter.
Identifiers
urn:nbn:se:umu:diva-5164 (URN)10.3109/08958378.2010.529181 (DOI)000284889300002 ()21110774 (PubMedID)
Available from: 2006-05-11 Created: 2006-05-11 Last updated: 2011-02-04Bibliographically approved

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