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Allergic airway disease: studies on diesel exhaust exposures, oxylipins and antioxidants
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Allergic airway disease, i.e. allergic rhinitis (AR) and asthma, is a common health problem. The prevalence is increasing in most countries of the world. Traffic-related air pollution has been found to induce and enhance allergic airway disease, but the underlying mechanisms are not known.

Oxylipins are fatty acid metabolites, of which several have been linked to asthmatic airway inflammation. Oxylipin profiles have previously been investigated in bronchoalveolar lavage (BAL), mainly reflecting the peripheral lung, but not in bronchial wash (BW), which better reflect the proximal airways.

The airway epithelium is covered by a respiratory tract lining fluid (RTLF) The RTLF contains antioxidants to protect from oxidative stress, which may be caused by exposure to air pollution. Previous studies have reported diminished levels of the antioxidant ascorbate (vitamin C) in the RTLF of patients with asthma. Little is known about the regulation of vitamin C in the lung.

The aim of this thesis was to investigate airway inflammatory responses to diesel exhaust exposure in patients with AR and allergic asthma; to evaluate oxylipin profiles in different regions of the lung in patients with allergic asthma; and to study the distribution of vitamin C transporters in the airways of patients with allergic asthma.

Diesel exhaust (PM10 100 μg/m3 for 2 h) induced a neutrophilic airway inflammation in healthy individuals evaluated 18 h after exposure. Patients with AR and asthma did not respond with an enhanced airway inflammation. However, a small increase in myeloperoxidase was found in BAL from patients with AR, as well as decreases in epithelial tryptase and BW stem cell factor. This indicates that other mechanisms than classical inflammation are responsible for the increased sensitivity to traffic-related air pollution in patients with allergic airway disease.

Oxylipin baseline profiles differed between peripheral and proximal airways in both allergic asthmatics and healthy individuals. Total oxylipin concentrations, and five individual oxylipins, primarily from the lipoxygenase (LOX) pathway, were elevated in BW from asthmatics compared to healthy controls, supported by immunohistochemical staining of 15-LOX-1 in the bronchial epithelium. This suggests that lung compartment-specific sampling should be considered in future studies.

Sodium dependent vitamin C transporter 2 (SVCT2) was, for the first time, found present in the human lung epithelium, localised mainly within goblet cells. A negative correlation between SVCT2+ goblet cells and vitamin C suggests that these cells may play a hitherto unknown function in ascorbate re-uptake and recycling at the air-lung interface.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2013. , 60 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1609
Keyword [en]
Asthma, allergic rhinits, diesel exhaust, airway inflammation, oxylipins, metabolomics, antioxidants, SVCT2, bronchoscopy
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
URN: urn:nbn:se:umu:diva-83493ISBN: 978-91-7459-749-3 (print)OAI: oai:DiVA.org:umu-83493DiVA: diva2:667719
Public defence
2013-12-19, Hörsal B, 9 tr, Norrlands Universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2013-11-28 Created: 2013-11-27 Last updated: 2014-05-12Bibliographically approved
List of papers
1. Proinflammatory doses of diesel exhaust in healthy subjects fail to elicit equivalent or augmented airway inflammation in subjects with asthma
Open this publication in new window or tab >>Proinflammatory doses of diesel exhaust in healthy subjects fail to elicit equivalent or augmented airway inflammation in subjects with asthma
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2011 (English)In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 66, no 1, 12-19 p.Article in journal (Refereed) Published
Abstract [en]

Exposure to diesel exhaust at concentrations consistent with roadside levels elicited an acute and active neutrophilic inflammation in the airways of healthy subjects. This response was absent in subjects with asthma, as was evidence supporting a worsening of allergic airway inflammation.

National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-39566 (URN)10.1136/thx.2010.140053 (DOI)20837873 (PubMedID)
Available from: 2011-02-01 Created: 2011-02-01 Last updated: 2017-12-11Bibliographically approved
2. Airway inflammatory responses to diesel exhaust in allergic rhinitics
Open this publication in new window or tab >>Airway inflammatory responses to diesel exhaust in allergic rhinitics
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2013 (English)In: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 25, no 3, 160-167 p.Article in journal (Refereed) Published
Abstract [en]

Context: Proximity to traffic, particularly to diesel-powered vehicles, has been associated with inducing and enhancing allergies. To investigate the basis for this association, we performed controlled exposures of allergic rhinitics to diesel exhaust (DE) at a dose known to be pro-inflammatory in healthy individuals.

Objective: We hypothesized that diesel-exhaust exposure would augment lower airway inflammation in allergic rhinitics.

Materials and methods: Fourteen allergic rhinitics were exposed in a double-blinded, randomized trial to DE (100 mu g/m(3) PM10) and filtered air for 2 h on separate occasions. Bronchoscopy with endobronchial mucosal biopsies and airway lavage was performed 18 h post-exposure, and inflammatory markers were assessed.

Results: No evidence of neutrophilic airway inflammation was observed post-diesel, however, a small increase in myeloperoxidase was found in bronchoalveolar lavage (p = 0.032). We found no increases in allergic inflammatory cells. Reduced mast cell immunoreactivity for tryptase was observed in the epithelium (p = 0.013) parallel to a small decrease in bronchial wash stem cell factor (p = 0.033). Discussion and conclusion: DE, at a dose previously shown to cause neutrophilic inflammation in healthy individuals, induced no neutrophilic inflammation in the lower airways of allergic rhinitics, consistent with previous reports in asthmatics. Although there was no increase in allergic inflammatory cell numbers, the reduction in tryptase in the epithelium may indicate mast cell degranulation. However, this occurred in the absence of allergic symptoms. These data do not provide a simplistic explanation of the sensitivity in rhinitics to traffic-related air pollution. The role of mast cells requires further investigation.

Keyword
Allergy, diesel exhaust, susceptibility
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-67599 (URN)10.3109/08958378.2013.765932 (DOI)000315185300004 ()
Available from: 2013-06-03 Created: 2013-03-25 Last updated: 2017-12-06Bibliographically approved
3. Lipid mediator profiles differ between lung compartments in asthmatic and healthy humans
Open this publication in new window or tab >>Lipid mediator profiles differ between lung compartments in asthmatic and healthy humans
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2014 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 43, no 2, 453-463 p.Article in journal (Refereed) Published
Abstract [en]

Oxylipins are oxidised fatty acids that can exert lipid mediator functions in inflammation, and several oxylipins derived from arachidonic acid are linked to asthma. This study quantified oxylipin profiles in different regions of the lung to obtain a broad-scale characterisation of the allergic asthmatic inflammation in relation to healthy individuals. Bronchoalveolar lavage fluid (BALF), bronchial wash fluid and endobronchial mucosal biopsies were collected from 16 healthy and 16 mildly allergic asthmatic individuals. Inflammatory cell counts, immunohistochemical staining and oxylipin profiling were performed. Univariate and multivariate statistics were employed to evaluate compartment-dependent and diagnosis-dependent oxylipin profiles in relation to other measured parameters. Multivariate modelling showed significantly different bronchial wash fluid and BALF oxylipin profiles in both groups ((RY)-Y-2[cum]=0.822 and Q(2)[cum]=0.759). Total oxylipin concentrations and five individual oxylipins, primarily from the lipoxygenase (LOX) pathway of arachidonic and linoleic acid, were elevated in bronchial wash fluid from asthmatics compared to that from healthy controls, supported by immunohistochemical staining of 15-LOX-1 in the bronchial epithelium. No difference between the groups was found among BALF oxylipins. In conclusion, bronchial wash fluid and BALF contain distinct oxylipin profiles, which may have ramifications for the study of respiratory diseases. Specific protocols for sampling proximal and distal airways separately should be employed for lipid mediator studies.

Keyword
airway inflammation, asthma, bronchoalveolar lavage, bronchial wash, lung compartments, oxylipin profiles
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-83487 (URN)10.1183/09031936.00209412 (DOI)000330824500018 ()
Note

Included in thesis in manuscript form

Available from: 2013-11-27 Created: 2013-11-27 Last updated: 2017-12-06Bibliographically approved
4. Vitamin C transporters in the airways of healthy and asthmatic humans
Open this publication in new window or tab >>Vitamin C transporters in the airways of healthy and asthmatic humans
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(English)Manuscript (preprint) (Other academic)
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine
Identifiers
urn:nbn:se:umu:diva-83488 (URN)
Available from: 2013-11-27 Created: 2013-11-27 Last updated: 2013-11-28Bibliographically approved

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