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Respiratory and cardiovascular effects of exposure to oxidative air pollutants
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: The negative effects of air pollution on morbidity and mortality have been known since the mid 20th century. The two most well known examples are the Meuse Valley disaster in the 1930’ies and the London black fog in December 1952. Whilst there are numerous epidemiological studies, in which associations between morbidity and mortality and high levels of pollutants have been reported, the underlying mechanisms are not clear. Two of the main air pollutants are particulate matter (PM) mostly emanating from diesel exhaust (DE), and ozone, both of which are highly oxidative. Exposure to DE has resulted in adverse effects both in the respiratory tract and in the cardiovascular system. High ozone levels have also been shown to be associated with increased admissions to hospital for respiratory as well as cardiovascular conditions.

The main aim of this thesis was to investigate the respiratory and cardiovascular effects of a combination of exposures to ozone and DE. DE generated during the urban part of the standardized European Transient Cycle (ETC) was compared to DE generated by an idling engine. It was also evaluated whether an acute exposure to ozone would have any effects on the cardiovascular system as assessed by venous occlusion forearm plethysmography and heart rate variability (HRV). In addition, fraction of exhaled nitric oxide (FENO) was evaluated as a potential marker for acute exposure to ozone or DE.

Methods: Four double-blind randomized cross-over exposure studies were conducted to investigate the effects of ozone and DE on both the respiratory tract and the vascular function in healthy volunteers. All of the exposures were performed in purposely built “walk-in” chambers with strictly controlled exposures. In the first study, the volunteers were exposed to DE (300µg/m3) generated by an idling engine or to air, for one hour in the morning and to ozone (200 ppb) for two hours in the afternoon. A bronchoscopy with bronchial wash (BW) and bronchoalveolar lavage (BAL) was performed 24 hours after the initial exposure. In study II and III, an assessment of vascular function using venous occlusion forearm plethysmography was performed after an exposure to DE (250 µg/m3) generated under transient running conditions, compared to air exposure (study II) and ozone and air exposure (study III). HRV was assessed under a 24 hour period starting before each exposure (study III). In study IV, FENO measurements were conducted after DE and ozone exposures to investigate whether the previously established airway inflammation would be detectable by this non-invasive method.

Results: DE exposure enhanced the established ozone-induced airway inflammation in terms of a pronounced neutrophilia in BW. DE generated under transient running conditions, impaired vascular function in healthy volunteers, whereas exposure to ozone did not. HRV were not altered by exposure to ozone. Exposure to DE caused a significant increase in FENO at the 10  (FENO10) and 50 (FENO50) mL/s flow rates at 6 hours post-exposure, but ozone exposure did not affect FENO at any flow rate or time point.

Conclusion: We have tried to mimic real-life exposure to air pollutants. In the first study, an exposure to DE followed by an exposure to ozone in the afternoon resulted in an enhanced airway inflammation, suggesting an additive or synergistic effect, supporting the epidemiological findings of unfavorable effects of the combination of these two air pollutants. DE generated by an engine running at the urban part of the standardized European Transient Cycle impaired two important and complementary aspects of vascular function, the regulation of vascular tone and endogenous fibrinolysis. This has previously been shown with DE generated at idling conditions. This suggests that the mechanisms behind the adverse effects can be found in the properties of the particles and not in the gaseous components. In these studies, exposure to ozone did not impair vascular function in healthy subjects, or cause any alterations in HRV. This suggests that the epidemiological evidence for an increased risk of cardiovascular mortality following acute exposure to ozone might not be totally accurate. Previous controlled exposure studies with ozone have not shown an airway inflammation affecting the endothelium, at least not in the same time-frame as following DE exposure. FENO could possibly be a useful tool for assessing airway inflammation caused by DE, whereas the powerful oxidant ozone did not affect FENO. This suggests that the airway inflammatory effects caused by these two pollutants are regulated via different mechanisms.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2011. , 45 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1443
Keyword [en]
Air Pollution, Particulate Matter, Diesel Exhaust, Ozone, Experimental Exposure studies
Keyword [sv]
Luftföroreningar, Partiklar, Disel avgaser, ozon, Experimentella exponerings studier
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine; Cardiology; biology, Environmental Science
Identifiers
URN: urn:nbn:se:umu:diva-46533ISBN: 978-91-7459-279-5 (print)OAI: oai:DiVA.org:umu-46533DiVA: diva2:439187
Public defence
2011-10-05, Sal B, Målpunkt T9, Norrlands Universitetssjukhus, 901 85 Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-09-09 Created: 2011-09-05 Last updated: 2011-09-12Bibliographically approved
List of papers
1. Diesel exhaust exposure enhances the ozone-induced airway inflammation in healthy humans
Open this publication in new window or tab >>Diesel exhaust exposure enhances the ozone-induced airway inflammation in healthy humans
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2008 (English)In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 31, no 6, 1234-1240 p.Article in journal (Refereed) Published
Abstract [en]

Exposure to particulate matter and ozone cause adverse airway reactions. Individual pollutant effects are often addressed separately, despite coexisting in ambient air. The present investigation was performed to study the effects of sequential exposures to diesel exhaust (DE) and ozone on airway inflammation in human subjects. Healthy subjects underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial wash (BW) sampling on two occasions. Once following a DE exposure (with 300 mug.m(-3) particles with a 50% cut-off aerodynamic diameter of 10 mum) with subsequent exposure to O(3) (0.2 ppm) 5 h later. The other bronchoscopy was performed after a filtered air exposure followed by an ozone exposure, using an identical protocol. Bronchoscopy was performed 24 h after the start of the initial exposure. Significant increases in neutrophil and macrophage numbers were found in BW after DE followed by ozone exposure versus air followed by ozone exposure. DE pre-exposure also raised eosinophil protein X levels in BAL compared with air. The present study indicates additive effects of diesel exhaust on the ozone-induced airway inflammation. Together with similar results from a recent study with sequential diesel exhaust and ozone exposures, the present data stress a need to consider the interaction and cumulative effects of different air pollutants.

Keyword
Air pollution, bronchoscopy, neutrophils, particulate matter, sequential exposure
National Category
Respiratory Medicine and Allergy
Identifiers
urn:nbn:se:umu:diva-19127 (URN)10.1183/09031936.00078407 (DOI)18321939 (PubMedID)
Available from: 2009-03-04 Created: 2009-03-04 Last updated: 2012-03-01Bibliographically approved
2. Impaired vascular function after exposure to diesel exhaust generated at urban transient running conditions
Open this publication in new window or tab >>Impaired vascular function after exposure to diesel exhaust generated at urban transient running conditions
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2010 (English)In: Particle and fibre toxicology, ISSN 1743-8977, Vol. 7, no 1, 19- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Traffic emissions including diesel engine exhaust are associated with increased respiratory and cardiovascular morbidity and mortality. Controlled human exposure studies have demonstrated impaired vascular function after inhalation of exhaust generated by a diesel engine under idling conditions.

OBJECTIVES: To assess the vascular and fibrinolytic effects of exposure to diesel exhaust generated during urban-cycle running conditions that mimic ambient 'real-world' exposures.

METHODS: In a randomised double-blind crossover study, eighteen healthy male volunteers were exposed to diesel exhaust (approximately 250 mug/m3) or filtered air for one hour during intermittent exercise. Diesel exhaust was generated during the urban part of the standardized European Transient Cycle. Six hours post-exposure, vascular vasomotor and fibrinolytic function was assessed during venous occlusion plethysmography with intra-arterial agonist infusions.

MEASUREMENTS AND MAIN RESULTS: Forearm blood flow increased in a dose-dependent manner with both endothelial-dependent (acetylcholine and bradykinin) and endothelial-independent (sodium nitroprusside and verapamil) vasodilators. Diesel exhaust exposure attenuated the vasodilatation to acetylcholine (P < 0.001), bradykinin (P < 0.05), sodium nitroprusside (P < 0.05) and verapamil (P < 0.001). In addition, the net release of tissue plasminogen activator during bradykinin infusion was impaired following diesel exhaust exposure (P < 0.05).

CONCLUSION: Exposure to diesel exhaust generated under transient running conditions, as a relevant model of urban air pollution, impairs vasomotor function and endogenous fibrinolysis in a similar way as exposure to diesel exhaust generated at idling. This indicates that adverse vascular effects of diesel exhaust inhalation occur over different running conditions with varying exhaust composition and concentrations as well as physicochemical particle properties. Importantly, exposure to diesel exhaust under ETC conditions was also associated with a novel finding of impaired of calcium channel-dependent vasomotor function. This implies that certain cardiovascular endpoints seem to be related to general diesel exhaust properties, whereas the novel calcium flux-related effect may be associated with exhaust properties more specific for the ETC condition, for example a higher content of diesel soot particles along with their adsorbed organic compounds.

Place, publisher, year, edition, pages
BioMed Central, 2010
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-35381 (URN)10.1186/1743-8977-7-19 (DOI)000282501600001 ()20653945 (PubMedID)
Available from: 2010-08-16 Created: 2010-08-16 Last updated: 2012-01-10Bibliographically approved
3. Short-Term Exposure to Ozone Does Not Impair Vascular Function or Affect Heart Rate Variability in Healthy Young Men
Open this publication in new window or tab >>Short-Term Exposure to Ozone Does Not Impair Vascular Function or Affect Heart Rate Variability in Healthy Young Men
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2013 (English)In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 135, no 2, 292-299 p.Article in journal (Refereed) Published
Abstract [en]

Air pollution exposure is associated with cardiovascular morbidity and mortality, yet the role of individual pollutants remains unclear. In particular, there is uncertainty regarding the acute effect of ozone exposure on cardiovascular disease. In these studies, we aimed to determine the effect of ozone exposure on vascular function, fibrinolysis, and the autonomic regulation of the heart. Thirty-six healthy men were exposed to ozone (300 ppb) and filtered air for 75min on two occasions in randomized double-blind crossover studies. Bilateral forearm blood flow (FBF) was measured using forearm venous occlusion plethysmography before and during intra-arterial infusions of vasodilators 2–4 and 6–8h after each exposure. Heart rhythm and heart rate variability (HRV) were monitored during and 24h after exposure. Compared with filtered air, ozone exposure did not alter heart rate, blood pressure, or resting FBF at either 2 or 6h. There was a dose-dependent increase in FBF with all vasodilators that was similar after both exposures at 2–4h. Ozone exposure did not impair vasomotor or fibrinolytic function at 6–8h but rather increased vasodilatation to acetylcholine (p = .015) and sodium nitroprusside (p = .005). Ozone did not affect measures of HRV during or after the exposure. Our findings do not support a direct rapid effect of ozone on vascular function or cardiac autonomic control although we cannot exclude an effect of chronic exposure or an interaction between ozone and alternative air pollutants that may be responsible for the adverse cardiovascular health effects attributed to ozone.

Place, publisher, year, edition, pages
Oxford University Press, 2013
Keyword
Air Pollution, blood flow, endothelium, fibrinolysis, oxidative stress, ozone, Luftföroreningar
National Category
Cardiac and Cardiovascular Systems
Research subject
Cardiology; Lung Medicine; biology, Environmental Science
Identifiers
urn:nbn:se:umu:diva-46528 (URN)10.1093/toxsci/kft157 (DOI)
Funder
Swedish Heart Lung FoundationFormas
Note

Manuscript title included in thesis: Ozone exposure does not impair vascular function or affect heart rate variability in healthy subjects

Available from: 2011-09-06 Created: 2011-09-05 Last updated: 2017-12-08Bibliographically approved
4. Fraction of exhaled nitric oxide after experimental exposure to diesel exhaust and ozone in man
Open this publication in new window or tab >>Fraction of exhaled nitric oxide after experimental exposure to diesel exhaust and ozone in man
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Fraction of exhaled nitric oxide (FENO) is a promising non-invasive index of airways inflammation that may be used to assess the respiratory effects of air pollution, and when sampled at multiple expiratory flow rates can measure inflammation at different levels of the airway tract. We evaluate FENO as a measure of airways inflammation after controlled exposure to dilute diesel exhaust and ozone.

Methods: Using a double blind randomised cross-over design, healthy volunteers (26±5 years) were exposed to either diesel exhaust (particle concentration 300 µg/m3) and filtered air for one hour (n=10), or ozone(300 ppb) and filtered air for 75 minutes (n=36). FENO was measured in duplicate at expiratory flow rates of 10, 50, 100 and 270 mL/s before, 6 and 24 hours after the end of each exposure.

Results: Exposure to diesel exhaust increased FENO at 6 hours compared to filtered air at expiratory flow rates of 10 mL/s [mean±SEM 60.8 ± 6.0 ppb versus 50.2 ± 5.9 ppb; P=0.01] and at 50 mL/s [18.6 ± 1.6 ppb versus 15.9 ± 1.5 ppb; P=0.011], but concentrations did not differ at higher flow rates. Increases in FENO following diesel exhaust were attenuated at 24 hours and exposure to ozone did not affect FENO at any flow rate or time point.

Conclusion: Exposure to diesel exhaust, but not ozone, increases the concentration of FENO in healthy subjects consistent with an inflammatory effect in the central airways. Differences in the induction of airway inflammation may explain divergent responses to diesel exhaust and ozone with implications for the use of FENO as an index of exposure to air pollution.

Keyword
Air Pollution, Particulate matter, Diesel exhaust, Ozone, exhaled NO, Luftföroreningar, partiklar, diesel avgaser, ozon, utandat NO
National Category
Respiratory Medicine and Allergy
Research subject
Lung Medicine; biology, Environmental Science
Identifiers
urn:nbn:se:umu:diva-46531 (URN)
Available from: 2011-09-06 Created: 2011-09-05 Last updated: 2011-09-12Bibliographically approved

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Citation style
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