Show simple item record

dc.contributor.advisorNewby, Daviden
dc.contributor.advisorBoon, Nicholasen
dc.contributor.authorMills, Nicholas Lintonen
dc.date.accessioned2010-11-15T16:03:26Z
dc.date.available2010-11-15T16:03:26Z
dc.date.issued2009
dc.identifier.urihttp://hdl.handle.net/1842/4282
dc.descriptionProject (03/017/15071)en
dc.description.abstractObservational studies have consistently demonstrated associations between exposure to air pollution and increased cardiovascular morbidity and mortality. These associations are strongest for fine particulate matter (PM), of which particulates from the combustion of fossil fuels are an important component. In Europe, the contribution to urban PM from diesel emissions is increasing with the popularity of diesel engines for road transport. Despite the strength of the epidemiological evidence and the emergence of promising hypotheses, the important constituents and biological mechanisms responsible for the cardiovascular effects of air pollution are largely unknown. It is possible that nanoparticulates or soluble components of PM may translocate into the bloodstream, resulting in direct effects on the vascular endothelium and thrombotic pathways. I investigated the potential for inhaled radiolabelled nanoparticulates to translocate into the circulation in man. Using two unique human exposure facilities I assessed the effects of exposure to combustion-derived particulates in dilute diesel exhaust and concentrated ambient fine and ultrafine particles on vascular endothelial, endogenous fibrinolytic and myocardial function in healthy volunteers and patients with stable coronary artery disease. In total, forty-two healthy men and thirty-two patients with stable coronary artery disease were exposed to particulates or filtered air for 1-2 hours in a series of double blind randomised crossover studies. At levels encountered in an urban environment, inhalation of dilute diesel exhaust impaired two important and complementary aspects of vascular function in man: the regulation of vascular tone and endogenous fibrinolysis. Vascular dysfunction persisted for up to 24-hours following exposure and was associated with an increase in systemic inflammatory cytokines. In patients with coronary heart disease exposure to diesel exhaust did not aggravate pre-existing vasomotor dysfunction, but did exacerbate exercise-induced myocardial ischemia and reduce acute endothelial tissue plasminogen activator release. In contrast, exposure to concentrated ambient particulates, low in combustion component, did not affect vascular function in either healthy volunteers or patients. I found little evidence that inhaled radiolabelled nanoparticles translocate into the circulation and suggest the adverse vascular effects of combustion derived air pollution are mediated primarily by their soluble components rather than by a direct interaction between nanoparticles and the vasculature. My findings have identified ischemic, vascular and thrombotic mechanisms that may explain in part the observations that exposure to combustion-derived air pollution is associated with adverse cardiovascular events including acute myocardial infarction. Ongoing research in this area will provide further insight into the adverse effects of PM, with the possibility of targeted interventions, such as the use of retrofit particle traps on diesel powered vehicles, to reduce the impact of environmental air pollution on cardiovascular disease a realistic goal.en
dc.contributor.sponsorBritish Heart Foundationen
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionMills NL, Törnqvist H, Gonzales M, Robinson SD, Boon NA Blomberg A, Sandstrom T, Newby DE, Donaldson K. Air pollution and atherothrombosis. Inhalation Toxicology 2007;19(Suppl. 1):1-9.en
dc.relation.hasversionMills NL, Törnqvist H, Robinson SD, Darnley K, Gonzales M, Boon NA, MacNee W, Donaldson K, Blomberg A, Sandstrom T, and Newby DE. Diesel exhaust inhalation causes vascular dysfunction and impaired endogenous fibrinolysis. Circulation 2005;112:3930-6.en
dc.relation.hasversionTörnqvist H, Mills NL, Gonzales M, Miller MR, Robinson SD, Megson IL, MacNee W, Donaldson K, Soderberg S, Newby DE, Sandström T, Blomberg A. Persistent endothelial dysfunction following diesel exhaust inhalation in man. Am J Respir Crit Care Med 2007:176:395-400.en
dc.relation.hasversionMills NL, Amin N, Robinson SD, Anand A, Davies J, de la Fuente J, Boon NA, MacNee W, Millar AM, Donaldson K, and Newby DE. Can inhaled carbon nanoparticles translocate into the circulation in humans? Am J Respir Crit Care Med 2006;173:426-31.en
dc.relation.hasversionMills NL, Törnqvist H, Gonzales M, Fink E, Robinson SD, Boon NA, Donaldson K, Blomberg A, Sandström T, and Newby DE. Ischemic and thrombotic effects of dilute diesel exhaust inhalation in men with coronary heart disease. N Engl J Med 2007;357:1075-1082.en
dc.relation.hasversionMills NL, Robinson SD, Fokkens P, Leseman D, Miller MR, Anderson D, Freney EJ, Heal MR, Donovan RJ, Blomberg A, Sandström T, MacNee W, Boon NA, Donaldson K, Newby DE, Cassee FR. Exposure to concentrated ambient particles does not affect vascular function in patients with coronary heart disease. Environ Health Perspect 2008; 116:709-715.en
dc.subjectair pollutionen
dc.subjectendotheliumen
dc.subjectfibrinolysisen
dc.titleEffects of combustion derived air pollution on vascular and fibrinolytic function in manen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


Files in this item

This item appears in the following Collection(s)

Show simple item record