Exposure to air pollution, particularly fine and ultrafine particulate matter derived from combustion sources, has been consistently associated with increased cardiovascular morbidity and mortality. Recent controlled exposure studies demonstrate that short-term exposure to diesel exhaust, which can contribute up to 40% of urban particulate air pollution, results in impaired vascular endothelial and fibrinolytic function in healthy volunteers, and increased exercise-induced myocardial ischaemia in patients with coronary heart disease. These observations may, in part, explain the observed increase in cardiovascular events following exposure to air pollution. Despite these observations there remain uncertainties regarding the key constituents of the air pollution mixture that mediate these adverse effects, and the underlying physiological and biological pathways involved. In these studies, using two controlled exposure facilities, I explored the vascular effects of the most prevalent gaseous component of the air pollution mixture – nitrogen dioxide – and the mechanisms responsible for impaired vasomotor function following exposure to diesel exhaust. Furthermore, I investigated the effect of acute exposure to “real-world” urban air pollution in both healthy volunteers and patients with coronary heart disease, and the effect of reducing that exposure using a simple facemask. In total, 10 healthy volunteers were exposed to nitrogen dioxide, and 29 healthy volunteers exposed to dilute diesel exhaust in a series of doubleblind randomised crossover studies. Exposure to nitrogen dioxide had no effect on either vasomotor function or endogenous fibrinolysis, providing indirect evidence that the adverse vascular effects are predominantly driven by particulate components. Following exposure to diesel exhaust there was no up regulation of endothelin-1 production, although there was increased vasoconstriction to intra-arterial infusion of endothelin-1. Following endothelin A receptor antagonism, there was attenuated vasodilatation following exposure to diesel exhaust as compared to air, an effect abrogated by endothelin B receptor antagonism. My findings suggest that the endothelin system does not play a central role in the adverse vascular effects of air pollution, but given the tonic interaction between the endothelin and nitric oxide systems, these observations could be explained by reduced nitric oxide bioavailability. Following diesel exhaust inhalation, plasma nitrite concentrations (as a marker for nitric oxide generation) are markedly increased without changes in haemodynamics or basal blood flow consistent with increased nitric oxide consumption. In the presence of a nitric oxide clamp, and without endogenous nitric oxide release, the vascular responses to vasodilators are similar. This perturbation of nitric oxide consumption and release appears to underlie the observed vascular endothelial effects. Fifteen healthy volunteers and 98 patients with coronary artery disease were recruited in Beijing, China. Subjects walked along a predefined city centre route for 2 hours in the presence and absence of a highly efficient facemask to reduce personal particulate air pollution exposure in an open label randomised crossover study. When wearing a facemask, there was an attenuation of exercise-induced increases in blood pressure, an improvement in heart rate variability, reduced myocardial ischaemia and subjects reported fewer symptoms. My findings have identified the biological mechanisms underlying the adverse vascular effects of exposure to diesel exhaust, and have helped to clarify the components responsible for these effects. Moreover, I have identified important benefits of reducing personal exposure to particulate matter using a simple facemask that have the potential to reduce cardiovascular events in patients living in urban or industrialised areas. Ongoing research in this area will provide further insight into the underlying vascular mechanisms, and the potential benefits of reducing particulate air pollution exposure, and may result in important targeted interventions to reduce the impact of air pollution on cardiovascular health.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:586305 |
| Date | January 2012 |
| Creators | Langrish, Jeremy Patrick |
| Contributors | Newby, D. E.; Mills, Nick |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/8144 |
Page generated in 0.0019 seconds