Oxidative Stress and the Effects of Air Pollution
Oxidative Stress and the Effects of Air Pollution
The epidemiological evidence for the cardiovascular effects of air pollution are compelling; however, this type of study is subject to different forms of bias and cannot investigate biological mechanisms, especially in terms of causality. To this end controlled exposure studies are required to assess the possible underlying pathophysiological mechanisms responsible for the observed acute and chronic effects of exposure to air pollutants. One clear benefit of controlled exposures is that, unlike studies in 'real-world' environments, they are both predictable and controllable. Furthermore, they can be used to separate out the differing effects of distinctive components of the air pollution mixture. In light of the epidemiological evidence, controlled exposure studies that focus on the cardiovascular system, have focused predominantly on the effects of combustion-derived PM, using either concentrated ambient particles (CAPs) from urban environments or dilute diesel exhaust to generate the exposures, in comparison to a control exposure of filtered clean air.
Controlled exposure studies in man have demonstrated important early changes in arterial hemodynamics as a result of PM exposure. Exposure to CAPs with ozone or dilute diesel exhaust leads to acute vasoconstriction of the brachial artery in both healthy volunteers and patients with metabolic syndrome, as well as an immediate and transient increase in central arterial stiffness, consistent with increases in arterial tone. Accordingly, shortly after exposure to CAPs and ozone there is a small increase in diastolic and mean arterial blood pressure. These acute effects may be driven by autonomic reflexes and changes in sympathetic nervous system activity. Heart rate variability (HRV) has been used to explore the action of inhaled PM on these pathways. Although data from controlled exposure studies are limited and somewhat inconsistent, PM exposure is generally associated with a reduction in HRV, suggesting that autonomic activity is altered by the exposure itself. The reduction in HRV following exposure to CAPs but not following dilute diesel exhaust exposure, suggests that the composition of the PM is critical for these actions.
Continuous electrocardiography during exposure to dilute diesel exhaust revealed an exacerbation of exercise-related myocardial ischemia in men with coronary heart disease. These findings concur with those from observational panel studies showing an association between the risk of ECG ST-segment depression and increasing exposure to ambient PM.
Controlled exposures to dilute diesel exhaust or CAPs with ozone are associated with impaired vascular vasomotor function due to endothelial dysfunction. These effects do not appear to be present immediately following the exposure but can be demonstrated from as early as 2 h after the exposure and up to 24 h, and have been shown to be mediated by the particulate phase of the inhaled pollutants.
Acute clinical cardiovascular events are primarily driven by arterial thrombosis complicating atheromatous plaque rupture. As well as the alterations in hemodynamics and vascular endothelial function that may predispose to plaque instability and rupture, exposure to PM has been shown to increase thrombus formation at sites of arterial injury. This increase in thrombogenicity is associated with an increase in platelet activation, suggesting this as a likely mechanism. Thrombus formation is highly dynamic and generation is balanced by clot turnover and breakdown (e.g., by release of the endogenous fibrinolytic enzyme tissue plasminogen activator from the vascular endothelium). The ability of the endothelium to release tissue plasminogen activator is also impaired following exposure to dilute diesel exhaust.
Long-term exposure to PM also promotes the development of atheromatous plaques. Much of this evidence is derived from animal models of atherosclerosis (see PM and oxidative stress in animal models of atherosclerosis), although observational studies in man have demonstrated that those living close to a major road have increased coronary artery calcium scores (a marker of complex atherosclerotic plaques), after correction for potential confounders. Additionally, background residential exposure to PM is associated with an increase in carotid intima–medial thickness (another surrogate marker of atheroma burden) and accelerated atheroma progression, albeit in a highly selected population.
The adverse cardiovascular effects of exposure to PM air pollution are summarized in Figures 3 & 4. Whilst these observations may help to explain the documented increase in cardiovascular events in those exposed to high levels of PM, the fundamental mechanism linking them remains elusive. Currently, oxidative stress is unique in that it has the potential to drive all of the above actions of PM, both locally and on a systemic level.
(Enlarge Image)
Figure 3.
Four examples of cardiovascular impairment following exposure to diesel exhaust in man.
(A) Impairment of vasodilatation (measured as increased forearm blood flow) to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) nitric oxide-mediated vasodilators. (B) Increased blood thrombogenicity (measured as ex vivo thrombus formation on the surface of a denuded arterial strip within a Badimon chamber). The low shear chamber mimics flow conditions of a mild-to-moderately stenosed coronary artery, high shear chamber mimics a patent coronary artery. (C) Impaired fibrinolysis (measured as release of t-PA in response to bradykinin infusion). (D) Increased myocardial ischemia (measured as increased ST-segment depression, using a 12-lead ECG during a 15 min exercise test). Volunteers were exposed to filtered air (red circles) or diluted diesel exhaust (300–350 µg/ml; blue circles) for 1 or 2 h.
bpm: Beats per min; t-PA: Tissue plasminogen activator.
(A & C) Data taken from. [51]
(B) Data taken from [54].
(D) Data taken from [44].
(Enlarge Image)
Figure 4.
The time course and numerous ways inhaled particulate matter alters cardiovascular function.
These diagrams are based largely on controlled exposures of concentrated ambient particles and dilute diesel exhaust in Edinburgh, Scotland, as well as inhalation of urban particulate matter in Bejing, China city center.
Controlled Exposures of Air Pollutants
Benefits of Controlled Exposure Studies
The epidemiological evidence for the cardiovascular effects of air pollution are compelling; however, this type of study is subject to different forms of bias and cannot investigate biological mechanisms, especially in terms of causality. To this end controlled exposure studies are required to assess the possible underlying pathophysiological mechanisms responsible for the observed acute and chronic effects of exposure to air pollutants. One clear benefit of controlled exposures is that, unlike studies in 'real-world' environments, they are both predictable and controllable. Furthermore, they can be used to separate out the differing effects of distinctive components of the air pollution mixture. In light of the epidemiological evidence, controlled exposure studies that focus on the cardiovascular system, have focused predominantly on the effects of combustion-derived PM, using either concentrated ambient particles (CAPs) from urban environments or dilute diesel exhaust to generate the exposures, in comparison to a control exposure of filtered clean air.
Air Pollution has Multiple Actions on the Cardiovascular System
Controlled exposure studies in man have demonstrated important early changes in arterial hemodynamics as a result of PM exposure. Exposure to CAPs with ozone or dilute diesel exhaust leads to acute vasoconstriction of the brachial artery in both healthy volunteers and patients with metabolic syndrome, as well as an immediate and transient increase in central arterial stiffness, consistent with increases in arterial tone. Accordingly, shortly after exposure to CAPs and ozone there is a small increase in diastolic and mean arterial blood pressure. These acute effects may be driven by autonomic reflexes and changes in sympathetic nervous system activity. Heart rate variability (HRV) has been used to explore the action of inhaled PM on these pathways. Although data from controlled exposure studies are limited and somewhat inconsistent, PM exposure is generally associated with a reduction in HRV, suggesting that autonomic activity is altered by the exposure itself. The reduction in HRV following exposure to CAPs but not following dilute diesel exhaust exposure, suggests that the composition of the PM is critical for these actions.
Continuous electrocardiography during exposure to dilute diesel exhaust revealed an exacerbation of exercise-related myocardial ischemia in men with coronary heart disease. These findings concur with those from observational panel studies showing an association between the risk of ECG ST-segment depression and increasing exposure to ambient PM.
Controlled exposures to dilute diesel exhaust or CAPs with ozone are associated with impaired vascular vasomotor function due to endothelial dysfunction. These effects do not appear to be present immediately following the exposure but can be demonstrated from as early as 2 h after the exposure and up to 24 h, and have been shown to be mediated by the particulate phase of the inhaled pollutants.
Acute clinical cardiovascular events are primarily driven by arterial thrombosis complicating atheromatous plaque rupture. As well as the alterations in hemodynamics and vascular endothelial function that may predispose to plaque instability and rupture, exposure to PM has been shown to increase thrombus formation at sites of arterial injury. This increase in thrombogenicity is associated with an increase in platelet activation, suggesting this as a likely mechanism. Thrombus formation is highly dynamic and generation is balanced by clot turnover and breakdown (e.g., by release of the endogenous fibrinolytic enzyme tissue plasminogen activator from the vascular endothelium). The ability of the endothelium to release tissue plasminogen activator is also impaired following exposure to dilute diesel exhaust.
Long-term exposure to PM also promotes the development of atheromatous plaques. Much of this evidence is derived from animal models of atherosclerosis (see PM and oxidative stress in animal models of atherosclerosis), although observational studies in man have demonstrated that those living close to a major road have increased coronary artery calcium scores (a marker of complex atherosclerotic plaques), after correction for potential confounders. Additionally, background residential exposure to PM is associated with an increase in carotid intima–medial thickness (another surrogate marker of atheroma burden) and accelerated atheroma progression, albeit in a highly selected population.
The adverse cardiovascular effects of exposure to PM air pollution are summarized in Figures 3 & 4. Whilst these observations may help to explain the documented increase in cardiovascular events in those exposed to high levels of PM, the fundamental mechanism linking them remains elusive. Currently, oxidative stress is unique in that it has the potential to drive all of the above actions of PM, both locally and on a systemic level.
(Enlarge Image)
Figure 3.
Four examples of cardiovascular impairment following exposure to diesel exhaust in man.
(A) Impairment of vasodilatation (measured as increased forearm blood flow) to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) nitric oxide-mediated vasodilators. (B) Increased blood thrombogenicity (measured as ex vivo thrombus formation on the surface of a denuded arterial strip within a Badimon chamber). The low shear chamber mimics flow conditions of a mild-to-moderately stenosed coronary artery, high shear chamber mimics a patent coronary artery. (C) Impaired fibrinolysis (measured as release of t-PA in response to bradykinin infusion). (D) Increased myocardial ischemia (measured as increased ST-segment depression, using a 12-lead ECG during a 15 min exercise test). Volunteers were exposed to filtered air (red circles) or diluted diesel exhaust (300–350 µg/ml; blue circles) for 1 or 2 h.
bpm: Beats per min; t-PA: Tissue plasminogen activator.
(A & C) Data taken from. [51]
(B) Data taken from [54].
(D) Data taken from [44].
(Enlarge Image)
Figure 4.
The time course and numerous ways inhaled particulate matter alters cardiovascular function.
These diagrams are based largely on controlled exposures of concentrated ambient particles and dilute diesel exhaust in Edinburgh, Scotland, as well as inhalation of urban particulate matter in Bejing, China city center.
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