Oxidative Stress and the Effects of Air Pollution
Oxidative Stress and the Effects of Air Pollution
Air pollution exposure is now considered as a risk factor for cardiovascular diseases. Although the absolute increase in risk associated with exposure is modest in comparison with other risk factors, such as poor diet, the ubiquitous nature of air pollution exposure means that the whole population is affected. Indeed, at the population-level it is arguably the most important risk factor for acute cardiovascular events. Importantly, air pollution exposure is entirely modifiable and it is clear that in order to reduce this risk, our primary aim should be to limit exposure. There is epidemiological evidence to support such a strategy: following the banning of the sale of bituminous coal in Dublin, Ireland in the early 1990s, air quality improved almost overnight and with a corresponding fall in the incidence of cardiovascular events. Cigarette smoke is another complex air pollutant, but it is notable that it shares many similar groups of reactive organic chemical species. Following the introduction of smoking bans in public places in many developed countries within the last decade, there has been a large reduction in the incidence of acute myocardial infarction among the general public. The challenge now is: how we can effectively implement interventions that could reduce levels of harmful PM. This is especially pertinent in developing countries where rapid economic development means an ever-increasing reliance on fossil fuels for domestic use, transport and industry, accompanied by the use of old and inefficient vehicles.
If it is not possible, at least in the short-term, to reduce the population exposure to PM air pollution, alternative interventions need to be considered. It has been argued that in order to design specific interventions to protect the public from the adverse effects of inhaled PM we require a greater understanding of the pathways involved. Our understanding of the later pathophysiological effects of PM air pollution is actually good, what is lacking is the intermediate stages of the processes: how are the effects of inhaled PM transferred and amplified to an extent that they can cause significant damage to the cardiovascular system. However, this missing step may not be of relevant if oxidative stress plays a crucial role at multiple sites of the pathway, then there is potential to develop therapies that act at one or more of these sites.
There is a noticeable deficit in studies testing the ability of pharmacological therapies to ameliorate the effects of air pollution in man. A few small epidemiological and panel studies have suggested that use of statins or β-blocker drugs can limit the effects of PM, although in specific populations and with limited end points investigated. Nevertheless, bearing in mind the slow progress of legislative changes to reduce combustion-derived PM, it is useful to consider whether current medical therapies may be useful adjunct intervention. The obvious pharmacological intervention would be to use antioxidants to eliminate significant oxidative stress. While there is now good evidence from animal models that a range of antioxidant compounds can prevent the effects of PM both in vitro and in vivo (see above), there is no such evidence in man. This is perhaps just a reflection of the difficulty in studying oxidative stress in man; however, the enthusiasm for such an approach to prevent the cardiovascular actions of PM is dented by the poor outcome data from clinical trials of antioxidant therapy in cardiovascular diseases in general. Nevertheless, it would be unwise to dismiss the potential therapeutic benefits of antioxidant therapies, especially where there is clear evidence for free radical-mediated pathways, as is the case with air pollution. There is a need for better-designed antioxidant therapies that have the capacity to specifically reach the locations under attack from the oxidative actions of PM (endothelial cells for example), or to provide antioxidants that can be readily recycled to replenish key endogenous antioxidant pools. Alternatively, consideration should be given to other classes of pharmacological agents, for example those that inhibit enzymatic sources of free radicals activated by PM (e.g., NADPH oxidase), or block the sensory receptors in the lung that could mediate the cardiovascular effects of PM via the autonomic nervous system.
It is interesting that, in general, the effects of PM exposure do not appear to be greater in patients with, and animal models of, cardiovascular disease compared with their healthy counterparts. In all likelihood, this can be explained by the presence of existing vascular disease, limiting the potential for inhaled PM to exert a further adverse effect. However, in the clinical scenario patients are usually on optimal medical therapy, which includes a number of medications that target the pathways known to exacerbate cardiovascular disease which may account for the reduced effects seen. Statins are now the first-line treatment for hypercholesterolemia and atherosclerotic diseases, and the combined action of these drugs to lower plasma cholesterol and exert an anti-inflammatory action would suggest that these drugs may afford some degree of protection from the actions of air pollution mediated by these pathways. Indeed, there is some preliminary evidence to suggest statins may confer a benefit in limiting oxidative stress following PM exposure in man in patients with impaired endogenous antioxidant pathways. Similarly, the antiplatelet and anti-inflammatory properties of aspirin, may also combat the effects of air pollution and β-blocker drugs may limit the neurohumoral responses to air pollution exposure. These observations raise questions as to whether we are underestimating the actions of air pollution in patients taking such medication, or more pressingly, are we overlooking readily available ways to limit the consequences of air pollution in those patients who are not prescribed these drugs.
From an economic point of view it is beneficial to target interventions towards high-risk groups, as is currently the normal practice with statins in the treatment of hypercholesterolemia. This could be with regards to targeting specific cardiovascular conditions, subsets of patients or even the genotypes of potentially high-risk groups (see the effect of statins in GST null populations;). Given the inherent costs in any pharmacological intervention, a more appropriate intervention is to reduce the exposure to PM air pollution of those thought to be at highest risk. There is limited evidence that use of personal respiratory protection in the form of a face-mask can reduce the adverse effects of exposure to PM, although it remains to be seen if such an intervention can reduce the incidence of acute cardiovascular events. While such an intervention would be cheap and readily achievable in the short-term, it is unlikely to be more than a temporary intervention until more stringent environmental controls can be implemented.
Despite the potential in the above interventions, the single most effective way to limit the health effects of air pollution in the general population is undoubtedly to reduce harmful emissions in the first place. The health effects of air pollution are strongly linked to the fine (and ultrafine) components, from traffic and industrial processes that burn fossil fuels. There is already evidence that reducing PM emissions from diesel engines by the use of a retrofit particle trap can abolish the adverse vascular effects of diesel exhaust exposure. Alternatively, modification of fuels and engine technology to ensure more complete combustion, such as the use of fuel additives like cerium oxide, can reduce PM emissions. This article highlights the importance of the composition of the emissions, and PM itself, and wide variation in the cardiovascular effects of different types of PM. Identification of the detrimental physiochemical properties of airborne PM will lead to improvements in fuel and engine technologies to limit the presence of these chemicals from emissions. A combined scientific and clinical approach using complementary techniques is now needed to establish the potential of these interventions in reducing the health effects of air pollution, paying specific attention to the whether these interventions can prevent the oxidative-stress driven actions of inhaled particles.
Future Perspective
Air pollution exposure is now considered as a risk factor for cardiovascular diseases. Although the absolute increase in risk associated with exposure is modest in comparison with other risk factors, such as poor diet, the ubiquitous nature of air pollution exposure means that the whole population is affected. Indeed, at the population-level it is arguably the most important risk factor for acute cardiovascular events. Importantly, air pollution exposure is entirely modifiable and it is clear that in order to reduce this risk, our primary aim should be to limit exposure. There is epidemiological evidence to support such a strategy: following the banning of the sale of bituminous coal in Dublin, Ireland in the early 1990s, air quality improved almost overnight and with a corresponding fall in the incidence of cardiovascular events. Cigarette smoke is another complex air pollutant, but it is notable that it shares many similar groups of reactive organic chemical species. Following the introduction of smoking bans in public places in many developed countries within the last decade, there has been a large reduction in the incidence of acute myocardial infarction among the general public. The challenge now is: how we can effectively implement interventions that could reduce levels of harmful PM. This is especially pertinent in developing countries where rapid economic development means an ever-increasing reliance on fossil fuels for domestic use, transport and industry, accompanied by the use of old and inefficient vehicles.
If it is not possible, at least in the short-term, to reduce the population exposure to PM air pollution, alternative interventions need to be considered. It has been argued that in order to design specific interventions to protect the public from the adverse effects of inhaled PM we require a greater understanding of the pathways involved. Our understanding of the later pathophysiological effects of PM air pollution is actually good, what is lacking is the intermediate stages of the processes: how are the effects of inhaled PM transferred and amplified to an extent that they can cause significant damage to the cardiovascular system. However, this missing step may not be of relevant if oxidative stress plays a crucial role at multiple sites of the pathway, then there is potential to develop therapies that act at one or more of these sites.
There is a noticeable deficit in studies testing the ability of pharmacological therapies to ameliorate the effects of air pollution in man. A few small epidemiological and panel studies have suggested that use of statins or β-blocker drugs can limit the effects of PM, although in specific populations and with limited end points investigated. Nevertheless, bearing in mind the slow progress of legislative changes to reduce combustion-derived PM, it is useful to consider whether current medical therapies may be useful adjunct intervention. The obvious pharmacological intervention would be to use antioxidants to eliminate significant oxidative stress. While there is now good evidence from animal models that a range of antioxidant compounds can prevent the effects of PM both in vitro and in vivo (see above), there is no such evidence in man. This is perhaps just a reflection of the difficulty in studying oxidative stress in man; however, the enthusiasm for such an approach to prevent the cardiovascular actions of PM is dented by the poor outcome data from clinical trials of antioxidant therapy in cardiovascular diseases in general. Nevertheless, it would be unwise to dismiss the potential therapeutic benefits of antioxidant therapies, especially where there is clear evidence for free radical-mediated pathways, as is the case with air pollution. There is a need for better-designed antioxidant therapies that have the capacity to specifically reach the locations under attack from the oxidative actions of PM (endothelial cells for example), or to provide antioxidants that can be readily recycled to replenish key endogenous antioxidant pools. Alternatively, consideration should be given to other classes of pharmacological agents, for example those that inhibit enzymatic sources of free radicals activated by PM (e.g., NADPH oxidase), or block the sensory receptors in the lung that could mediate the cardiovascular effects of PM via the autonomic nervous system.
It is interesting that, in general, the effects of PM exposure do not appear to be greater in patients with, and animal models of, cardiovascular disease compared with their healthy counterparts. In all likelihood, this can be explained by the presence of existing vascular disease, limiting the potential for inhaled PM to exert a further adverse effect. However, in the clinical scenario patients are usually on optimal medical therapy, which includes a number of medications that target the pathways known to exacerbate cardiovascular disease which may account for the reduced effects seen. Statins are now the first-line treatment for hypercholesterolemia and atherosclerotic diseases, and the combined action of these drugs to lower plasma cholesterol and exert an anti-inflammatory action would suggest that these drugs may afford some degree of protection from the actions of air pollution mediated by these pathways. Indeed, there is some preliminary evidence to suggest statins may confer a benefit in limiting oxidative stress following PM exposure in man in patients with impaired endogenous antioxidant pathways. Similarly, the antiplatelet and anti-inflammatory properties of aspirin, may also combat the effects of air pollution and β-blocker drugs may limit the neurohumoral responses to air pollution exposure. These observations raise questions as to whether we are underestimating the actions of air pollution in patients taking such medication, or more pressingly, are we overlooking readily available ways to limit the consequences of air pollution in those patients who are not prescribed these drugs.
From an economic point of view it is beneficial to target interventions towards high-risk groups, as is currently the normal practice with statins in the treatment of hypercholesterolemia. This could be with regards to targeting specific cardiovascular conditions, subsets of patients or even the genotypes of potentially high-risk groups (see the effect of statins in GST null populations;). Given the inherent costs in any pharmacological intervention, a more appropriate intervention is to reduce the exposure to PM air pollution of those thought to be at highest risk. There is limited evidence that use of personal respiratory protection in the form of a face-mask can reduce the adverse effects of exposure to PM, although it remains to be seen if such an intervention can reduce the incidence of acute cardiovascular events. While such an intervention would be cheap and readily achievable in the short-term, it is unlikely to be more than a temporary intervention until more stringent environmental controls can be implemented.
Despite the potential in the above interventions, the single most effective way to limit the health effects of air pollution in the general population is undoubtedly to reduce harmful emissions in the first place. The health effects of air pollution are strongly linked to the fine (and ultrafine) components, from traffic and industrial processes that burn fossil fuels. There is already evidence that reducing PM emissions from diesel engines by the use of a retrofit particle trap can abolish the adverse vascular effects of diesel exhaust exposure. Alternatively, modification of fuels and engine technology to ensure more complete combustion, such as the use of fuel additives like cerium oxide, can reduce PM emissions. This article highlights the importance of the composition of the emissions, and PM itself, and wide variation in the cardiovascular effects of different types of PM. Identification of the detrimental physiochemical properties of airborne PM will lead to improvements in fuel and engine technologies to limit the presence of these chemicals from emissions. A combined scientific and clinical approach using complementary techniques is now needed to establish the potential of these interventions in reducing the health effects of air pollution, paying specific attention to the whether these interventions can prevent the oxidative-stress driven actions of inhaled particles.