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Interaction with the lung cell membrane leads to Atherosclerosis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Substance interaction with lung resident cell membrane components leading to atherosclerosis||non-adjacent||High||Moderate||Ulla Vogel (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
This KER presents the association between the interaction of stressors with the lungs and atherosclerosis as the outcome. The evidence of the KER presented is based on mouse models of human atherosclerosis.
Evidence Collection Strategy
Evidence Supporting this KER
The biological plausibility is moderate. Exposure to different stressors have been shown to induce the progression of atherosclerotic in mouse models of human atherosclerosis (see below). In humans, it has been hypothesized that air pollution, an example of stressor that interacts with the lungs, and cardiovascular diseases are linked by three pathways: i) translocation of inflammatory mediators from the lungs to the systemic circulation, ii) activation of alveolar receptors that results in the alteration of autonomic response and changes in cardiovascular function, and iii) translocation of particles (stressors) from the lungs to the systemic circulation 1,2.
Uncertainties and Inconsistencies
ApoE-/- mice seem to have a moderate plaque progression when feed a normal diet, instead of high-fat diet, and exposed to the stressor for a short period 6.
Known modulating factors
- Following the ban of coal in Dublin, a decrease of 70% of black smoke (35 μg/m3) was observed along with a 10.3% decrease (p<0.0001) in cardiovascular deaths 10.
- A prospective study following postmenopausal women from USA for 6 years observed that an increase of 10 μg of PM2.5 (particulate matter with a diameter of less than 2.5 μm) was associated with 24% increased risk of cardiovascular event and a 76% increased risk of death from a cardiovascular disease 11.
- Beelen et al. analyzed data from 22 European cohort studies on long-term exposure to air pollution and associations with cardiovascular diseases mortality. It was obtained that a PM2.5 increase of 5 μg/m3 was associated with 21% increased risk of death from cerebrovascular disease, while an increase of 10 μg/m3 of PM10 (particulate matter with a diameter of less than 10 μm) was associated with an 22% increased risk of death from cerebrovascular disease 12.
- Results from 11 cohort studies on long-term exposure to air pollution and incidence of acute coronary events showed a 13% increased risk of coronary events associated to 5 μg/m3 increase of PM2.5, and a 12% increased risk of coronary events associated to 10 μg/m3 increase of PM10 13.
- A cohort study of population living in Denmark between 2005 and 2017, and aged more than 50 years old, showed that a 5 μg/m3 increase of PM2.5 was associated to a 22% increased risk of stroke, while an increase of 1.85 μg/m3 increase of PM2.5 was associated to a 5.3% increased risk of myocardial infarction 14,15.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Mouse models of human atherosclerosis has been shown to present atherosclerotic lesion progression after exposure to concentrated ambient particles, welding fumes and diesel exhaust particles 3,5,7.
In humans, epidemiological studies have shown that air pollution, as a stressor that interacts with the lungs, is a risk factor for cardiovascular diseases 14.
1 Miller, M. R. & Newby, D. E. Air pollution and cardiovascular disease: car sick. Cardiovasc Res 116, 279-294, doi:10.1093/cvr/cvz228 (2020).
2 Van Eeden, S., Leipsic, J., Paul Man, S. F. & Sin, D. D. The relationship between lung inflammation and cardiovascular disease. Am J Respir Crit Care Med 186, 11-16, doi:10.1164/rccm.201203-0455PP (2012).
3 Chen, L. C. & Nadziejko, C. Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. V. CAPs exacerbate aortic plaque development in hyperlipidemic mice. Inhal Toxicol 17, 217-224, doi:10.1080/08958370590912815 (2005).
4 Li, Z. et al. Cardiovascular effects of pulmonary exposure to single-wall carbon nanotubes. Environ Health Perspect 115, 377-382, doi:10.1289/ehp.9688 (2007).
5 Erdely, A. et al. Inhalation exposure of gas-metal arc stainless steel welding fume increased atherosclerotic lesions in apolipoprotein E knockout mice. Toxicol Lett 204, 12-16, doi:10.1016/j.toxlet.2011.03.030 (2011).
6 Mikkelsen, L. et al. Modest effect on plaque progression and vasodilatory function in atherosclerosis-prone mice exposed to nanosized TiO(2). Part Fibre Toxicol 8, 32, doi:10.1186/1743-8977-8-32 (2011).
7 Miller, M. R. et al. Diesel exhaust particulate increases the size and complexity of lesions in atherosclerotic mice. Part Fibre Toxicol 10, 61, doi:10.1186/1743-8977-10-61 (2013).
8 Christophersen, D. V. et al. Accelerated atherosclerosis caused by serum amyloid A response in lungs of ApoE(-/-) mice. FASEB J 35, e21307, doi:10.1096/fj.202002017R (2021).
9 Dockery, D. W. et al. An association between air pollution and mortality in six U.S. cities. N Engl J Med 329, 1753-1759, doi:10.1056/NEJM199312093292401 (1993).
10 Clancy, L., Goodman, P., Sinclair, H. & Dockery, D. W. Effect of air-pollution control on death rates in Dublin, Ireland: an intervention study. Lancet 360, 1210-1214, doi:10.1016/S0140-6736(02)11281-5 (2002).
11 Miller, K. A. et al. Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med 356, 447-458, doi:10.1056/NEJMoa054409 (2007).
12 Beelen, R. et al. Long-term exposure to air pollution and cardiovascular mortality: an analysis of 22 European cohorts. Epidemiology 25, 368-378, doi:10.1097/EDE.0000000000000076 (2014).
13 Cesaroni, G. et al. Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE Project. BMJ 348, f7412, doi:10.1136/bmj.f7412 (2014).
14 Poulsen, A. H. et al. 'Source-specific' air pollution and risk of stroke in Denmark. Int J Epidemiol 52, 727-737, doi:10.1093/ije/dyad030 (2023).
15 Poulsen, A. H. et al. Source-Specific Air Pollution Including Ultrafine Particles and Risk of Myocardial Infarction: A Nationwide Cohort Study from Denmark. Environ Health Perspect 131, 57010, doi:10.1289/EHP10556 (2023).
16 Vaduganathan, M., Mensah, G. A., Turco, J. V., Fuster, V. & Roth, G. A. The Global Burden of Cardiovascular Diseases and Risk: A Compass for Future Health. J Am Coll Cardiol 80, 2361-2371, doi:10.1016/j.jacc.2022.11.005 (2022).