Interaction with the lung cell membrane leads to Atherosclerosis

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 (M. R. Miller & Newby, 2020; Van Eeden, Leipsic, Paul Man, & Sin, 2012).

Any substance that is inhaled will interact with a component of the respiratory system, including cells. Any study that shows that inhalation exposure leads to atherosclerosis is considered evidence for this KER, even if the specific interaction between the substance and the respiratory system has not been investigated. For this KER, exposure through the respiratory system (inhalation, aspiration or intratracheal instillation) of stressors was considered as interaction with lung resident cell membrane components (Key event 1495), while atherosclerosis is measured as atherosclerotic lesions (i.e. plaques) size or area (Key event 1443).

• ApoE^-/- and double knockout ApoE-/-LDLr^-/- mice exposed to concentrated ambient particles (110 µg/m³) for 6h/d, 5d/week for 5 months develop severe atherosclerosis. ApoE^-/- mice exposed to concentrated ambient particles presented a 57% increase in aortic intima surface coverage by atherosclerotic lesion than mice exposed to air (Chen & Nadziejko, 2005).
• Intrapharyngeal aspiration of singlewalled carbon nanotubes into ApoE^-/- mice (20 µg/mouse every 2 weeks for 8 weeks) induced a significant increase in plaque progression (Li et al., 2007).
• ApoE^-/- mice on a Western diet showed an increase in atherosclerotic lesion area after exposure to fumes from gas metal arc-stainless steel welding (40 mg/m³) for 3h/day for 10 days (Erdely et al., 2011).
• A modest increase in atherosclerotic plaque area was observed in ApoE^-/- mice after intratracheal instillation of titanium dioxide nanoparticles (0.5 mg/kg) once a week for four weeks (Mikkelsen et al., 2011).
• ApoE^-/- mice, fed a Western diet and exposed to diesel exhaust particles through oropharyngeal aspiration (35 µg) twice a week for four weeks, presented an increased atherosclerotic lesions area(M. R. Miller et al., 2013).
• Intratracheal instillation of human serum amyloid A once a week for 10 weeks in ApoE^-/- mice (on Western-type diet) induced atherosclerotic plaque progression (Christophersen et al., 2021).

In addition, several epidemiological studies have shown that exposure to particulate matter from air pollution is associated to cardiovascular diseases (i.e. due to progression of atherosclerosis):

• A prospective study in six cities from USA showed that air pollution was associated with death from cardiopulmonary diseases (Dockery et al., 1993).
• In Dublin, there was a decrease in black smoke concentration in air, along with a significant decrease in the number of cardiovascular deaths, after the 1990 ban on coal sales (Clancy, Goodman, Sinclair, & Dockery, 2002).

ApoE^-/- mice seem to have a moderate plaque progression even when feed a normal diet, instead of high-fat diet, and exposed to the stressor for a short period (Mikkelsen et al., 2011).

• A decrease of 70% of black smoke (35 μg/m³) was observed along with a 10.3% decrease (p<0.0001) in cardiovascular deaths  following the ban of coal in Dublin (Clancy et al., 2002).
• An increase of 10 μg of PM_2.5 (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, in postmenopausal women from USA (K. A. Miller et al., 2007).
• A PM_2.5 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 (Beelen et al., 2014). These results where analyzed from 22 European cohort studies on long-term exposure to air pollution and associations with cardiovascular diseases mortality (Beelen et al., 2014).
• 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 PM_2.5, and a 12% increased risk of coronary events associated to 10 μg/m³ increase of PM₁₀ (Cesaroni et al., 2014).