Where There Is Smoke, There Is Fire Impact of Air Pollution on HDL (High-Density Lipoprotein) Function and Inflammation

It has long been recognized that cigarette smoking is causally linked to not only lung cancer but also to cardiovascular disease (CVD). There is now growing evidence that air pollution is also a major contributor to CVD, particularly ischemic heart disease, and stroke.^1,2 It is also associated with cardiometabolic diseases like diabetes mellitus and obesity.^3,4 Although the effect of air pollution on health at the individual level may be relatively small, because of the large number of individuals exposed, it is estimated to be a major modifiable risk factor and may be even more important than other better-known CVD risk factors, such as increased body mass index, smoking, and diabetes mellitus.⁵ In fact, the Global Burden of Disease Study estimated in 2016 that air pollution accounted for as much as 19% of all cases of CVD.⁶ Mortality from outdoor air pollution is also projected to double in the next 30 years,⁷ but the underlying mechanisms for all these concerning trends are not well understood.

In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Li et al⁸ from the Peking University First Hospital in Beijing, China, report on the results of the Beijing AIRCHD Study, which was designed to examine the effect of air pollution on various measures of HDLs (high-density lipoproteins), including their function. Unlike proatherogenic LDLs (low-density lipoproteins), HDLs in numerous epidemiological studies are inversely related to CVD and hence are often used as a negative risk biomarker for CVD.⁹ HDLs have been proposed to decrease CVD based on their ability to promote the efflux of excess cellular cholesterol. Assays based on this function (cholesterol efflux capacity) show a stronger inverse association with CVD than the cholesterol content of HDL (HDL-C)—the standard clinical laboratory test for HDL.⁹ In this study of 73 nonsmoking, healthy, young adults living in Beijing, exposure to both gaseous air pollution (NO₂, CO, and SO₂) and particulate matter (PM) was measured at 4 different times during the course of a 14-month period. PM, which are small particles that can come from the soil but in urban areas are mostly produced from the combustion of fossil fuels, are well known to be proinflammatory.¹⁰ PM <2.5 μM in diameter can enter the lower airways where they stimulate alveolar macrophages to produce the proinflammatory cytokines IL (interleukin)-6 and TNF-α (tumor necrosis factor-α).¹⁰ PM frequently contain transition metals like iron and thus are also prooxidants.¹ In addition, like many other small particles, PM can stimulate the inflammasome to generate proinflammatory cytokines, IL-1β and IL-18.¹¹ The average daily exposure to PM <2.5 μM in diameter and black carbon—another air pollutant monitored in the AIRCHD Study—was 62.9 and 3.8 μg/m³, respectively, which is quite high compared with that in many other parts of the world. Similar to several other studies,^12,13 subjects exposed the most to air pollutants had a significant reduction in HDL-C, as much as a 2.8-mg/dL decrease. LDL cholesterol or other apolipoprotein B–related parameters were not reported in this study, but it has previously been found that they are positively related to air pollution exposure.¹⁴ The function of HDL as determined by the cholesterol efflux capacity assay decreased as much as 5% in individuals with the greatest exposure to PM <2.5 μM in diameter, black carbon, and CO. The antioxidant capacity of HDL was also found to decrease with air pollution exposure. Consistent with the loss of the antioxidant capacity of HDL, oxidized LDL and malondialdehyde levels were increased in these same subjects. Finally, C-reactive protein—a generalized marker of inflammation—was positively associated with air pollution, particularly with SO₂. Given that systemic inflammation can lower HDL-C and can also interfere with HDL function by changing their proteome and lipidome,⁹ this observation could potentially explain many of the HDL-related findings in this study.

Because of its observational design, causality cannot be inferred from this study, but the described lipid and lipoprotein changes are consistent with several other clinical studies^12,13 and with short-term interventional studies of human subjects acutely exposed to air pollution.¹⁵ In addition, it has been shown in Apoe-KO mice that air pollutants can accelerate high-fat diet–induced atherosclerosis and that their HDLs become less anti-inflammatory.^16,17 It is important to note, however, that it has not been definitively established whether HDLs are only a biomarker for CVD or if they are also causally related to its pathogenesis.⁹ To date, therapies that raise HDL-C in multiple clinical trials have not reduced CVD events. One should also consider the possibility of a selection bias in the AIRCHD Study and that other environmental factors could be confounders. For example, it was recently found that low ambient temperatures, during the winter,¹³ which often correspond to peak air pollution levels in Beijing, can also lower HDL-C levels, as well as cholesterol efflux capacity of HDLs.

Besides the negative impact of air pollutants on lipoprotein levels and their function, other pathogenic mechanisms could also be involved in the link between air pollution and CVD. In case of PM exposure (Figure), 3 main pathways have been proposed⁷: (1) PM stimulate local inflammation in the lung that then triggers systemic inflammation, leading to endothelial dysfunction and a prothrombotic state, (2) PM cause sympathetic autonomic stimulation by activating pulmonary sensory receptors, which leads to norepinephrine and epinephrine release, vasoconstriction, hypertension, and increased heart rate, (3) ultrafine PM <0.1 μM can via the lung enter the circulation where they can travel to target tissues like the vascular wall and stimulate local inflammation by activating the inflammasome. These 3 pathways, of course, are not mutually exclusive, and there are many points at which the alterations in lipoprotein metabolism observed in the AIRCHD Study could potentially interact with these pathways.

Figure.

Major pathways for promotion of cardiovascular disease by particulate air pollution. HDL indicates high-density lipoprotein; and PM, particulate matter.

Finally, HDL has also recently been linked to pulmonary function.^16,18 Low HDL-C, for example, has been associated with increased eosinophilic inflammation and disease severity in asthmatics.^19,20 Furthermore, treatment of a murine model of asthma with apolipoprotein A-I mimetic peptides attenuates the development of airway inflammation, remodeling, and hyperresponsiveness.²¹ The interesting results of the AIRCHD Study are, therefore, likely to stimulate the much needed future research on the perplexing nexus between air pollution, pulmonary function, HDL metabolism, and CVD.