Air Pollution and Disease Mechanisms

 Ref

Front Public Health. 2022 Jul 14;10:882569. doi: 10.3389/fpubh.2022.882569

The Physiological Effects of Air Pollution: Particulate Matter, Physiology and Disease

Jack T Pryor 1,2, Lachlan O Cowley 1, Stephanie E SimParticulate Matter

Abstract

Nine out of 10 people breathe air that does not meet World Health Organization pollution limits. 

Air pollutants include gasses and particulate matter and collectively are responsible for ~8 million annual deaths.

 Particulate matter is the most dangerous form of air pollution, 

causing inflammatory and oxidative tissue damage. 

A deeper understanding of the physiological effects of particulate matter is needed for effective disease prevention and treatment.

 This review will summarize the impact of particulate matter on physiological systems, and where possible will refer to apposite epidemiological and toxicological studies. By discussing a broad cross-section of available data, 

we hope this review appeals to a wide readership and provides some insight on the impacts of particulate matter on human health.

Particulate matter (PM) are solid compounds suspended in air that are sufficiently small to be inhaled (Figure 1). PM is categorized by particle diameter (measured in μm); PM0.1, PM2.5 and PM10 whilst ambient concentration is usually quantified as μg/m3. Some PM are of natural origin (bushfires, dust, sea spray, aerosols, etc.) but anthropogenic PM (diesel, coal and biomass combustion and emissions from metal refineries etc.) are the most dangerous to health (13). High atmospheric concentrations of human-made PM, and toxic and oxidative chemical characteristics render them disproportionately hazardous (13). Elemental and complex chemical species of PM are diverse, with surface shape, chemistry and charge impacted by emission source and environmental conditions. PM chemistry can change through reactions with other airborne PM and be affected by the oxidative effects of ozone and low ambient pH (14, 15).

Figure 1.

Figure 1Particulate Matter

Particulate matter (PM) are solid compounds suspended in air that are sufficiently small to be inhaled (Figure 1). PM is categorized by particle diameter (measured in μm); PM0.1, PM2.5 and PM10 whilst ambient concentration is usually quantified as μg/m³. Some PM are of natural origin (bushfires, dust, sea spray, aerosols, etc.) but anthropogenic PM (diesel, coal and biomass combustion and emissions from metal refineries etc.) are the most dangerous to health (13). High atmospheric concentrations of human-made PM, and toxic and oxidative chemical characteristics render them disproportionately hazardous (13). Elemental and complex chemical species of PM are diverse, with surface shape, chemistry and charge impacted by emission source and environmental conditions. PM chemistry can change through reactions with other airborne PM and be affected by the oxidative effects of ozone and low ambient pH (14, 15).

Figure 1.

Open in a new tab

To scale illustration of the relative sizes of PM10, PM2.5, and PM0.1. Representative macrophage and mitochondria are included to scale for reference.

Open in a new tab

To scale illustration of the relative sizes of PM10, PM2.5, and PM0.1. Representative macrophage and mitochondria are included to scale for reference.onds 1,*

Disease Mechanisms

According to the World Health Organization, air pollution and climate change are the collective No. 1 threat to human health (25).

 Air pollution contributes to 9% of all global human deaths, and of these, 58% are from ischemic heart disease and cerebrovascular disease, 18% are from chronic obstructive pulmonary disease and acute lower respiratory tract infections, 6% are from lung cancer. Causes of death in the remaining 18% are mixed and many (12).

 Not all PM equally toxic, with the pathophysiological mechanisms varying between PM species (26).

 PM are mutagenic, can cause oxidative damage, activate inflammatory signal cascades and induce cell death (27–30).

 Toxicological research has investigated the differential oxidative and inflammatory effects of PM species (including black carbon, ammonia, nitrate and sulfate) and PM of varying origin (13).

 A common anthropogenic source of PM is incomplete combustion of diesel, gasoline, coal, and biomass (13).

 Trace metal content significantly contributes to the oxidative potential of PM (13, 26).

 The oxidative effects of PM can damage mitochondria, endoplasmic reticulum and DNA, can be carcinogenic and activate cell death signaling pathways (26).

 Inside cells, iron-based PM can overwhelm superoxide dismutase and glutathione peroxidase activity, inducing ferroptosis (29).

 PM2.5 can activate cytokine-dependent autophagy pathways, signaling through toll-like receptors, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, and via cyclooxygenase 2-mitochondrial and prostaglandin E synthase. Here, increased tissue levels of C-reactive protein, tumor necrosis factor-α, interleukins 1, 6 and 8 (31–34). Inflammatory, oxidative, and toxic mechanisms are the primary effectors of PM-induced cell damage. Tissue-specific pathophysiology is an important determining factor in health outcomes, is discussed below and outlined in Figure 4.

Respiratory Disease

The lungs are the primary site of PM-induced pathophysiology and best characterized in terms of the effects of PM exposure. Each 10 μg/m3 increase in ambient PM10 has been linked to a 0.58% increase in respiratory mortality, whist the same increase of PM2.5 has been associated with a 2.07% increase in respiratory disease hospitalization (35, 36). 

Research has shown human exposure to PM to be associated with multiple respiratory diseases including chronic obstructive pulmonary disease, asthma, interstitial lung damage and lung cancers (37–39). 

For patients with idiopathic pulmonary fibrosis, PM exposure has been shown to correlate with reduced lung forced vital capacity (39).

Ex vivo analysis of mouse lungs exposed to PM2.5 for three months exhibited significantly elevated levels of PM2.5, carbon monoxide, nitrogen oxides, interleukin-4, tumor necrosis factor-α and transforming growth factor-β1 when compared to controls (40). 

Of these circulating factors, interleukin-4 is known to promote B lymphocyte production of immunoglobulin E; a driver of allergic diseases including asthma and chronic obstructive pulmonary disease (41). 

PM2.5 exposure has been shown to induce pulmonary fibrosis both in vivo and in vitro experiments (42).

 PM2.5 increased tissue concentrations of transforming growth factor-β1; a fibroblast chemokine that can decrease protease secretion and increase extracellular expression of collagen and fibronectin (43).

 In a mouse model of idiopathic pulmonary fibrosis, ex vivo histological analysis revealed that exposure to black carbon PM2.5 aggravated lung inflammation and exacerbated histopathological changes to lung tissue including increased inflammatory cell infiltration and epithelial cell hyperplasia (44). 

This study also found that exposure to black carbon PM2.5 exacerbated already elevated interleukin-6 mRNA and reduced interferon-γ mRNA expression (44).

 Together, these preclinical studies not only highlight the potential danger of PM to health but also suggest that PM can increase the severity of existing health conditions like idiopathic pulmonary fibrosis. Increased counts of neutrophils, lymphocytes, eosinophils, M1 and M2 macrophages have been found in PM-exposed lung tissue (40).

 Whilst M1 macrophages can induce oxidative damage to lung epithelia, chronic elevation of M2 macrophages can cause pulmonary fibrosis and lung cancer (45–47).

 Mechanisms by which PM may induce fibrosis include increased intracellular edema, microvilli density, lamellar bodies and the density of macrophages containing endocytosed PM (40). 

In mice, PM2.5 exposure reduced mitochondrial density, increased NADPH oxidase 2 expression, significantly reduced total lung capacity, inspiratory capacity, and lung compliance (48). 

This same study found that PM2.5 exposure increased lung epithelia expression of N-Cadherin and reduced that of E-Cadherin; markers of epithelial-mesenchymal transition, a process common to cancer metastasis (48).

Cardiovascular Disease

Air pollution is associated with elevated cardiovascular disease risk and cardiovascular disease-related mortality (49).

 PM2.5 exposure is linked to higher risk of heart attack, heart failure, ischemic heart disease, stroke, atherosclerosis, arrhythmia, hypertension, preeclampsia and neonatal hypertension (50–52). 

Air pollution exacerbates cardiovascular mortality risk for people with pre-existing cardiopulmonary disease (49). 

In adults, exposure to PM exposure has been linked to elevated systolic blood pressure and elevated pulse pressure, 

whilst in children, it has been found to associate with increased mean pulmonary arterial pressure and increased plasma endothelin-1 concentration (53, 54).

 Endothelin-1 is an endogenous atherogenic vasoconstrictor and may contribute to PM induced atherosclerotic plaque accumulation (55).

 The Multi Ethnic Study of Atherosclerosis (MESA) found short-term PM2.5 exposure to associate with to decreased flow-mediated vasodilation and vasoconstriction, indicating that particulates may impair endothelial function (56).

 Analysis of the same MESA cohort revealed a correlation between exposure to black carbon PM and pulmonary vascular remodeling (57).

 Here, changes in vascular volume – indicative of elevated blood pressure – were comparable to the effect of >15 pack years of cigarette smoking (57).

 PM exposure has been found to exacerbate high-risk atherosclerotic plaque progression, plaque destabilization and coronary calcification (58). 

PM exposure has also been linked to atrial fibrillation and reduced heart rate variability, with the later exacerbated by pre-existing diabetes (59).

 Preclinical models have demonstrated that PM can induce hypertension in healthy animals, secondary disease in animal models of heart failure and hypertension, and induce symptoms of cardiovascular dysfunction via central and renal cardiovascular regulation disruption (60–63).

 Exposure of rats to black carbon PM for 4 weeks dose and time dependently increased blood pressure (60). Four-day PM2.5 exposure to spontaneously hypertensive rats significantly increased heart rate and blood pressure and reduced heart rate variability (61). 

In a mouse model of chronic left ventricular heart failure, PM2.5 exposure significantly exacerbated lung oxidative stress, lung fibrosis, inflammation, vascular remodeling, and right ventricle hypertrophy (62, 63).

 Hypertensive, angiotensin II-infused apoe−/− mice, exposed to PM2.5 for 4 weeks had a significantly increased incidence of abdominal aortic aneurysm compared to controls (64).

 Here, aortic aneurysm was associated with significant vascular elastin degradation, increased maximal abdominal aortic diameter and elevated expression of senescence proteins P16 and P21 (64).

 Increased vascular P21 is implicated in the development of atherosclerosis, causes of which include inflammation, hemodynamic damage and aberrant lipid metabolism (65, 66). 

Multiple models have shown PM2.5 exposure to stimulate endothelial release of inflammatory cytokines and adhesion molecules, promote macrophage infiltration, vascular smooth muscle cell dysfunction and plaque formation (67).

 Hypertensive, apolipoprotein-deficient mice exposed to PM2.5 for 3 months exhibited increased atherosclerotic lesion area, hepcidin and iron plaque depositions, increased plasma iron, ferritin, total cholesterol, low density cholesterol, vascular endothelial derived growth factor, monocyte chemoattractant protein-1 and pro-atherosclerotic cytokines interleukin 6 and tumor necrosis factor-α (64). 

Both blood pressure and heart rate are partially regulated by the central nervous system, with sympathetic output from the hypothalamus significantly impacting cardiovascular tone (68).

 Is In wild-type mice, long-term PM2.5 exposure has been found to increase basal blood pressure; an effect that was reversed with central alpha-2 adrenergic receptor antagonism. Concurrent inflammation of the hypothalamic arcuate nucleus was observed in hypertensive PM2.5-exposed mice (69).

Increased noradrenergic signaling in the hypothalamic periventricular nucleus is known to increase sympathetic output and cardiovascular tone (70). 

Exposure of lean Brown Norway rats to PM for 1 day increased noradrenaline concentrations in the paraventricular nucleus and corticotropin releasing hormone concentration in

 the median eminence (71).