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The Proceedings of the American Thoracic Society 6:564-569 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200905-026RM
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Particulate Matter Exposure in Children

Relevance to Chronic Obstructive Pulmonary Disease

Jonathan Grigg1

1 Blizard Institute of Cell and Molecular Science, Centre for Paediatrics, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Jonathan Grigg, M.D., Centre for Paediatrics, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine, Queen Mary University London, 4 Newark Street, London E1 2AT, UK. E-mail: jg33{at}le.ac.uk; j.grigg{at}qmul.ac.uk

ABSTRACT

The effect of exposure to air pollution during childhood on the development of lung disease in adulthood remains to be defined. A common component of air pollution from fossil fuels, environmental tobacco smoke, and burning of solid fuels such as biomass is particulate matter (PM) less than 10 µm in aerodynamic diameter (PM10) consisting of aggregates of carbon spherules less than 10 nanometers. Epidemiologic studies suggest that the normal growth in lung function during childhood is impaired by long-term inhalation of carbonaceous PM10. The most convincing evidence for an effect of PM on lung growth is from a longitudinal study performed in Southern California, where the majority of ambient PM is derived from fossil fuels. Whether exposure of children to high levels of PM from biomass fuel combustion also impairs lung function growth remains unclear. A direct link between exposure of children to PM and increased vulnerability to respiratory disease in adulthood is provided by studies showing an association between life-long biomass smoke and the development of chronic obstructive pulmonary disease (COPD) in non–cigarette-smoking women. Since carbonaceous PM is a component of mainstream cigarette smoke, there may be significant overlap in the cellular and molecular mechanisms underling the adverse health effects of PM in children and the development of COPD in adult smokers. Studies of children, especially in the developing world, will therefore provide insights into the pathogenesis of COPD.

Key Words: COPD • particles • children • infection

There are several reasons why environmental exposures in childhood are relevant to understanding the pathogenesis of chronic obstructive pulmonary disease (COPD). First, attenuation of lung growth due to air pollution in childhood is a risk factor for adult-onset respiratory disease. Second, there may be common cellular and molecular mechanisms underlying impaired pulmonary innate host defenses in children exposed to air pollution, and the susceptibility to infection in COPD. Third, lung damage initiated in childhood may contribute to an emerging global health issue, namely, COPD due to biomass smoke exposure (1).

Carbonaceous particulate matter (PM) is a common component of emissions from fossil fuel combustion (Figure 1), burning of tobacco (resulting in environmental tobacco smoke [ETS]), and biomass fuels. For regulatory purposes, PM is considered "inhalable" if its mass is below 10 µm in aerodynamic diameter (PM10), but there is continuing debate whether the adverse health effects of PM are associated more with smaller particles (i.e., < 2.5 µm [PM2.5]), or the black carbon component (2). Transmission electron microscopy (TEM) of PM from both vehicular exhaust and biomass smoke show aggregates of spherical primary particles of carbon, consisting of concentric carbon layers surrounding several nuclei (3). Vehicular and biomass PM also have the same graphitic composition, and ratio of organic to total carbon. But PM from vehicular exhaust tends to be smaller (e.g., 24 nm vs. 31 nm for wood smoke), and has higher levels of polyaromatic hydrocarbons (3). Carbonaceous PM in sidestream smoke (ETS) tends to be smaller than PM in mainstream smoke (4), but a comparison study with biomass PM has not been done.


Figure 1
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  		Figure 1. Ambient particulate matter (PM) sampled from a British city and imaged using electron microscopy. Inhalable PM (< 10 µm in aerodynamic diameter) consists of aggregates of very small carbon spherules. Scale bar = 100 nm. PM from biomass smoke consists of similar aggregates of carbon spherules. Reprinted by permission from Reference 58.

 
In epidemiologic studies, there is a high degree of intercorrelation with other potentially toxic compounds, which makes identification of the independent effect of PM. For example, an association between nitrogen dioxide (NO2) and children's lung function (5) could be due to NO2 per se, or because NO2 is an very good marker for PM exposure in urban environments. It is therefore important to establish biological plausibility in animal and cell models, and to date most evidence points to PM as the causal agent. A lack of biological plausibility for NO2 has led the American Academy of Pediatrics to conclude that the association between health effects and NO2 in children should be "treated with caution since an independent role cannot be clearly established" (6). This review focuses on the evidence that exposure of children to PM adversely affects lung growth, and increases their vulnerability to infection. Associations between PM and conditions such as school-age asthma, and short-term changes in lung function, are not reviewed in detail.

DEVELOPMENTAL VULNERABILITIES

Postnatal lung growth is divided into the first 3 years of life where new alveoli are developed, and later childhood where lung growth occurs by expansion. The effect of very early environmental exposures may therefore be more damaging, or at least qualitatively different, to exposures in later childhood (7). The higher breathing rate in children also increases risk of PM-induced lung damage. For example, Bennet and Zeman (8, 9) exposed healthy children and adults to aerosolized 2-µm particles, and found that rate of particle deposition normalized to lung surface area was 35% greater in children (8). Young children may also be more vulnerable to oxidative stress–mediated injury to the airway. Oxidative stress is a putative mechanism for both PM-induced lung injury (10), and the development of COPD (11). Data on developmental changes in antioxidant defenses in human airway cells are limited. One of the very few studies that compared mRNA and activity levels of superoxide dismutases (SOD), catalase (CAT), and glutathione peroxidase (GPx) in human adult, neonatal, and fetal lung tissue found conflicting results. On one hand, SOD and CAT mRNA expression and CAT activity tended to be lower in the fetus and neonate. On the other hand, SOD enzyme activity was not impaired in the fetus, and GPx activity tended to be higher in the neonate compared with adult lung tissue (12). Whether a functionally relevant immaturity in pulmonary oxidant defenses is present in young children therefore remains unclear.

LUNG GROWTH AND PM

Entering adulthood with impaired lung function is a nonspecific risk factor for respiratory disease in adulthood. Lower lung function per se is also a risk factor for diseases in childhood that may cause further structural damage to the developing lung. For example, infants with lower lung function in the first weeks of life (i.e., before their first respiratory infection) are at increased risk of developing respiratory syncytial virus (RSV)-bronchiolitis (13). This primary infection of the bronchioles triggers persistent wheezing, and presumably structural changes in the lung, in a subgroup of infants (14).

There is convincing evidence that exposure to PM increases the prevalence of respiratory symptoms in young children. For example, in a British cohort of 4,400 preschool children, we found a significant association between exposure to primary PM10 at the home address and prevalence of cough without a cold (15). Analysis of data from the 3rd U.S. National Health and Nutrition Examination Survey (1988–1994) found that exposure to ETS is associated with increased prevalence of pediatric asthma, wheezing, and chronic bronchitis (16). However, a question relevant to COPD is whether PM attenuates long-term lung growth. The tracking of lung function from infancy to early adulthood (17) suggests that damaging exposures in the first years of life may have a disproportionate influence on attainment of maximal lung function in early adulthood. But measuring lung function in infants is difficult (18), and the association between environmental PM and infant's lung function remains unknown. The most convincing evidence that PM impairs lung growth comes from studies of school-age children, in whom spirometry is easier to perform. The seminal 12 Community California study (19) measured the change (growth) in lung function in 1,759 school-age children over an 8-year period. Reduced lung function growth was associated with increased PM exposure, with a difference in annual growth in forced vital capacity between the least to most polluted community of –60 ml (95% confidence interval [CI], –190 to –70) for PM10, and –78 ml (95% CI, –167 to –11) for ambient elemental carbon. Thus the proportion of young adults with clinically significantly reduced lung function (of < 80% predicted) was fivefold higher in communities with the highest levels of background inhalable PM. A small number of children in the study moved between communities. In this subset, lung function growth increased when a child moved from an area of high background PM to a less polluted area (20). These data suggest that PM exerts a small but continuous "downward pressure" on lung function growth. When this pressure is relieved, the deviation in lung function ceases and, if there is sufficient time, compensatory lung growth recovers some of the deficit. It is interesting to note that PM also exerts a "downward pressure" on the normal decline in adult lung function associated with aging (21), and there may be a common mechanism underlying effects in children and adults.

Further evidence that PM impairs lung function in healthy children is provided by our cross-sectional study into the association between the amount of carbon in lower airway macrophages and lung function in healthy children. Drawing on the observation that increased chronic exposure to PM in an animal model causes a dose-dependent increase in the amount of elemental carbon in lower airway macrophages (AM) (the major phagocyte for inhaled elemental carbon) (22), we hypothesized that children with higher levels of AM carbon have lower levels of lung function. Using image analysis, we quantified the area of carbon in AM from 64 children of nonsmoking parents. Median carbon was calculated for each children from 100 cells, and for each increase of 1.0 µm2 in AM carbon we found a –17% (95% CI, –5.6 to –28.4) change in forced expiratory volume in one second (FEV1) (Figure 2), and –34.7% (95% CI, –11.3 to –58.1) change in the forced expiratory flow between 25 and 75% of the forced vital capacity (Figure 3) (23). We did not directly measure individual exposure to PM, and it is unclear whether AM carbon reflects shorter- or longer-term individual exposure (24). Indirect evidence that AM carbon reflects longer-term exposure is provided by our recent observation that AM carbon in adults in Malawi tracks with the PM-emitting capacity of fuel used for cooking and lighting (25).


Figure 2
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  		Figure 2. (A) An airway macrophage obtained by induced sputum from a healthy child and imaged under light microscopy. The black material is inhaled carbon. Reprinted by permission from Reference 23. (B) A section of an airway macrophage obtained from a healthy infant undergoing elective surgery using bronchoalveolar lavage and imaged using electron microscopy. The inhaled material is agglomerations of carbon spherules of a morphology similar to that of fossil fuels in ambient air in a British city (see Figure 1). Scale bar = 1,000 nm. Reprinted by permission from Reference 59.

 

Figure 3
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  		Figure 3. Association between the area of carbon (area of black material) in airway macrophages and (A) forced respiratory volume in 1 second (FEV1), (B) forced vital capacity (FVC), (C) mid-expiratory flow between 25% and 75% of the forced vital capacity (FEF25–75), and (D) FEV1/FVC ratio. Data are from healthy school-age children of nonsmoking parents. The median area of carbon was calculated from 100 airway macrophages per child. There is a significant inverse association for all values, except for the FEV1/FVC ratio. Reprinted by permission from Reference 23.

 
There is some evidence that ETS suppresses lung function growth. A cross-sectional study of 20,000 children aged 6 to 12 years found a weak association between decreased pediatric lung function and current passive smoking (i.e., the association between FEV1 and ETS was –0.5%) (26). Children living in homes using biomass fuels for cooking, heating, and lighting are exposed to very much higher levels of PM than are children living in homes where parents smoke and use clean fuels (e.g., a mean indoor level of 200 µg/m3 PM per 24 h [27]). Exposure to biomass PM starts in infancy and continues during childhood. Indeed, in biomass smoke–exposed Ethiopian children, we found much higher levels of airway macrophage carbon compared with healthy children living in the United Kingdom (28) (Figure 4). Although the Southern California study strongly suggests that exposure to biomass PM impairs lung growth (19), no longitudinal study of lung function has been done in the developing world. A cross-sectional study of 1,505 school-age children in rural India found significantly lower lung function in children living in the households using solid biomass fuel compared with children living in the households using liquefied petroleum gas (FVC = 2.1 vs. 3.8 L/s FEV1 = 2.3 vs. 2.9 L/s) (29). A small study in Ecuador also concluded that children living in households cooking with biomass fuel have lower FVC and FEV1 compared with children living in households cooking exclusively with liquefied petroleum gas (30). Since chronic exposure to biomass smoke is associated with adult-onset COPD (31, 32), longitudinal studies of lung function in children are urgently needed in developing world populations.


Figure 4
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  		Figure 4. Airway macrophage from a biomass smoke–exposed Ethiopian imaged under light microcopy. There is a large amount of phagocytosed carbon in the cytoplasm. The cell is representative of maximum airway macrophage carbon loading found in both children and adults. Reprinted by permission from Reference 58.

 
Although cell and animal studies have shown a range of adverse effects of PM (10), few of these are relevant to lung growth. Mauad and coworkers (33) exposed pregnant rats and their offspring to filtered (PM2.5 2.9 µg/m3) and nonfiltered (16.8 µg/m3) urban air in two open-top chambers, 20 m from a street with heavy traffic in São Paulo, Brazil. Study groups were (1) nonexposed (filtered air), (2) prenatal, (3) postnatal, and (4) prenatal and postnatal exposure. Mice prenatally and postnatally exposed to urban PM2.5 had a smaller surface to volume ratio and reduced inspiratory and expiratory volumes at higher levels of transpulmonary pressure compared with animals exposed to filtered air (33). The mechanism for this PM-mediated effect remains unknown.

PM AND BACTERIAL INFECTION

Increased vulnerability to bacterial infection of the lower respiratory tract is a hallmark of COPD (34). Recent data from human bronchial epithelial cells exposed to cigarette smoke suggest that this may, in part, be due to suppression of antibacterial host defense (35). Similarly, in children, there is good evidence that exposure to PM increases vulnerability to bacterial infection. This association between PM and bacterial infection in children is important because (1) exposure to PM is ubiquitous and (2) infection is common, with 156 million new episodes of pneumonia per year in young children worldwide (151 million of these in the developing world) (36). Ten percent of these episodes are life-threatening (36). A recent meta-analysis of studies performed in the developing world estimated that the odds ratio for severe pneumonia in children under 5 years of age exposed to smoke from biomass and other high PM-emitting fuels is 1.78 (95% CI, 1.45–2.18) (37). Few studies in the developed world have assessed the association between PM and vulnerability of children to bacterial infection. Barnett and coworkers (38) recently reported a 2.4% (95% CI, 0.1–4.7) increase in hospital admissions for doctor-diagnosed "pneumonia or bronchitis" in children less than 5 years of age per interquartile increase in fossil fuel–derived PM2.5 (mean of the current and previous day). Suzuki and colleagues (39) reported an independent association between ETS and hospitalizations for pneumonia (adjusted odds ratio 1.55; 95% CI, 1.25–1.92) in a cross-sectional survey of 24,781 Vietnamese preschool children, and estimated that 29% of pneumonia in this population is attributed to ETS. Further studies are needed to replicate these data. Even fewer studies of environmental exposures and infection have identified casual pathogens. However, Streptococcus pneumoniae is likely to be important, since it is the commonest etiologic agent for pneumonia in young children (40, 41). Pneumococcal infection in children is associated with being carried on mothers' back while cooking (which increases PM exposure to cooking smoke), and exposure to ETS (42). A putative mechanism whereby environmental factors increase vulnerability to pneumococcal pneumonia is via increased nasopharyngeal carriage (43, 44). Increased adhesion of pneumococci to the buccal epithelium of rats chronically exposed to cigarette smoke provides indirect evidence for an effect of PM on carriage (45), but modeling this interaction using human cells has not been done. In addition, few animal studies provide biological plausibility for the robust epidemiologic association between PM and vulnerability to infection. In mice, fossil fuel–derived PM increases mortality from aerosolized Group C Streptococcus (46), and increased numbers of S. pneumoniae are present in lung tissue 24 hours after exposure to concentrated ambient particles from fossil fuel combustion (47). In vitro studies suggest that ability of PM to induce oxidative stress may be important for health effects (10, 48), but the relationship between oxidative stress and susceptibility of lung cells to infection is unclear.

COPD

Evidence that COPD is a PM-mediated disease is provided by the presence of widespread multiple black (anthracotic) pigmented areas in the bronchial wall, alveolar septae, and within alveolar macrophages of adults with biomass smoke (49–51)– and cigarette smoke (50, 52)–associated COPD. A putative sequence is that chronic exposure to PM (1) reduces attainment of maximal lung function in childhood, (2) accelerates lung function decline in adulthood, (3) stimulates airway mucus production, and (4) impairs pulmonary innate immunity. If exposure to PM during childhood is high, then symptoms suggestive of COPD will develop early. For example, chronic phlegm production occurs in over 10% of young adult women exposed to biomass smoke (53). Permanent bronchial obstruction results from direct PM-mediated lung injury and repeated bacterial infection, if high PM exposure either continues (biomass) or starts (smoking) in adulthood. Evidence that PM per se increases vulnerability of adults to infection is provided by the association between exposure to indoor coal smoke and mortality from adult pneumonia (54). If there is a link between PM exposure in childhood and vulnerability to COPD, then childhood symptoms such as chronic bronchitis (55) may be a marker of COPD vulnerability. This vulnerability, in turn, may reflect a common genetic vulnerability to PM, for example, due to functionally relevant polymorphisms in antioxidant genes (56, 57).

In conclusion, studies into the interaction between PM and infection in animal and cell models, when combined with further epidemiological studies (Table 1), are needed to provide insights into the vulnerability factors for COPD, and to identify markers of vulnerability to COPD that are present in childhood.


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  		TABLE 1. RESEARCH QUESTIONS

 
FOOTNOTES

Conflict of Interest Statement: J.G. received lecture fees from AstraZeneca ($1,001 to $5,000) and GlaxoSmithKline up to $1,000.

(Received in original form May 7, 2009; accepted in final form August 12, 2009)

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