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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 758-762, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200702-183UP

Pulmonary and Critical Care Updates

Update in Environmental and Occupational Medicine 2006

Tim S. Nawrot1, Abderrahim Nemmar1,2 and Benoit Nemery1

1 School of Public Health, Occupational and Environmental Medicine, Unit of Lung Toxicology, KU Leuven, Leuven, Belgium; and 2 Department of Physiology, College of Medicine, Sultan Qaboos University, Al-khod, Oman

Correspondence and requests for reprints should be addressed to Benoit Nemery, M.D., Ph.D., Eenheid voor Longtoxicologie, Herestraat 49, O&N 706, B-3000 Leuven, Belgium. E-mail: ben.nemery{at}med.kuleuven.be

EPIDEMIOLOGIC STUDIES

Outdoor Air Pollution
Although air pollution consists of a heterogeneous mixture of gases and particles, most recent research has concerned the adverse effects of particulate matter (PM). PM consists of primary particles, such as diesel soot or other combustion-derived particles, which are emitted directly into the atmosphere, and secondary particles, which are created in the atmosphere through complex physicochemical transformation of gases. Airborne PM is generally defined on the basis of the size distribution of the particles. Thus, PM10 and PM2.5 stand for PM with median aerodynamic diameters of less than 10 µm and 2.5 µm, respectively. Ultrafine particles (UFPs) have a diameter of less than 100 nm (0.1 µm). These particles exhibit a high rate of deposition in human alveoli. An excellent and extensive general review on the topic of air pollution has been recently published by Pope and Dockery (1).

It has long been known that air pollution can adversely affect human health. Extreme levels of pollution may cause markedly increased mortality rates, as occurred with the Meuse Valley fog of 1930 (2) and the London smog of 1952 (3). These historical episodes together with the landmark report of the Harvard Six Cities study (4) initiated successful efforts to pass legislation aimed at reducing air pollution. In the original Harvard Six Cities cohort of 8,111 adults followed up for 14 to 16 years, the adjusted overall mortality rate for the most polluted city versus the least polluted city was 1.26. Cardiovascular deaths accounted for the largest single category of the increased mortality. Of the measured air pollutants, PM2.5 was most strongly associated with mortality. In an extended follow-up of the Harvard Six Cities study (5), the city-specific average PM2.5 levels were lower during the later period of follow-up (during the 1990s) than in the initial period (1974–1989), and mortality risk ratios were also lower in the second period. The reported increased relative risk in overall mortality associated with each 10-µg/m3 increase in PM2.5 modeled as an average over the entire follow-up was 1.16 (95% confidence interval [CI], 1.07–1.26), whereas the corresponding hazard ratio for a 10-µg/m3 increase in PM2.5 modeled as an average in the year of death was 1.14 (95% CI, 1.06–1.22). In an editorial (6), Brunekreef argued that this observation is important because, until now, it was not clear whether the cohort studies showed effects that resulted from lifetime cumulative exposures. The new findings suggest that both recent exposure in the last year and long-term exposures matter. This is consistent with pollution affecting vulnerable individuals whose susceptibility itself may to some extent have been increased by their lifelong, cumulative exposure to air pollution.

One of the most impressive aspects of the initial Harvard Six Cities study (4) and other studies (reviewed in References 7 and 8) is that the risk of death associated with exposure to air pollution is higher for cardiac diseases than for all other causes, including lung diseases. The mechanisms for these acute and chronic cardiovascular effects of inhaled pollutants have not yet been entirely elucidated, but the lungs are likely to play an important role (7).

The inflammation that occurs in the lungs in response to damage caused by pollutants may have systemic consequences. In other words, the lungs are not merely a portal of entry for pollutants, they probably also mediate cardiovascular responses to a substantial extent. This is the rationale for attempting to link repeated measurements of markers of inflammation (and coagulation) with concurrent levels of air pollution in a susceptible segment of the population.

Using a panel approach, Rückerl and colleagues (9) linked particulate levels in the air with markers of inflammation (C-reactive protein [CRP], intracellular adhesion molecule [ICAM]) and coagulation (von Willebrand factor, factor VII) measured in 544 blood samples of 57 patients collected during 12 scheduled visits per patient. The study revealed that not all markers rose consistently at the same time: for example, von Willebrand factor appeared to be more strongly related with pollution if 5-day average exposures for PM and other pollutants were taken into account, whereas CRP and ICAM rose 2 days after an air pollution peak. A strength of this study is that, through repeated measures, each subject served as his or her own control. Using a similar epidemiologic design, Rabinovitch and colleagues (10) showed a positive association between fine-particulate air pollution and a biomarker of airway inflammation, urinary leukotriene E4 (LTE4), in a school-based panel study of 73 schoolchildren with asthma. Urinary LTE4 was associated with morning hourly ambient exposure to PM2.5. In an accompanying editorial, Delfino (11) pointed to the importance of air pollutants in causing acute airway responses in subjects with persistent asthma, most of whom were receiving inhaled corticosteroids.

The October 2003 forest fires in Southern California caused a peak exposure of air pollution with PM increased 10 to 20 times above normal values for several days. Although many previous wildfire studies had focused on hospital admissions and emergency room visits, there had been less research into the consequences of wildfire smoke on children's health (12). Künzli and colleagues (13) took the opportunity of an ongoing study (California Children's Health cohort) to investigate reported respiratory symptoms, medication use, school absenteeism, and doctor visits in 5,551 children and 873 adolescents with various degrees of exposure to wildfire smoke. A report of fire smoke smell indoors for more than 6 days was associated with more than fourfold higher rates of eye symptoms, approximately threefold increased rates of dry cough and sneezing, and more than twofold higher rates of cold, sore throat, wet cough, medication use, physician visits, and missed school due to symptoms (13).

Exposure to air pollution during childhood may impair the development of the lung and thus lead to a lower level of peak pulmonary function in early adulthood. Kulkarni and associates (14) were able to show in children that the load (measured as a surface) of carbon particles found in airway macrophages, recovered from induced sputum, correlated with their exposure to PM and that this biologic index of exposure was inversely correlated with lung function. Thus, each 1.0-µg/m3 increase in primary PM10 was associated with an increase of 0.10 µm2 in the carbon content of airway macrophages, and each increase of 1.0 µm2 in carbon content was associated with a reduction of 17% in FEV1, of 12.9% in FVC, and of 34.7% in forced expiratory flow, midexpiratory phase (FEF25–75%). These results strengthen the observations from Gauderman and colleagues (15) who reported that increased exposure to PM10 was associated with impaired growth of lung function.

Another area of concern relating to air pollution is lung cancer. A recent European cohort study (EPIC [European Prospective Investigation into Cancer and Nutrition]) yielded a positive, but nonsignificant association between lung cancer incidence and residence near heavy traffic roads (hazard ratio: 1.46; CI, 0.89–2.40) (16). However, in the same cohort, a significant interaction was found between the exposure variable "distance from heavy traffic road" and polymorphisms in genes coding for base excision repair (XRCC1-Arg399Gln) and double-strand break repair (BRCA2-Asn372His) (17). Cadmium is a ubiquitous environmental pollutant in industrialized countries. In a population-based prospective cohort study in an area close to three zinc smelters in Belgium, the risk of lung cancer was 3.58 higher than in a reference population from an area with low exposure to cadmium (18). Urinary excretion of cadmium over 24 hours is a biomarker of lifetime exposure to cadmium. The risk for lung cancer increased by 70% for a doubling of 24-hour urinary cadmium excretion (18).

Indoor Air Pollution
Three studies (19–21) and one editorial (22) in the past year were devoted to the adverse consequences of parental smoking on the health of their children, in various periods of life from infancy to adulthood. Because of the high concordance between maternal smoking during pregnancy and exposure to environmental tobacco smoke (ETS) in early childhood, it is difficult to disentangle the effects of ETS exposure in utero from those in infancy. In a well-designed pooled analysis of about 20 000 children from nine European countries and North America, Moshammer and colleagues found that both in utero and postnatal ETS exposure was associated with poorer pulmonary function in childhood (19). Although the proportion of children exposed to ETS in the prenatal period alone was small (2.3%), many children were exposed to both in utero smoking and current ETS exposure. Maternal smoking during pregnancy had a substantial negative impact on postnatal ETS exposure on all spirometric indices, ranging from –0.9% for FEV to –5.1% for MEF25.

In a randomized exposure trial of 19 ragweed allergen–sensitive subjects who were challenged intranasally with allergen after having been exposed to either clean air or ETS, Gilliland and associates (20) showed that common variants in GSTM1 and GSTP1 (which are important enzymes in oxidant defense) influence the enhancement of allergic responses by ETS. Thus, subjects with (presumed) lower antioxidant defenses experienced more pronounced responses to ETS and allergen challenge. This study provides further evidence that the severity of common allergic airway diseases is a consequence of the interplay between genes and environmental exposures.

In the Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA), the impact of ETS exposure was assessed in 1,661 asymptomatic never-smokers examined at baseline and 11 years later (21). Continued exposure to ETS was associated with the development of cough, with subjects with underlying bronchial hyperresponsivenes showing a reduced lung function compared with nonexposed subjects without bronchial hyperresponsiveness (21).

Indoor pollutants, such as particulate matter and nitrogen dioxide, have also been linked to respiratory effects (23–25). In 772 children younger than 12 years, exposure to indoor NO2 at levels well below 53 ppb (outdoor air pollution standard) was associated with respiratory symptoms among children with asthma in multifamily housing (indicator for lower social economic status) (23). Regalado and coworkers (25) measured particle concentrations indoors while cooking with biomass fuel in the homes of 841 women living in a rural community in Mexico. The peak indoor concentration of PM10 often exceeded 2,600 µg/m3 during biomass combustion. Peak concentrations of PM10 were associated with significant reduction in FEV1 (–81 ml), FVC (–122 ml), and FEV1% predicted (–4.7%). The estimated cumulative exposure to biomass was significantly related to the occurrence of cough and phlegm (25). As pointed out by Jaakkola and Jaakola in an accompanying editorial (26), this study demonstrates that it is feasible to carry out high-quality and relevant research in developing countries.

Occupational Lung Disease: Acute Inhalation Incidents
One interesting animal study (27) investigated the potential for mycobacteria to induce hypersensitivity pneumonitis (HP) in a murine model, because mycobacteria have been implicated as causal agents in outbreaks of HP among machinists exposed to metalworking fluid. The authors showed that repeated intranasal exposures of mice to metalworking fluid containing Mycobacterium immunogenum led to granulomatous lesions and other pulmonary changes compatible with HP, thus strengthening the possibility that mycobacteria and constituents of metalworking fluids are involved in the causation of HP in machinists. Three studies concerned the long-term sequelae of acute inhalation injury caused by exceptional events, such as terrorism (28) and chemical warfare (29), or by more common accidents (30).

The fire and collapse of the World Trade Center (WTC) in New York City on September 11, 2001, resulted in the massive release of combustion products from fuel and burning structures. Analyses of the dust suggest that the primary irritant effect was derived from its alkalinity (31). Several articles on the sequelae of exposure to WTC dust have been published. A cross-sectional analysis in the initial weeks after September 11th showed cough and substantial decrements in ventilatory function in New York City firefighters and rescue workers (32). A subsequent study in a sample of these subjects documented that a high proportion of the most heavily exposed subjects had evidence of airway hyperresponsiveness, and hence reactive airways dysfunction syndrome (RADS) (28). The same investigators recently showed that exposure to WTC dust caused an average decrease in FEV1 of 372 ml during the year after September 11th, which corresponds with an age-related decline of 12 years (33). In an editorial, Balmes stressed that these findings could only be made thanks to the availability of good predisaster pulmonary function data, and concluded that emergency workers must be better protected from unnecessary exposures to irritant dusts (34).

Another disease entity, tracheobronchomalacia, was added by Ghanei and colleagues (29) to the "litany of adverse chronic respiratory tract outcomes" (35) linked to inhalation injury. Using high-resolution computed tomography scans, they documented tracheobronchomalacia (often accompanied by air trapping suggestive of bronchiolitis obliterans) in 13 of 300 cases, randomly selected among a staggering 12,000 subjects who fell victim of exposure to sulfur mustard in the Iran–Iraq war of the 1980s.

The long-term consequences of a less spectacular, but much more common type of "disaster" were studied by Bonetto and associates (30) in 10 children who had been exposed accidentally to excessive levels of chlorine in a swimming pool. The investigators studied the time course of pulmonary function and novel indices of respiratory tract inflammation or damage, such as exhaled NO, LTB4 in exhaled breath condensate, and serum levels of CC16 up to 15 months after the event. Interestingly, FENO was decreased early after the acute exposure. LTB4 remained elevated in exhaled breath condensate for several months, even after pulmonary function had recovered.

EXPERIMENTAL STUDIES

Inhaled air pollutants can cause lung inflammation, which can induce alterations in autonomic nervous control of heart rhythm and release of inflammatory mediators into the blood, thus affecting extrapulmonary organs. Both pulmonary and systemic inflammation may occur through oxidative stress responses to reactive oxygen species (ROS). Another possibility is that UFPs with a diameter less than 100 nm are able to translocate into the systemic circulation, and affect cardiovascular endpoints more directly.

The increased production of oxidants is a common feature of acute and chronic inflammatory lung diseases, including those resulting from particle inhalation. The cellular effects of oxidant stress are modulated by synthesis of proteins that have protective properties, such as heme oxygenase (HO)-1. HO-1 is an enzyme that degrades heme into bilirubin, free iron, and carbon monoxide. In the lungs, HO-1 is highly expressed in alveolar macrophages, but it is also found in epithelial cells, fibroblasts, and endothelial cells. The clear target and ultimate goal of most research in HO-1 is to find novel therapeutic uses (36). In this context, Sato and colleagues (37) investigated whether and to what extent HO-1 can play a role in mitigating silica-mediated lung injury. To this end, silicosis was studied in both a murine model and in 46 male patients diagnosed with silicosis. HO-1 was found to be persistently expressed in the lung lesions of patients with silicosis. The serum HO-1 levels were correlated with VC and FEV1 in patients with silicosis. Furthermore, serum HO-1 correlated inversely with serum 8-hydroxydeoxyguanosine concentration, a marker of oxidative DNA damage. In mice, silica exposure caused acute leukocyte infiltration with subsequent development of silicotic lesions. Pulmonary inflammation was prevented by pretreatment of mice with hemin, an inducer of HO-1, and enhanced by zinc protoporphyrin, an inhibitor of HO-1. This study provided novel evidence that HO-1 is synthesized in the lungs of patients with silicosis, and showed experimentally that pretreatment with HO-1 mitigates silica-induced lung injury. The fact that the serum levels of HO-1 were increased confirms that lung inflammation caused by silica may be responsible for systemic effects (38).

CO is a gaseous pollutant and is considered an indicator of combustion-related pollution. CO is also a product of degradation of heme by HO. Recent experimental evidence, however, supports the concept that expression of HO-1 or administration of CO can exert therapeutic effects in a variety of diseases. These include allo- and xenotransplantation, prevention of post-transplantation arteriosclerosis, intimal hyperplasia after balloon injury, respiratory dysfunction, and hyperacute endotoxic shock. In animal models, the most common protocol has involved pretreatment with 250 ppm CO in air for 1 to 2 hours with the disease-inducing stimulus given subsequently. To evaluate the effect of CO on cardiovascular function, Favory and coworkers (39) used a similar concentration (i.e., 250 ppm) for 90 minutes in rats and then investigated myocardial function in an isolated heart model. They showed that CO promotes abnormalities in coronary vascular relaxation, myocardial contractility, and mitochondrial respiration. Their findings, therefore, support the contention that CO exposure may induce heart hypoxia and dysfunction through mechanisms including increased heart oxygen demand, reduced coronary blood flow reserve, and inhibition of heart cell respiration. Consequently, the results of this work contrast with other studies (40–43) that show beneficial pulmonary and systemic effects of CO at a concentration of 250 ppm. Hence, before envisaging clinical application of CO, careful toxicologic studies must be performed in different organs to investigate the effects of dose, duration of exposure, and time at which CO should be administered.

The tumor suppressor protein p53, a transcriptional factor that is critically involved in the cellular response to DNA damage, causes mitochondrial dysfunction and apoptosis. After their study showing that p53-dependent transcription mediates asbestos-induced alveolar epithelial cell mitochondrial dysfunction and apoptosis (44), Soberanes and colleagues (45) evaluated whether p53 is required for PM-induced apoptosis in both human and rodent alveolar type 2 cells. They showed that PM-induced apoptosis in A549 cells was characterized by increased p53 mRNA and protein expression, mitochondrial translocation of Bax (a proapoptotic member of the Bcl-2 protein family) and p53, a reduction in mitochondrial membrane potential change, and caspase-9 activation. Similar observations were made in both human and rodent alveolar type 2 cells. These effects were prevented by inhibiting p53-dependent transcription. Interestingly, using A549 cells that are incapable of mitochondrial ROS production, the authors showed that mitochondrial dysfunction, apoptosis, and p53 protein expression were abolished. The authors concluded that strategies aimed at inhibiting PM-induced mitochondrial ROS production and mitochondrial DNA damage are able to maintain the integrity of the lung epithelial barrier and prevent airway remodeling and malignant transformation.

The underlying pathophysiologic mechanisms linking small airway remodeling and cigarette smoke are still unclear. One hypothesis that challenges the notion that inflammation drives fibrosis links the development of small airway remodeling solely to growth factor production. Churg and coworkers investigated this hypothesis in mice exposed to smoke once (2–24 h) or repeatedly (daily for 1 wk to 6 mo) (46). They evaluated the induction of profibrotic growth factors using laser-capture microdissection of small airways, and performed morphometric analysis. Acute smoke exposure induced growth factors, such as connective tissue growth factor, transforming growth factor beta1, and platelet-derived growth factors A and B, and procollagen production. These effects were already significant at 2 hours and decreased back to baseline by 24 hours. This decline is in contrast with smoke-induced inflammation, which increases over 24 hours (47), suggesting that inflammation is not the cause of the production of growth factors. Chronic exposure to cigarette smoke induced growth factor and procollagen production, which persisted through 1 week, 1 month, and 6 months, and morphometric analyses demonstrated the presence of more collagen at 6 months. The authors concluded that the observed effects are related to growth factor production. Thus, the main message of this study is that smoke can acutely induce growth factor and procollagen production in small airways independently of inflammation, and that these effects persist with repeated cigarette smoke exposure. Such findings imply that interference with growth factor production and signaling could be an effective approach to therapy.

In relation to the possibility that UFPs translocate from the lungs into the blood circulation, various studies have been conducted in different animal models. The amount of UFPs that appear to translocate into blood and extrapulmonary organs differed among these studies (48–50). Recent articles (51, 52) provided morphologic data illustrating that inhaled particles are transported into the pulmonary capillary space, presumably by transcytosis. It has also been shown that, after intranasal delivery, polystyrene microparticles (1.1 µm) can translocate to tissues in the systemic compartment (53). More recently, the translocation of inhaled UFPs to the central nervous system via an olfactory neuronal pathway has been reported (54, 55). Given that this neuronal translocation pathway was also demonstrated in nonhuman primates, it is likely to be operative in humans as well (54). However, the issue of particle translocation in humans is still contradictory. Mills and colleagues (56) investigated this question by using an aerosol of technetium-99m–labeled carbon particles. The majority of these particles were 4 to 20 nm in diameter, but they rapidly formed aggregates of 100 nm in the inhaled aerosol. No significant radioactivity was found over the liver region. The nature of the radioactivity found in blood (4.4%) consisted mainly of pertechnetate, as analyzed by thin layer chromatography. These results contrast with previous findings that were also based on inhaling an aerosol of technetium-99m–labeled carbon particles (57), in which particle-bound radioactivity (also assessed by TLC) was detected in blood within 1 minute, reaching a maximum between 10 and 20 minutes, and remaining at this level for up to 60 minutes. Gamma camera images showed substantial radioactivity over the liver and other areas of the body. The discrepancies between these two studies may be related to the chromatography technique or the Technegas particles (size and composition) from Technegas generators with a different history and age. Further studies with other types of radioactive labeling should clarify the issue.

FOOTNOTES

T.S.N. is a fellow of the Flemish Scientific Fund (FWO).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form February 2, 2007; accepted in final form February 2, 2007

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