help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nawrot, T.
Right arrow Articles by Nemery, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nawrot, T.
Right arrow Articles by Nemery, B.
American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 948-952, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.2601010

Pulmonary and Critical Care Updates

Update in Environmental and Occupational Medicine 2005

Tim Nawrot, Abderrahim Nemmar and Benoit Nemery

Unit of Lung Toxicology (Pneumology), K.U. Leuven, School of Public Health, Leuven, Belgium

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

Although air pollution consists of a heterogeneous mixture of gases and particles, most recent research has been devoted to 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 (1, 2). 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 less than 10 µm and 2.5 µm, respectively. Ultrafine particles (UFPs) have a diameter less than 100 nm (0.1 µm). These particles demonstrate very high deposition in human alveoli (3).

EXPERIMENTAL STUDIES

One mechanism through which inhaled particles exert adverse effects is pulmonary inflammation. Several experimental studies investigated the mechanisms or the effects of particle-induced inflammation in the lung.

Experimental Studies in Animals
Arimoto and colleagues (4) tested the hypothesis that free radicals are generated in vivo, 24 h after intratracheal coadministration of diesel exhaust particles (DEP) and bacterial endotoxin (LPS) to rats or mice. They applied the electron spin resonance (ESR) spin-trapping technique to detect free radicals, as they had previously done using asbestos or residual oil fly ash (5). DEP and LPS were shown to synergize to form lipid peroxidation–derived free radicals in the lung, in parallel with neutrophil inflammation and lung injury. NADP-reduced oxidase or inducible nitric oxide synthase (iNOS) did not appear instrumental in these processes, because genetic inactivation of these enzymes, using knockout mice, did not affect free radical generation or lung inflammation. In contrast, these responses were inhibited by pretreatment with GdCl3 (an inhibitor of macrophage activation), allopurinol (an inhibitor of xanthine oxidase), or Desferal (an iron chelator). The authors concluded that activated macrophages and the local activity of xanthine oxidase are important in the pathogenesis of oxidant lung injury caused by coadministration of DEP and LPS.

After their studies showing prothrombotic effects mediated by platelet activation in peripheral vessels after the administration of DEP (6–8), Nemmar and coworkers (9) investigated, in hamsters, the relationship between pulmonary inflammation, induced 24 h after intratracheal instillation of silica particles, and enhanced thrombus development, measured after photochemically induced endothelial damage in a femoral vein. Either the selective depletion of lung macrophages (by intratracheal administration of clodronate liposomes) or the depletion of circulating monocytes and neutrophils (by intraperitoneal injection of cyclophosphamide) reduced the silica-induced increase in macrophages and neutrophils in bronchoalveolar lavage (BAL) fluid, respectively, as well as the enhanced thrombogenicity. Silica-induced inflammation was accompanied by increased neutrophil elastase levels in BAL fluid and in plasma. Pretreatment with clodronate liposomes abolished the rise of neutrophil elastase in BAL fluid and in plasma, indicating that pulmonary macrophage–neutrophil cross-talk resulted in the release of neutrophil elastase into the blood circulation. Specific inhibition of neutrophil elastase in the lung did not affect lung inflammation, but reduced peripheral thrombogenicity, suggesting that neutrophil elastase could have a role as a platelet "primer." These studies provide experimental and mechanistic plausibility for the epidemiologically established association between the occurrence of acute coronary events and peaks of particulate air pollution, a topic that will be discussed later in this article. Interestingly, recent experimental data in an apoE–/– mouse model show that long-term exposure to low concentrations of PM2.5 altered vasomotor tone, induced vascular inflammation, and potentiated atherosclerosis (10), also supporting the epidemiologic observations of adverse cardiovascular effects of long-term exposure to urban air pollution (11).

Tobacco smoke is an aerosol consisting of gaseous and particulate pollutants. To understand how tobacco smoking contributes to the development and increased severity of asthma, Moerloose and colleagues (12) assessed the influence of cigarette smoke on airway inflammation and airway responsiveness in an ovalbumin-induced model for asthma in BALB/c mice. They showed that acute concurrent exposure to allergen and mainstream cigarette smoke enhanced airway inflammation and airway responsiveness in previously sensitized BALB/c mice. Their findings therefore support the hypothesis that the development of asthmatic symptoms in young adults with atopy is enhanced by starting active smoking. Fattouh and colleagues (13), who also used a model of ovalbumin asthma in BALB/c mice, found that a potent allergen (or "inflammogen"?), such as house dust mite, leads to a lung microenvironment that promotes the development of allergic sensitization to ovalbumin.

Proskocil and colleagues (14) showed, in neonatal rhesus monkeys, that vitamin C supplementation has the potential to limit the deleterious effects of maternal smoking during pregnancy on the offspring's lung function.

Controlled-exposure Studies in Humans
Acute ozone exposure causes more airway inflammation in subjects with asthma compared with healthy subjects (15, 16). Arjomandi and colleagues (15, 17) examined in 14 subjects with mild asthma whether repeated exposures to ozone (0.2 ppm for 1 h on 4 consecutive d) cause a progression of airway inflammation. No increase in acute neutrophilic response was found, although the number of macrophages and white blood cells in the BAL increased during successive exposure days. The role of macrophages in the chronic response to oxidant-induced injury must be further elucidated.

Studies in vitro or in animals have demonstrated that UFPs, when compared with larger particles on a mass basis, have a higher predicted pulmonary deposition, greater potential to induce pulmonary inflammation (probably because of their larger surface area), and enhanced oxidant capacity (well reviewed by Oberdörster and colleagues [3]). However, this concept has hardly been verified in human subjects. Thus, in a very nice study, Beckett and coworkers (18) tested in 12 healthy volunteers whether a 2-h exposure to about 500 µg/m3 (i.e., one-tenth of the current permissible exposure limit for 8 h) of freshly generated ultrafine zinc oxide particles (median diameter, 40 nm; median particle number, 46 million/cm3) would be more potent than a similar exposure to fine zinc oxide particles (median diameter, 291 nm; median particle number, 0.19 million/cm3). Disappointingly, neither exposure produced changes in symptoms, or in the physiologic, hematologic, or cardiac electrophysiologic parameters studied, and it was therefore impossible to determine whether inhaled UFPs are more potent than fine particles in healthy adults. So, the concept that UFPs are more hazardous remains to be verified, particularly for "susceptible" subjects, such as those with preexisting cardiorespiratory disease.

EPIDEMIOLOGIC STUDIES

Occupational Risks
In a follow-up to the European Community Respiratory Health Survey, Sunyer and colleagues (19) investigated the decline in pulmonary function and the appearance of respiratory symptoms according to occupational exposures among young adults (n = 8,540), randomly selected from the general population across Europe. Subjects were 25- to 40 yr old at the initial examination and they were studied again 9 yr later. No differences were found in the decline of FEV1 between subjects exposed to dusts, gases, and fumes and those not exposed. However, exposure to mineral dust, or to gases and fumes, was associated in men with a 94% (95% confidence interval [CI], 29–191%) and 53% (–1 to 136%) higher risk of developing chronic bronchitis, respectively.

In industrial countries the most frequent occupational respiratory disease is occupational asthma, and occupational factors are thought to contribute to 15% of adult cases of asthma (statement of American Thoracic Society) (20). In a very comprehensive State-of-the-Art article on occupational asthma, Mapp and colleagues (21) discuss the clinical presentations of the disease in its multiple forms (i.e., allergic asthma and irritant-induced asthma), as well as its epidemiology (including genetics), pathophysiology, natural history and long-term consequences, management, and prevention. An important addition to our clinical knowledge of occupational asthma is provided by the case-control study of Le Moual and colleagues (22), who analyzed asthma severity according to potential exposure to known asthmogens, as derived from a job-exposure matrix. Compared with control subjects, patients with severe asthma were found to be four times more likely to be exposed to occupational asthmogens. The strongest association was found for exposure to industrial cleaning agents. The main message of this study is that work-related factors should always be considered in any adult with new onset or worsening of asthma, particularly when the asthma is severe (23). Having said this, the diagnosis of occupational asthma remains difficult, particularly when the cause is a low-molecular-weight chemical (24).

In a cross-sectional survey of 197 shipyard welders and 150 control subjects, Han and colleagues (25) evaluated several markers of oxidative stress in serum. Irrespective of age and smoking status, welders had higher serum levels of proteins (+7%), glutathione peroxidase activity (+12%), aconitase (+70%), total antioxidant status (+7%), and isoprostane (+143%) compared with control subjects. The higher serum total antioxidant status and glutathione peroxidase activity in welders suggest that increased oxidative stress, as reflected by isoprostane levels, triggers the up-regulation of antioxidant defense mechanisms. The higher oxidative stress reported in welders is in line with another recent report that shows a positive correlation between chromium in plasma and urinary malondialdehyde in welders but not in tanners (26).

The blood beryllium lymphocyte proliferation test is considered to have high sensitivity and specificity for beryllium sensitization, but the rate of progression from beryllium sensitization to chronic beryllium disease is unknown. Newman and colleagues (27) found in a cohort of 55 beryllium-sensitized workers that 17 subjects (31%) developed granulomatous lung inflammation within 1 to 9.5 yr (average, 3.8 yr). This corresponds to a conversion rate of 8%/yr from being diagnosed as beryllium-sensitized to having signs of chronic beryllium disease. In an accompanying editorial, Cullen (28) concludes that the new data support the adoption of the blood beryllium lymphocyte proliferation test as a screening tool in beryllium-exposed workers, even though critical questions remain regarding the relevance and natural history of subclinical manifestations of chronic beryllium disease.

Environmental Risks
Malignant mesothelioma is mainly caused by occupational exposure to asbestos, but it can also arise as a result of nonoccupational exposure to anthropogenic or geologic sources of asbestos in the environment. In a register-based, case-control study of incident mesothelioma cases in California between 1988 and 1997 (with matched cases of pancreatic cancer taken as controls), Pan and colleagues (29) were able to demonstrate a statistically significant association between the risk of mesothelioma and proximity of the patient's residence to ultramafic rocks (used as a proxy for naturally occurring asbestos). Thus, the odds of mesothelioma decreased by 6.3% (95% CI, 1.8–10.5) for each 10 km that patients lived farther from the nearest naturally occurring asbestos source. The association was independent of age, sex, and, remarkably, occupational exposure to asbestos. In an accompanying editorial, Goldberg and Luce (30) stress the scientific and public health importance this unique Californian study has by showing that a risk of mesothelioma exists even at low doses of asbestos.

Environmental Tobacco Smoke
Three studies were devoted to the adverse consequences of parental smoking on the health of their children, in various periods of life from infancy to adulthood. In a study of 76 healthy infants (1.5–34.7 mo), Tepper and colleagues (31) found a lower baseline lung function but not a higher airway reactivity in those exposed to tobacco smoke (documented by cotinine in hair). In schoolchildren, Wenten and colleagues (32) looked at the effects of passive smoking on absences from school, as influenced by genotype. Skorge and colleagues (33) concluded from a cohort study of 2,819 adults monitored for 11 yr that up to 25% of asthma in adulthood could be attributed to (self-reported) passive smoking in utero or during childhood. Maternal smoking in pregnancy was associated with a threefold increase in the risk of asthma. These studies add to the growing evidence on the deleterious effects of exposure to environmental tobacco smoke (ETS).

The Case-Crossover Design in the Air Pollution Epidemiology
Three studies (34–36) were published that used a case-crossover design to assess the consequences of air pollution on health. The case-crossover design represents a relatively novel approach to study acute health effects. It was developed in the early 1990s by Maclure (37) and Maclure and Mittleman (38) to study effects of short-term exposures on the risk of acute events, such as myocardial infarction. Recently, the case-crossover design has been applied to assess effects of short-term exposures to air pollution. The major advantage of the approach is the ability to control for confounding. In the case-crossover design, all the study subjects have experienced the event. The hazard period is defined as the average time period that is relevant for the acute effect of the event, and this period is compared with control times. Thus, subjects serve as their own controls at an individual level. In contrast, the traditional time-series studies cannot control for varying individual characteristics since the unit of observation consists of daily counts of the event rather than of individuals.

Forastiere and colleagues (35) present new data from Rome on the association between out-of-hospital deaths from coronary heart disease and several measures of air pollution. PM10 was high (average, 52.1 µg/m3 during the study period [1998–2000]). The relative risk of out-of-hospital death increased by 7.6% (95% CI, 2.0–13.6%) for each 27,790 particles per cm3 increment (interquartile range) in mean daily particle number counts, taken as a proxy for UFPs (diameter < 0.1 µm). The same consortium (Health Effects of Air Pollution on Susceptible Subpopulations) also reported robust and significant positive associations, across Europe, between cardiac readmissions in 22,006 survivors of a first myocardial infarction and average 24-h concentrations of PM10 (39).

Weather-related differences over the seasons may modify the association between air pollution and mortality. Because outdoor temperature and ozone concentrations are strongly related, simple statistical adjustments for confounding may be inadequate and some effects of ozone may be indirectly caused by temperature. Schwartz (40) addressed this problem of collinearity by using a case-crossover approach, taking a control day with the same temperature as the event day. During the warm season, mortality was 37% higher (95% CI, 7–44%) for a 10-ppb increase in maximum hourly ozone concentration, with matching on outdoor temperature. The corresponding result in which regression modeling was used to control for daily outdoor temperature did not differ from the temperature-matched approach. These findings remove the uncertainty about the role of ozone on mortality, which stemmed from possible inadequate control for outdoor temperature.

An improved understanding of the contribution made by environmental exposures to disease burden in children is essential given the current increasing rates of childhood illnesses such as asthma. Barnett and colleagues (34) investigated the role of different air pollutants on the respiratory health of children living in Australia and New Zealand using a case-crossover design. Notwithstanding the much lower level of air pollutants in these countries compared with regions in Europe or North America, the authors reported significant associations between air pollutants (NO2, particles, and SO2) and hospital admissions in children for pneumonia and acute bronchitis (age groups, 0 and 1–4 yr), respiratory disease (0, 1–4, 5–14 yr), and asthma (5–14 yr). The largest association reported in this study, for all urban centers of Australia and New Zealand combined, was a 6.0% increase in asthma admissions for a 5.1-ppb increase in NO2, in the 5- to 14-yr age group.

Interventions in Cardiovascular Effects of Air Pollution
Beside the case-crossover study of Forastiere and colleagues (35), two other studies (36, 41) and an editorial (42) were devoted to air pollution and cardiovascular endpoints. Although the relative risk estimates linked to air pollution are stronger for morbidity and mortality from respiratory diseases than from cardiovascular diseases, the attributable risk for cardiovascular disease is considerably greater than that for respiratory disease, because more people are affected by cardiovascular disease. Thus, based on an ecologic study approach, it is assumed that 6% of coronary heart disease deaths (43) and 11% of the deaths from stroke (44) can be attributed to air pollution in the general population. 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. The inflammation that occurs in the lungs in response to the deposition of particles 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 (45).

Romieu and colleagues (41) and Schwartz and colleagues (36) used heart rate variability as their endpoint of interest, because it provides information on cardiovascular homeostasis as regulated by the autonomous nervous system. Decreased vagal control of the heart is probably mediated through pulmonary responses to particles. Based on the known beneficial effects of n-3 polyunsaturated fatty acids in the prevention of cardiovascular disease and sudden death, Romieu and colleagues (41) designed a randomized double blind trial in 50 nursing home residents to evaluate the effect of n-3 polyunsaturated fatty acids, given as fish oil, compared with soy oil, on the reduction of heart rate variability associated with PM2.5. They observed that, at baseline, the high-frequency component of heart rate variability was inversely and significantly correlated with the PM2.5 concentrations in the air, whereas in the postsupplementation phase, PM2.5 lost its significance, with fish oil appearing to be beneficial compared with soy oil.

Envirogenomics
Studies of gene–environment interactions aim to describe how genetic and environmental factors jointly influence the risk of developing a disease, and determine susceptibility of individuals or subgroups in the population. Five studies (32, 36, 46–48) focused on the role of genetic variations (polymorphisms) in modifying the effect of exposure to diseases relevant in occupational or environmental medicine.

Schwartz and colleagues (36) studied a gene-by-drug-by-environment interaction by looking at the effects of a genetic variation in glutathione-S-transferases (GSTM1), combined with statin treatment and exposure to fine particles, on changes in heart rate variability in 497 men of the Normative Aging Study cohort. Glutathione pathways play a key role in cellular defenses against reactive oxygen species and genetic variation in GSTM1 modifies the response to air pollutants (49). Drugs that modify oxidant defenses may also influence susceptibility to particle-induced inflammatory or prooxidative responses. Clinical trials have demonstrated that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) greatly reduce cardiovascular morbidity and mortality in patients with and without coronary artery disease (50–52). In addition to their cholesterol lowering effect, statins also have potent antiinflammatory and antioxidative properties (53). Animal studies showed beneficial effects of statins on respiratory endpoints (54, 55). Schwartz and colleagues found that the effect of PM2.5 on heart rate variability was confined to persons missing the allele for GSTM1, but the association was only apparent in those not under statin treatment (36). Unfortunately, the authors could not validate their interpretation by measuring markers of systemic inflammation, such as C-reactive protein, but current indirect evidence points to oxidative stress and inflammation as mechanisms for particulate-induced cardiovascular effects.

Gene–exposure interactions might also determine the interindividual variation in responses to other air pollutants, such as ozone, endotoxin, or cigarette smoke. Thus, Yang and colleagues (48) investigated the response to ozone in 51 subjects, of whom 15 (29%) had mild asthma and 25 (49%) had rhinitis, according to polymorphisms in the genes encoding for tumor necrosis factor-{alpha} (TNF), lymphotoxin-{alpha} (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1). They found that TNF G homozygotes (–308G/A) had a higher response to ozone in terms of FEV1 (–8.9%; 95% CI, –0.8 to –11.5) than A allele carriers. Variation in the other genes did not reach the level of significance. Unfortunately, the authors did not measure intermediate phenotypes, which might link lung function with ozone exposure, such as markers of inflammation. Furthermore, the sample size was not large enough to accommodate sex-specific analyses or study the impact of the genetic variants with a lower frequency (e.g., those involving TLR4). Because of these limitations, the pathophysiologic interpretations in humans should be considered as hypothesis-generating and should be confirmed in further larger well-controlled genetic epidemiologic studies. Nevertheless, these observations are supported by rodent models and have implications for understanding the differential susceptibility to ozone in humans.

Occupational and domestic environments represent a source of exposure to endotoxins. Thorne and colleagues (56) explored the association between asthma symptoms and endotoxin concentration in 2,552 house dust samples representative for the United States. The authors found that endotoxin concentrations in bedrooms above the first quartile (> 16.6 EU/mg) increased the odds of having asthma symptoms during the past year by 2.8.

Two studies (46, 47) investigated how the host response to inhaled endotoxins varies in relation to genetic predisposition. Microsomal epoxide hydrolase (mEH) detoxifies reactive oxygen species. Within a cohort of cotton textile workers followed for 20 yr, Hang and colleagues (46) studied, in 499 participants (47% control subjects), the associations between polymorphisms in the gene coding for mEH, endotoxin exposure, and the deterioration of lung function during follow-up. Independently of relevant covariates, workers exposed to endotoxins had a 3.23-ml higher (95% CI, 1.0–5.5) annual decline in FEV1 than the control subjects. Moreover, among the workers exposed to endotoxins, lung function declined faster in those carrying alleles associated with slower mEH enzyme activity, suggesting that inefficient metabolism of reactive oxygen species may accelerate the lung function deterioration with aging when exposure to endotoxins is high.

Another pathway that might determine interindividual susceptibility to endotoxins encompasses the binding of endotoxins to the CD14 receptor, which then results in the activation of host defense mechanisms, such as release of proinflammatory cytokines. A common –159C->T polymorphism of the CD14 gene is associated with higher plasma levels of soluble CD14 in carriers of the T allele. Based on these observations, LeVan and colleagues (47) tested the hypothesis, among 97 farmers exposed to endotoxins, that carriers of this allele have a lower lung function. FEV1 and FVC were significantly lower in CD14 –159 TT homozygotes than in their CC counterparts. The prevalence of wheezing increased with the number of copies of the CD14 –159 T allele: compared with CD14 –159 CC homozygotes, with the odds of wheezing increased by 10.5 and 12.5% for carriers of the CT and TT alleles, respectively. Along similar lines, the authors found that farmers who are homozygous for the G allele at the –1619 loci were more likely to have decreased pulmonary function and a higher prevalence of wheeze compared with those carrying the A allele.

Wenten and colleagues (32) examined in their study where they had demonstrated that children exposed to ETS had half as much school absences for lower respiratory illnesses compared with non–ETS-exposed children, if this response varied according to TNF –308G/A polymorphism. In children exposed to ETS, the school absence rates for respiratory illnesses increased with the number of copies of the TNF –308 A allele, suggesting that a common genetic variant increases the detrimental health effects of ETS in children.

FOOTNOTES

DOI: 10.1164/rccm.2601010

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

Received in original form January 10, 2006; accepted in final form January 12, 2006

REFERENCES

  1. Brook RD, Franklin B, Cascio W, Hong Y, Howard G, Lipsett M, Luepker R, Mittleman M, Samet J, Smith SC Jr, et al. Air pollution and cardiovascular disease: a statement for healthcare professionals from the Expert Panel on Population and Prevention Science of the American Heart Association. Circulation 2004;109:2655–2671.[Abstract/Free Full Text]
  2. Brunekreef B, Holgate ST. Air pollution and health. Lancet 2002;360:1233–1242.[CrossRef][Medline]
  3. Oberdörster G, Oberdorster E, Oberdörster J. Nanotoxicology: an emerging discipline evolving from studies of ultrafine particles. Environ Health Perspect 2005;113:823–839.[Medline]
  4. Arimoto T, Kadiiska MB, Sato K, Corbett J, Mason RP. Synergistic production of lung free radicals by diesel exhaust particles and endotoxin. Am J Respir Crit Care Med 2005;171:379–387.[Abstract/Free Full Text]
  5. Kadiiska MB, Ghio AJ, Mason RP. ESR investigation of the oxidative damage in lungs caused by asbestos and air pollution particles. Spectrochim Acta A Mol Biomol Spectrosc 2004;60:1371–1377.[Medline]
  6. Nemmar A, Hoet PH, Vermylen J, Nemery B, Hoylaerts MF. Pharmacological stabilization of mast cells abrogates late thrombotic events induced by diesel exhaust particles in hamsters. Circulation 2004;110:1670–1677.[Abstract/Free Full Text]
  7. Nemmar A, Nemery B, Hoet PH, Vermylen J, Hoylaerts MF. Pulmonary inflammation and thrombogenicity caused by diesel particles in hamsters: role of histamine. Am J Respir Crit Care Med 2003;168:1366–1372.[Abstract/Free Full Text]
  8. Nemmar A, Hoet PH, Dinsdale D, Vermylen J, Hoylaerts MF, Nemery B. Diesel exhaust particles in lung acutely enhance experimental peripheral thrombosis. Circulation 2003;107:1202–1208.[Abstract/Free Full Text]
  9. Nemmar A, Nemery B, Hoet PH, Van RN, Hoylaerts MF. Silica particles enhance peripheral thrombosis: key role of lung macrophage–neutrophil cross-talk. Am J Respir Crit Care Med 2005;171:872–879.[Abstract/Free Full Text]
  10. Sun Q, Wang A, Jin X, Natanzon A, Duquaine D, Brook RD, Aguinaldo JG, Fayad ZA, Fuster V, Lippmann M, et al. Long-term air pollution exposure and acceleration of atherosclerosis and vascular inflammation in an animal model. JAMA 2005;294:3003–3010.[Abstract/Free Full Text]
  11. Kunzli N, Jerrett M, Mack WJ, Beckerman B, LaBree L, Gilliland F, Thomas D, Peters J, Hodis HN. Ambient air pollution and atherosclerosis in Los Angeles. Environ Health Perspect 2005;113:201–206.[Medline]
  12. Moerloose KB, Pauwels RA, Joos GF. Short-term cigarette smoke exposure enhances allergic airway inflammation in mice. Am J Respir Crit Care Med 2005;172:168–172.[Abstract/Free Full Text]
  13. Fattouh R, Pouladi MA, Alvarez D, Johnson JR, Walker TD, Goncharova S, Inman MD, Jordana M. House dust mite facilitates ovalbumin-specific allergic sensitization and airway inflammation. Am J Respir Crit Care Med 2005;172:314–321.[Abstract/Free Full Text]
  14. Proskocil BJ, Sekhon HS, Clark JA, Lupo SL, Jia Y, Hull WM, Whitsett JA, Starcher BC, Spindel ER. Vitamin C prevents the effects of prenatal nicotine on pulmonary function in newborn monkeys. Am J Respir Crit Care Med 2005;171:1032–1039.[Abstract/Free Full Text]
  15. Basha MA, Gross KB, Gwizdala CJ, Haidar AH, Popovich J Jr. Bronchoalveolar lavage neutrophilia in asthmatic and healthy volunteers after controlled exposure to ozone and filtered purified air. Chest 1994;106:1757–1765.[Abstract/Free Full Text]
  16. Scannell C, Chen L, Aris RM, Tager I, Christian D, Ferrando R, Welch B, Kelly T, Balmes JR. Greater ozone-induced inflammatory responses in subjects with asthma. Am J Respir Crit Care Med 1996;154:24–29.[Abstract]
  17. Arjomandi M, Witten A, Abbritti E, Reintjes K, Schmidlin I, Zhai W, Solomon C, Balmes J. Repeated exposure to ozone increases alveolar macrophage recruitment into asthmatic airways. Am J Respir Crit Care Med 2005;172:427–432.[Abstract/Free Full Text]
  18. Beckett WS, Chalupa DF, Pauly-Brown A, Speers DM, Stewart JC, Frampton MW, Utell MJ, Huang LS, Cox C, Zareba W, et al. Comparing inhaled ultrafine versus fine zinc oxide particles in healthy adults: a human inhalation study. Am J Respir Crit Care Med 2005;171:1129–1135.[Abstract/Free Full Text]
  19. Sunyer J, Zock JP, Kromhout H, Garcia-Esteban R, Radon K, Jarvis D, Toren K, Kunzli N, Norback D, d'Errico A, et al. Lung function decline, chronic bronchitis, and occupational exposures in young adults. Am J Respir Crit Care Med 2005;172:1139–1145.[Abstract/Free Full Text]
  20. Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K, Mapp C, Milton D, Schwartz D, Toren K, Viegi G. American Thoracic Society Statement: occupational contribution to the burden of airway disease. Am J Respir Crit Care Med 2003;167:787–797.[Free Full Text]
  21. Mapp CE, Boschetto P, Maestrelli P, Fabbri LM. Occupational asthma. Am J Respir Crit Care Med 2005;172:280–305.[Abstract/Free Full Text]
  22. Le Moual M, Siroux V, Pin I, Kauffmann F, Kennedy SM. Asthma severity and exposure to occupational asthmogens. Am J Respir Crit Care Med 2005;172:440–445.[Abstract/Free Full Text]
  23. Malo JL. Asthma might be more severe if it is work-related. Am J Respir Crit Care Med 2005;172:406.[Free Full Text]
  24. Vandenplas O, Ghezzo H, Munoz X, Moscato G, Perfetti L, Lemiere C, Labrecque M, L'Archeveque J, Malo JL. What are the questionnaire items most useful in identifying subjects with occupational asthma? Eur Respir J 2005;26:1056–1063.[Abstract/Free Full Text]
  25. Han SG, Kim Y, Kashon ML, Pack DL, Castranova V, Vallyathan V. Correlates of oxidative stress and free-radical activity in serum from asymptomatic shipyard welders. Am J Respir Crit Care Med 2005;172:1541–1548.[Abstract/Free Full Text]
  26. Goulart M, Batoreu MC, Rodrigues AS, Laires A, Rueff J. Lipoperoxidation products and thiol antioxidants in chromium exposed workers. Mutagenesis 2005;20:311–315.[Abstract/Free Full Text]
  27. Newman LS, Mroz MM, Balkissoon R, Maier LA. Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk. Am J Respir Crit Care Med 2005;171:54–60.[Abstract/Free Full Text]
  28. Cullen MR. Screening for chronic beryllium disease: one hurdle down, two to go. Am J Respir Crit Care Med 2005;171:3–4.[Free Full Text]
  29. Pan XL, Day HW, Wang W, Beckett LA, Schenker MB. Residential proximity to naturally occurring asbestos and mesothelioma risk in California. Am J Respir Crit Care Med 2005;172:1019–1025.[Abstract/Free Full Text]
  30. Goldberg M, Luce D. Can exposure to very low levels of asbestos induce pleural mesothelioma? Am J Respir Crit Care Med 2005;172:939–940.[Free Full Text]
  31. Tepper RS, Williams-Nkomo T, Martinez T, Kisling J, Coates C, Daggy J. Parental smoking and airway reactivity in healthy infants. Am J Respir Crit Care Med 2005;171:78–82.[Abstract/Free Full Text]
  32. Wenten M, Berhane K, Rappaport EB, Avol E, Tsai WW, Gauderman WJ, McConnell R, Dubeau L, Gilliland FD. TNF-308 modifies the effect of second-hand smoke on respiratory illness-related school absences. Am J Respir Crit Care Med 2005;172:1563–1568.[Abstract/Free Full Text]
  33. Skorge TD, Eagan TM, Eide GE, Gulsvik A, Bakke PS. The adult incidence of asthma and respiratory symptoms by passive smoking in uterus or in childhood. Am J Respir Crit Care Med 2005;172:61–66.[Abstract/Free Full Text]
  34. Barnett AG, Williams GM, Schwartz J, Neller AH, Best TL, Petroeschevsky AL, Simpson RW. Air pollution and child respiratory health: a case-crossover study in Australia and New Zealand. Am J Respir Crit Care Med 2005;171:1272–1278.[Abstract/Free Full Text]
  35. Forastiere F, Stafoggia M, Picciotto S, Bellander T, D'Ippoliti D, Lanki T, von KS, Nyberg F, Paatero P, Peters A, et al. A case-crossover analysis of out-of-hospital coronary deaths and air pollution in Rome, Italy. Am J Respir Crit Care Med 2005;172:1549–1555.[Abstract/Free Full Text]
  36. Schwartz J, Park SK, O'Neill MS, Vokonas PS, Sparrow D, Weiss S, Kelsey K. Glutathione-S-transferase M1, obesity, statins, and autonomic effects of particles: gene-by-drug-by-environment interaction. Am J Respir Crit Care Med 2005;172:1529–1533.[Abstract/Free Full Text]
  37. Maclure M. The case-crossover design: a method for studying transient effects on the risk of acute events. Am J Epidemiol 1991;133:144–153.[Abstract/Free Full Text]
  38. Maclure M, Mittleman MA. Should we use a case-crossover design? Annu Rev Public Health 2000;21:193–221.[CrossRef][Medline]
  39. von Klot S, Peters A, Aalto P, Bellander T, Berglind N, D'Ippoliti D, Elosua R, Hormann A, Kulmala M, Lanki T, et al. Ambient air pollution is associated with increased risk of hospital cardiac readmissions of myocardial infarction survivors in five European cities. Circulation 2005;112:3073–3079.[Abstract/Free Full Text]
  40. Schwartz J. How sensitive is the association between ozone and daily deaths to control for temperature? Am J Respir Crit Care Med 2005;171:627–631.[Abstract/Free Full Text]
  41. Romieu I, Tellez-Rojo MM, Lazo M, Manzano-Patino A, Cortez-Lugo M, Julien P, Belanger MC, Hernandez-Avila M, Holguin F. Omega-3 fatty acid prevents heart rate variability reductions associated with particulate matter. Am J Respir Crit Care Med 2005;172:1534–1540.[Abstract/Free Full Text]
  42. Cascio WE. Cardiopulmonary health effects of air pollution: is a mechanism emerging? Am J Respir Crit Care Med 2005;172:1482–1484.[Free Full Text]
  43. Maheswaran R, Haining RP, Brindley P, Law J, Pearson T, Fryers PR, Wise S, Campbell MJ. Outdoor air pollution, mortality, and hospital admissions from coronary heart disease in Sheffield, UK: a small-area level ecological study. Eur Heart J 2005;26:2543–2549.[Abstract/Free Full Text]
  44. Maheswaran R, Haining RP, Brindley P, Law J, Pearson T, Fryers PR, Wise S, Campbell MJ. Outdoor air pollution and stroke in Sheffield, UK: a small-area level geographical study. Stroke 2005;36:239–243.[Abstract/Free Full Text]
  45. Nemery B, Abraham E. Environmental health and the AJRCCM. Am J Respir Crit Care Med 2005;172:1484–1485.[Free Full Text]
  46. Hang J, Zhou W, Wang X, Zhang H, Sun B, Dai H, Su L, Christiani DC. Microsomal epoxide hydrolase, endotoxin, and lung function decline in cotton textile workers. Am J Respir Crit Care Med 2005;171:165–170.[Abstract/Free Full Text]
  47. LeVan TD, Von ES, Romberger DJ, Lambert GP, Martinez FD, Vasquez MM, Merchant JA. Polymorphisms in the CD14 gene associated with pulmonary function in farmers. Am J Respir Crit Care Med 2005;171:773–779.[Abstract/Free Full Text]
  48. Yang IA, Holz O, Jorres RA, Magnussen H, Barton SJ, Rodriguez S, Cakebread JA, Holloway JW, Holgate ST. Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function. Am J Respir Crit Care Med 2005;171:171–176.[Abstract/Free Full Text]
  49. Gilliland FD, Li YF, Saxon A, Diaz-Sanchez D. Effect of glutathione-S-transferase M1 and P1 genotypes on xenobiotic enhancement of allergic responses: randomised, placebo-controlled crossover study. Lancet 2004;363:119–125.[CrossRef][Medline]
  50. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685–696.[CrossRef][Medline]
  51. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–1278.[CrossRef][Medline]
  52. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149–1158.[CrossRef][Medline]
  53. Shishehbor MH, Brennan ML, Aviles RJ, Fu X, Penn MS, Sprecher DL, Hazen SL. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003;108:426–431.[Abstract/Free Full Text]
  54. Fessler MB, Young SK, Jeyaseelan S, Lieber JG, Arndt PG, Nick JA, Worthen GS. A role for hydroxy-methylglutaryl coenzyme a reductase in pulmonary inflammation and host defense. Am J Respir Crit Care Med 2005;171:606–615.[Abstract/Free Full Text]
  55. Lee JH, Lee DS, Kim EK, Choe KH, Oh YM, Shim TS, Kim SE, Lee YS, Lee SD. Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med 2005;172:987–993.[Abstract/Free Full Text]
  56. Thorne PS, Kulhankova K, Yin M, Cohn R, Arbes SJ Jr, Zeldin DC. Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am J Respir Crit Care Med 2005;172:1371–1377.[Abstract/Free Full Text]




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nawrot, T.
Right arrow Articles by Nemery, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nawrot, T.
Right arrow Articles by Nemery, B.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2006 American Thoracic Society