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ABSTRACT |
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METHODS
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The role of the genetic polymorphism of NAD(P)H:quinone oxidoreductase (NQO1) and glutathione-S-transferase µ-1 (GSTM1) in the responsiveness to O3-induced acute effects was investigated in 24 healthy nonsmokers performing 2-h bike rides at ambient O3 varying from 32 to 103 ppb. Before and after rides, each subject performed spirometric tests and provided a blood sample for the measurement of the Clara cell protein CC16. NQO1 and GSTM1 polymorphisms were characterized by polymerase chain reaction- based methods. The 8-hydroxy-2'-deoxyguanosine (8-OHdG) adduct was also measured in DNA of peripheral leukocytes. Rides at O3 > 80 ppb resulted in significant decrements of pulmonary function tests and increased levels of serum CC16, consistent with mild impairment in respiratory function and increased lung epithelial permeability, respectively. Whereas NQO1wt and GSTM1null subjects showed both functional changes and increased serum CC16 after acute O3 exposure, people with other haplotypes showed a rise in serum CC16 but no changes in lung function tests. In NQO1wt and GSTM1null subjects, partial correlation analysis showed that functional decrements and increased serum CC16 are closely associated with each other and with O3 levels, whereas no such relationships were found among subjects bearing other haplotypes. An increased reaction rate between O3 and hydroquinones would be consistent with the greater increase in 8-OHdG after O3 exposure in this "susceptible" group.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Ground-level ozone (O3), which is formed as a result of photochemical reactions between nitrogen oxides and volatile organic compounds, occurs in nonurban areas in western Europe at average concentrations ranging from 40 to 70 parts per billion (ppb), but 1-h maximal values may reach 150 ppb in northern Italy (1). O3 is known to induce a variety of pulmonary effects, including decrement of lung function, increased airways responsiveness, and inflammatory reaction (2, 3). These effects have occurred even at the lowest concentration tested, i.e., 160 µg/m3 (80 ppb) for 6.6 h (4). To prevent adverse effects, the U.S. Environmental Protection Agency (EPA) replaced the 1-h health-based standard of 120 ppb for O3 with an 8-h standard of 80 ppb (5) whereas the European Union has recommended the values of 180 and 360 µg/m3 for 1 h as the thresholds for information and for warning of the public, respectively (1).
To assess the early effects of pollutants on the integrity of the lung epithelial barrier, which is the ultimate target of ozone, a new approach based on the assay in serum of lung-derived protein has recently been developed. The 15.8 kDa Clara cell protein (CC16) is secreted in large amounts at the surface of airways from which it diffuses passively into the serum (6, 7). CC16 has been proposed as a biomarker of increased permeability of the epithelial lung barrier, one of the earliest signs of toxic lung injury by air pollutants (6, 8). The sensitivity of serum CC16 concentration to O3 exposure was assessed in a field study on healthy volunteers (9). Despite its exposure- related trend, this biomarker showed a high interindividual variability, thus corroborating the hypothesis of a different susceptibility to O3-induced effects on the lung epithelium barrier.
O3 toxicity is related to its strong oxidizing ability giving rise to radicals and reactive oxygen species (ROS), whose formation is modulated by antioxidants, which may modify O3 acute effects on lung function (10, 11). A relationship between decrements in lung function and airway inflammation after O3 exposure has not been demonstrated, any heterogeneity in the response being attributed to sampling variability or to a poor predictivity of lung function decrements toward early inflammatory response, rather than to the dilution of effects in susceptible subgroups (12, 13).
Members of the same species show different sensitivity and
responsiveness to ozone related to their genetic background (14). Linkage analysis in recombinant inbred mice suggests that a complex interaction of genes, mainly encoding proinflammatory cytokines (e.g., tumor necrosis factor-
[TNF]), may account for
ozone-induced lung inflammation in susceptible (inflammatory-prone) strains (15). The inflammatory response to ozone is associated with the induction of enzymes
namely, nicotinamide
adenin dinucleotide phosphate (NAD(P)):quinone oxidoreductase (NQO1 or DT-diaphorase) and glutathione-S-transferases
(GSTs)through transcriptional mechanisms leading to a coordinate sequence of biochemical responses (16). Whereas NQO1
plays a detoxifying role catalyzing the direct conversion of quinones to hydroquinones without the generation of semiquinones
thereby limiting the redox cycling of such compounds and the associated oxidative stresshydroquinones are a target of ozone,
which gives rise to semiquinones and hydroxyl radicals, with subsequent cellular damage (17). GSTs and glutathione (GSH)-peroxidase protect cells against the toxic effects of ROS, by implementing the rate of GSH conjugation of hydroquinones and
scavenging the hydroxyl radical, respectively (18, 19).
The present study was aimed at evaluating whether the polymorphism of enzymes known to modulate the response to or to protect from epithelial oxidative damage, namely NQO1 and class µ-1 GST (GSTM1-1), accounts for the interindividual variability in the responsiveness to O3 occurring during episodes of photochemical pollution.
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METHODS |
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INTRODUCTION
METHODS
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DISCUSSION
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Subjects and Study Design
Twenty-four healthy nonsmoker volunteers (15 women and 9 men, aged 28.5 ± 3.4 yr) gave their written informed consent to participate in the study, which had been approved by the local ethical committee. None of them had history of asthma or allergies, and all had normal baseline spirometry. According to the protocol, each subject randomly covered two rides at O3 airborne concentrations above and below 80 ppb, respectively, in an open green area inside the town. O3 concentration data were obtained from the nearest station of a local monitoring network operated by the Agenzia Regionale Prevenzione e Ambiente of the Emilia-Romagna region (ARPAER), which was located along the cycling circuit, i.e. within 300 m from the most distant point. Continuous O3 measurements were made by using a dual-cell ultraviolet (UV) photometric analyzer (Thermoelectron, model 49-100; Thermo-Environmental Corp., Franklin, MA) calibrated twice a month by the gas-phase titration (GPT) method, using NO2 as the calibrator. Ambient O3 concentrations were expressed as the mean of continuous (i.e., every second) O3 monitoring. The 2-h mean O3 concentrations varied between 32 and 103 ppb (median 78 ppb). Immediately before and after each run, the subjects provided a blood sample for the assay of serum CC16, which was measured as previously described (20). 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and deoxyguanosine (dG) in DNA samples extracted from peripheral leukocytes were analyzed by high-performance liquid chromatography with electrochemical coulometric and UV absorbance detectors, respectively (21). 8-OHdG concentrations are expressed as 8-OHdG molecules per 105 dG.
Genotype Characterization
The genotypes of GSTM1 and NQO1 were characterized by molecular biology techniques, according to the procedures described respectively by Arand and coworkers (22) and Traver and coworkers (23), using genomic DNA extracted with Nucleon BACC2 (Amersham International plc, Little Chalfont, Buckinghamshire, UK) from peripheral blood after buffy-coat enrichment. Frequencies of both allele and genotype among volunteers are summarized in Table 1. Allele frequencies were assessed only for the NQO1 polymorphism, as the method used to analyze GSTM1 does not allow the identification of heterozygotes. The distribution of NQO1 genotypes was in Hardy-Weinberg equilibrium. Both the NQO1 and GSTM1 genotype frequencies agreed with published figures for white populations (24, 25). When genotype combinations were considered, the following distributions were obtained: 14 people were homozygous wild-type (wt/wt = NQO1wt), 10 were carrying at least one null allele (wt/na and na/na = NQO1defective), 11 subjects were GSTM1 positive (GSTM1pos), and 13 subjects failed to express GSTM1 (GSTM1null). Eight subjects were NQO1wt and GSTM1null (33%), six were NQO1 wt and GSTM1pos (25%), five were NQO1defective and GSTM1pos (21%), and five were NQO1defective and GSTM1null (21%). These figures are comparable to those obtained in a local reference population of 300 white subjects, 30% of whom were bearing the NQO1wt and GSTM1null genotypes, and are very similar to expected values for genotype frequencies.
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Spirometry Measurements
Lung function was assessed indoors using a spirometer equipped with a Fleisch pneumotachometer (Fukuda Sangyo, Tokyo, Japan). To avoid possible confounding effects of ozone exposure occurring before the ride, baseline lung function was also assessed a few weeks before the ride, when airborne O3 concentration averaged 45 ppb (range: 28 to 72 ppb). The day of the run, subjects were tested within 30 min before and after, while wearing nose clips. Respiratory function tests included FVC, FEV1, peak expiratory flow (PEF), and maximal expiratory flows at 25%, 50%, and 75% of vital capacity (MEF25-50-75). Mean values for FEV1 and FVC were obtained from the three best acceptable test values of lung function, according to the recommendation of the American Thoracic Society (26).
Statistical Analysis
Statistical analysis was carried out using the Statistical Package for Social Sciences SPSS/9.0 (SPSS, Chicago, IL). The Kolmogorov-Smirnov test was used to assess the gaussian nature of the distribution. The differences between lung function tests in the same individuals were assessed by Student's t test for paired samples. Association between variables was assessed by Pearson's correlation analysis. The partial correlation method was used to analyze the interrelationship among O3 and changes in lung function and serum CC16.
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RESULTS |
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After 2-h rides performed at ambient O3 exceeding 80 ppb, most lung function parameters showed significant decrements, whereas serum CC16 was significantly increased. Such changes were mainly accounted for by a subgroup of subjects bearing both NQO1wt and GSTM1null genotypes (Table 2). Despite its small size, this subgroup showed statistically significant decrements in FEV1 (p = 0.026), MEF50 (p = 0.010), MEF75 (p = 0.040), and PEF (p = 0.037) as well as an increase in serum CC16 (p = 0.012). No significant differences were apparent for the other combinations of NQO1 and GSTM1 genotypes.
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A more detailed analysis was carried out comparing both preride and postride values with baseline function tests recorded a few weeks before the acute challenge. Figure 1 shows percent variations of FEV1 over baseline values. Among NQO1wt and GSTM1null subjects preride FEV1 were already decreased compared with baseline, such a systematic decrement being greater than in subjects with other genotypes. Moreover, in NQO1wt and GSTM1null individuals, the variability of the response to O3 was much lower than in subjects bearing other combinations of genotypes.
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Linear regression models relating percentage changes in pulmonary function tests and biomarkers of epithelial lung damage to ambient ozone, after adjustment for sex and age, demonstrated average declines by 3% in FEV1 (r2 = 0.228, p = 0.01), 3.4% in FVC (r2 = 0.147, p = 0.005), 10% in MEF50 (r2 = 0.227, p = 0.001), and 8.9% in PEF (r2 = 0.118, p = 0.01) for each 50-ppb increment in O3. The increase in serum CC16 was also correlated with O3 airborne concentrations (r2 = 0.151, p = 0.005) independently from sex and age.
The association between O3 concentrations and changes in lung function and serum CC16 was mainly accounted for by the subgroup of subjects bearing both NQO1wt and GSTM1null genotypes (Table 3). In this subgroup, decrement in lung function and increase in serum CC16 were also strongly correlated. The correlation between O3 concentrations and changes in lung function disappeared after control for changes in serum CC16. Also, the correlation between O3 levels and changes in CC16 was no longer apparent after control for changes in FEV1. Control for O3 concentrations did not modify the correlation between changes in CC16 and FEV1.
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) IN BOTH LUNG FUNCTION TESTS
AND SERUM CC16 IN SUBJECTS BEARING BOTH
NQO1wt AND GSTM1null GENOTYPE*
In subjects characterized by other combinations of genotypes (NQO1wt and GSTM1null or NQO1defective and GSTM1 either pos or null), no relationships were detectable between ambient O3 and functional or biochemical changes, nor was any parameter of lung function correlated with serum CC16 changes (Table 4).
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The relationship between ambient O3 concentrations and changes in serum CC16 is shown in Figure 2. Whereas among subjects carrying the NQO1wt and GSTM1null genotypes the postride increase in serum CC16 was closely related to ambient O3 concentrations (r2 = 0.48, p < 0.001), such a relationship was not apparent in volunteers with the other combinations of NQO1 and GSTM1. The negative correlation between changes in lung function tests and changes in serum CC16 is shown in Figure 3. Again, no such relationship was apparent in subjects bearing other combinations of NQO1 and GSTM1 genotypes.
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Although this test was not included in the original protocol, we obtained the cooperation of 16 volunteers to measure 8-OHdG both before and after exposure to O3 concentrations exceeding 80 ppb (Figure 4). In subjects carrying both the NQO1wt and GSTM1null genotypes, the increase in 8-OHdG after 2-h exposure to O3 exceeding 80 ppb was higher as compared with other genotypes. In NQO1wt and GSTM1null subjects, mean values (± SEM) before and after exposure were 4.53 ± 0.37 and 7.47 ± 1.64 8-OHdG/105 dG, before and after exposure, respectively (p < 0.001). The corresponding values recorded among subjects bearing other genotypes were 5.18 ± 1.21 and 6.65 ± 1.41, respectively (p = 0.066).
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DISCUSSION |
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INTRODUCTION
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The present study shows that O3-related effects are mainly apparent in a subgroup of volunteers characterized by a combination of NQO1wt and GSTM1null genotypes. NQO1 and GSTs, which are highly expressed in the lung (19, 27), are regulated at the transcriptional level by redox-sensitive antioxidant-responsive elements (AREs). Induction of AREs is driven by a diverse array of chemicals including hydroquinones, peroxides, and dimercaptans, all of which share the property of generating pro-oxidant conditions within the cell (28). NQO1 catalyzes a two-electron reduction of several endogenous substances and ubiquitous pollutants, giving rise to hydroquinones that are readily excreted after conjugation with GSH. In Figure 5, we propose a sequence of events accounting for biochemical and functional changes observed among NQO1wt and GSTM1null subjects after O3 exposure. Whereas NQO1 is thought to play a detoxifying role limiting redox cycling of labile semiquinone radicals both to quinones and hydroquinones, thus reducing the production of superoxide anion, hydrogen peroxide, and ultimately of the hydroxyl radical (OH°) (17, 29), NQO1-generated hydroquinones are targets of O3 which oxidizes them to semiquinones and gives rise to the hydroxyl radical (30). In GSTM1 positive subjects, such an increased production of hydroquinones can be neutralized by GSH conjugation. People carrying the NQO1wt genotype, but lacking GSTM1, are less able to conjugate hydroquinones, a condition which could favor their responsiveness to O3. The measurement of 8-OHdG provides indirect evidence of oxidative stress and increased formation of OH° among these subjects (Figure 5). Subsequent events may include epithelial damage, increased permeability, and an inflammatory response accounting for lung function decrements.
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Partial correlation analysis among subjects bearing both NQO1wt and GSTM1null genotype showed a strong intercorrelation between O3 concentrations, and changes in both lung function tests and serum CC16. Whereas the correlation between O3 concentrations and changes in lung function tests disappeared after control for changes in CC16, and that between O3 levels and changes in serum CC16 disappeared after control for decrements in FEV1, the relationship between increase in CC16 and decrement of FEV1 was not affected by control for O3 concentrations. As a whole, partial correlation analysis suggests that in NQO1wt and GSTM1null subjects the same mechanisms elicited by O3 exposure, possibly an inflammatory reaction, underlie both functional decrements and increased serum CC16. In these "susceptible" subjects, baseline concentrations of serum CC16 were lower compared with other subgroups (Table 2), suggesting that the number or function of Clara cells may be reduced as a consequence of chronic toxicity. Even though the exact in vivo function of CC16 protein remains to be elucidated, there is growing evidence that CC16 plays a modulatory role in controlling airway inflammation in response to oxidant stress through the inhibition of phospholipase A2 (31) and phagocyte chemotaxis, as well as by reducing the production of proinflammatory cytokines (32). Therefore, lower CC16 concentrations might account for a greater inflammatory response by NQO1wt and GSTM1null subjects.
Studies in both humans and animals indicate that the assay for CC16 is a sensitive noninvasive test allowing the detection of early damage to the respiratory epithelium caused by O3. Acute exposure of mice and rats to O3 produces a transient dose-dependent elevation of CC16 in serum (33, 34). Interestingly, the O3-induced intravascular leakage of CC16 in mice correlates with the most sensitive strain C57Bl/6. In the latter, the exposure to 80 ppb of O3 for 4 h produced a significant increase of CC16 in serum, whereas albumin, a classic marker of disruption and increased permeability to plasmaproteins of the air-blood barrier, increased in the pulmonary lining fluid collected by bronchoalveolar lavage 8 h after exposure (34).
The results of the present study show a dissociation between the behavior of serum CC16 and lung function tests among people carrying the NQO1wt and GSTM1null genotypes (significant and correlated changes of both serum CC16 and functional parameters) and other genotypes (no functional impairment despite increased serum CC16). These findings are consistent with the hypothesis that oxidative damage to epithelial cells may be associated with an inflammatory reaction, which is possibly modulated by both the rate of generation of ROS and Clara cell secretion. Indeed, the genetic polymorphism for the Clara cell protein CC16 has been associated with an increased risk of asthma, asthmatic children showing lower mean plasma CC16 levels compared with nonasthmatic subjects (35). Interestingly, baseline and afterride serum CC16 levels were lower in NQO1wt and GSTM1null subjects. Although it is currently thought that decrements in lung function are not correlated with changes in early markers of inflammation (13, 36), such a relationship seems to exist in a subgroup of "susceptible" individuals.
In addition to endogenous quinones, ubiquitous pollutants
such as polycyclic aromatic hydrocarbons and nitroaromatics
are converted to o-quinones and then to hydroquinones by
NQO1. This would explain why acute effects of O3 exposure
are greater in polluted urban environments than in rural settings. Such a hypothesis will be tested in a prospective study
aimed (1) at confirming that subjects bearing the NQO1wt
and GSTM1null genotypesidentified retrospectively in the
present studyare particularly vulnerable to O3, and (2) at
comparing the effects of pure O3 with that of similar concentrations occurring during episodes of photochemical smog.
Recent estimates suggest a 0.41% increase in the rate of death
for each increase in O3 concentration of 10 ppb during the summer months (37). Such serious health effects might result from exposure not only to O3, but also to a complex mixture of irritants and oxidants, including particulate matter, peroxy-acyl nitrates, and aldehydes, associated with O3 in photochemical pollution.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Enrico Bergamaschi, Laboratory of Industrial Toxicology, Dept. of Clinical Medicine, Nephrology, and Health Sciences, University of Parma Medical School, I-43100 Parma, Italy. E-mail: enrico.bergamaschi{at}unipr.it
(Received in original form June 12, 2000 and in revised form January 24, 2001).
Acknowledgments: The authors gratefully acknowledge Dr. Licia Rossi and Dr. Stefania Cavazzini for their skillful assistance in the fieldwork, and Eriberto DeMunaris of ARPAER who provided records on O3 airborne concentrations.
Supported by the European Commission (Contr. QLK4-1999-01308) and the program on sustainable development of the Belgian Federal Government (DD/ MD006).
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References |
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C. Chen, M. Arjomandi, I. B. Tager, N. Holland, and J. R. Balmes Effects of antioxidant enzyme polymorphisms on ozone-induced lung function changes Eur. Respir. J., October 1, 2007; 30(4): 677 - 683. [Abstract] [Full Text] [PDF]
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 S. J. London Gene-Air Pollution Interactions in Asthma Proceedings of the ATS, July 1, 2007; 4(3): 217 - 220. [Abstract] [Full Text] [PDF]
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 J. Schwartz, S. K. Park, M. S. O'Neill, P. S. Vokonas, D. Sparrow, S. Weiss, and K. Kelsey Glutathione-S-Transferase M1, Obesity, Statins, and Autonomic Effects of Particles: Gene-by-Drug-by-Environment Interaction Am. J. Respir. Crit. Care Med., December 15, 2005; 172(12): 1529 - 1533. [Abstract] [Full Text] [PDF]
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 D. Olivieri and E. Scoditti Impact of environmental factors on lung defences Eur. Respir. Rev., December 1, 2005; 14(95): 51 - 56. [Abstract] [Full Text] [PDF]
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I. A. Yang, O. Holz, R. A. Jorres, H. Magnussen, S. J. Barton, S. Rodriguez, J. A. Cakebread, J. W. Holloway, and S. T. Holgate Association of Tumor Necrosis Factor-{alpha} Polymorphisms and Ozone-induced Change in Lung Function Am. J. Respir. Crit. Care Med., January 15, 2005; 171(2): 171 - 176. [Abstract] [Full Text] [PDF]
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A. Spira, J. Beane, V. Pinto-Plata, A. Kadar, G. Liu, V. Shah, B. Celli, and J. S. Brody Gene Expression Profiling of Human Lung Tissue from Smokers with Severe Emphysema Am. J. Respir. Cell Mol. Biol., December 1, 2004; 31(6): 601 - 610. [Abstract] [Full Text] [PDF]
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 A. K. Bauer, A. M. Malkinson, and S. R. Kleeberger Susceptibility to neoplastic and non-neoplastic pulmonary diseases in mice: genetic similarities Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L685 - L703. [Abstract] [Full Text] [PDF]
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 L. L. Chen, I. B. Tager, D. B. Peden, D. L. Christian, R. E. Ferrando, B. S. Welch, and J. R. Balmes Effect of Ozone Exposure on Airway Responses to Inhaled Allergen in Asthmatic Subjects Chest, June 1, 2004; 125(6): 2328 - 2335. [Abstract] [Full Text] [PDF]
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J. Sunyer Chronic effects of ozone in children Eur. Respir. J., February 1, 2004; 23(2): 185 - 186. [Full Text] [PDF]
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G. L. David, I. Romieu, J. J. Sienra-Monge, W. J. Collins, M. Ramirez-Aguilar, B. E. del Rio-Navarro, N. I. Reyes-Ruiz, R. W. Morris, J. M. Marzec, and S. J. London Nicotinamide Adenine Dinucleotide (Phosphate) Reduced:Quinone Oxidoreductase and Glutathione S-Transferase M1 Polymorphisms and Childhood Asthma Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1199 - 1204. [Abstract] [Full Text] [PDF]
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S.R. Kleeberger Genetic aspects of susceptibility to air pollution Eur. Respir. J., May 1, 2003; 21(40_suppl): 52S - 56s. [Abstract] [Full Text] [PDF]
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A. H. Snyder, M. E. McPherson, J. F. Hunt, M. Johnson, J. S. Stamler, and B. Gaston Acute Effects of Aerosolized S-Nitrosoglutathione in Cystic Fibrosis Am. J. Respir. Crit. Care Med., April 1, 2002; 165(7): 922 - 926. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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