Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response.

BACKGROUND: Diesel exhaust (DE) induces neutrophilia and lymphocytosis in experimentally exposed humans. These responses occur in parallel to nuclear migration of NF-κB and c-Jun, activation of mitogen activated protein kinases and increased production of inflammatory mediators. There remains uncertainty regarding the impact of DE on endogenous antioxidant and xenobiotic defences, mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) respectively, and the extent to which cellular antioxidant adaptations protect against the adverse effects of DE. METHODS: Using immunohistochemistry we investigated the nuclear localization of Nrf2 and AhR in the epithelium of endobronchial mucosal biopsies from healthy subjects six-hours post exposure to DE (PM10, 300 µg/m3) versus post-filtered air in a randomized double blind study, as a marker of activation. Cytoplasmic expression of cytochrome P450s, family 1, subfamily A, polypeptide 1 (CYP1A1) and subfamily B, Polypeptide 1 (CYP1B1) were examined to confirm AhR activation; with the expression of aldo-keto reductases (AKR1A1, AKR1C1 and AKR1C3), epoxide hydrolase and NAD(P)H dehydrogenase quinone 1 (NQO1) also quantified. Inflammatory and oxidative stress markers were examined to contextualize the responses observed. RESULTS: DE exposure caused an influx of neutrophils to the bronchial airway surface (p = 0.013), as well as increased bronchial submucosal neutrophil (p < 0.001), lymphocyte (p = 0.007) and mast cell (p = 0.002) numbers. In addition, DE exposure enhanced the nuclear translocation of the AhR and increased the CYP1A1 expression in the bronchial epithelium (p = 0.001 and p = 0.028, respectively). Nuclear translocation of AhR was also increased in the submucosal leukocytes (p < 0.001). Epithelial nuclear AhR expression was negatively associated with bronchial submucosal CD3 numbers post DE (r = -0.706, p = 0.002). In contrast, DE did not increase nuclear translocation of Nrf2 and was associated with decreased NQO1 in bronchial epithelial cells (p = 0.02), without affecting CYP1B1, aldo-keto reductases, or epoxide hydrolase protein expression. CONCLUSION: These in vivo human data confirm earlier cell and animal-based observations of the induction of the AhR and CYP1A1 by diesel exhaust. The induction of phase I xenobiotic response occurred in the absence of the induction of antioxidant or phase II xenobiotic defences at the investigated time point 6 h post-exposures. This suggests DE-associated compounds, such as polycyclic aromatic hydrocarbons (PAHs), may induce acute inflammation and alter detoxification enzymes without concomitant protective cellular adaptations in human airways.

Air pollution and trajectories of adolescent conduct problems: the roles of ethnicity and racism; evidence from the DASH longitudinal study.

PURPOSE: No known UK empirical research has investigated prospective associations between ambient air pollutants and conduct problems in adolescence. Ethnic minority children are disproportionately exposed to structural factors that could moderate any observed relationships. This prospective study examined whether exposure to PM2.5 and NO2 concentrations is associated with conduct problems in adolescence, and whether racism or ethnicity moderate such associations. METHODS: Longitudinal associations between annual mean estimated PM2.5 and NO2 concentrations at the residential address and trajectories of conduct problems, and the potential influence of racism and ethnicity were examined school-based sample of 4775 participants (2002-2003 to 2005-2006) in London, using growth curve models. RESULTS: Overall, in the fully adjusted model, exposure to lower concentrations of PM2.5 and NO2 was associated with a decrease in conduct problems during adolescence, while exposure to higher concentrations was associated with a flattened trajectory of conduct symptoms. Racism amplified the effect of PM2.5 (ß = 0.05 (95% CI 0.01 to 0.10, p < 0.01)) on adolescent trajectories of conduct problems over time. At higher concentrations of PM2.5, there was a divergence of trajectories of adolescent conduct problems between ethnic minority groups, with White British and Black Caribbean adolescents experiencing an increase in conduct problems over time. CONCLUSION: These findings suggest that the intersections between air pollution, ethnicity, and racism are important influences on the development of conduct problems in adolescence.

Associations between air pollutants and blood pressure in an ethnically diverse cohort of adolescents in London, England.

Longitudinal evidence on the association between air pollution and blood pressure (BP) in adolescence is scarce. We explored this association in an ethnically diverse cohort of schoolchildren. Sex-stratified, linear random-effects modelling was used to examine how modelled residential exposure to annual average nitrogen dioxide (NO2), particulate matter (PM2.5, PM10) and ozone (O3), measures in µg/m3, associated with blood pressure. Estimates were based on 3,284 adolescents; 80% from ethnic minority groups, recruited from 51 schools, and followed up from 11-13 to 14-16 years old. Ethnic minorities were exposed to higher modelled annual average concentrations of pollution at residential postcode level than their White UK peers. A two-pollutant model (NO2 & PM2.5), adjusted for ethnicity, age, anthropometry, and pubertal status, highlighted associations with systolic, but not diastolic BP. A µg/m3 increase in NO2 was associated with a 0.30 mmHg (95% CI 0.18 to 0.40) decrease in systolic BP for girls and 0.19 mmHg (95% CI 0.07 to 0.31) decrease in systolic BP for boys. In contrast, a 1 µg/m3 increase in PM2.5 was associated with 1.34 mmHg (95% CI 0.85 to 1.82) increase in systolic BP for girls and 0.57 mmHg (95% CI 0.04 to 1.03) increase in systolic BP for boys. Associations did not vary by ethnicity, body size or socio-economic advantage. Associations were robust to adjustments for noise levels and lung function at 11-13 years. In summary, higher ambient levels of NO2 were associated with lower and PM2.5 with higher systolic BP across adolescence, with stronger associations for girls.

Ascorbate prevents placental oxidative stress and enhances birth weight in hypoxic pregnancy in rats.

This study isolated the effects of maternal hypoxia independent of changes in maternal nutrition on maternal circulatory and placental molecular indices of oxidative stress and determined whether maternal antioxidant treatment conferred protection. Pregnant rats were subjected to normoxic pregnancy or 13% O2 chronic hypoxia for most of gestation with and without maternal treatment with vitamin C in the drinking water. Maternal hypoxia with and without vitamin C did not affect maternal food or water intake and led to a significant increase in maternal and fetal haematocrit. At gestational day 20, maternal plasma urate and L-cysteine concentrations, and placental levels of 4-hydroxynonenal and heat shock protein 70 were increased while placental heat shock protein 90 levels were decreased in hypoxic pregnancy. The induction of maternal circulatory and placental molecular indices of oxidative stress in hypoxic pregnancies was prevented by maternal treatment with vitamin C. Maternal hypoxia during pregnancy with or without vitamin C increased placental weight, but not total or compartmental volumes. Maternal treatment with vitamin C increased birth weight in both hypoxic and normoxic pregnancies. The data show that maternal hypoxia independent of maternal undernutrition promotes maternal and placental indices of oxidative stress, effects that can be prevented by maternal treatment with vitamin C in hypoxic pregnancy. While vitamin C may not be the ideal candidate of choice for therapy in pregnant women, and taking into consideration differences in ascorbic acid metabolism between rats and humans, the data do underlie that antioxidant treatment may provide a useful intervention to improve placental function and protect fetal growth in pregnancy complicated by fetal hypoxia.

Ozone exposure enhances mast-cell inflammation in asthmatic airways despite inhaled corticosteroid therapy.

Asthmatics are recognised to be more susceptible than healthy individuals to adverse health effects caused by exposure to the common air pollutant ozone. Ozone has been reported to induce airway neutrophilia in mild asthmatics, but little is known about how it affects the airways of asthmatic subjects on inhaled corticosteroids. We hypothesised that ozone exposure would exacerbate the pre-existent asthmatic airway inflammation despite regular inhaled corticosteroid treatment. Therefore, we exposed subjects with persistent asthma on inhaled corticosteroid therapy to 0.2 ppm ozone or filtered air for 2 h, on 2 separate occasions. Lung function was evaluated before and immediately after exposure, while bronchoscopy was performed 18 h post exposure. Compared to filtered air, ozone exposure increased airway resistance. Ozone significantly enhanced neutrophil numbers and myeloperoxidase levels in airway lavages, and induced a fourfold increase in bronchial mucosal mast cell numbers. The present findings indicate that ozone worsened asthmatic airway inflammation and offer a possible biological explanation for the epidemiological findings of increased need for rescue medication and hospitalisation in asthmatic people following exposure to ambient ozone.

Depletion of urate in human nasal lavage following in vitro ozone exposure.

Ozone, a strong oxidant present in summer smog, is thought to primarily react with antioxidant molecules found in the epithelial lining fluid of the respiratory tract. In humans, as much as 40% of inhaled ozone can be removed in the nasal cavity where the major extracellular antioxidant has been identified as uric acid. The present study was undertaken to examine urate/oxidant interactions in human nasal lavage fluid following in vitro exposure to ozone at concentrations relevant to the U.K. Lavage fluid was collected from 8 volunteers using a modified Foley catheter which permits prolonged contact of isotonic saline with the anterior nasal cavity. Nasal lavage samples in multiwell plates were exposed to ozone at concentrations of 50, 100 and 250 ppb. Samples were removed at intervals from 15 to 240 min following exposure and assayed for uric acid depletion. Uric acid concentrations in the nasal lavage were found to fall from 8.52 (time zero) to 3.99 microM, 0.05 and 0.07 microM after 240 min at 50, 100 and 250 ppb ozone respectively. At a non-environmentally relevant ozone concentration of 1000 ppb, uric acid was completely depleted after 60 min. Regression analysis showed a linear correlation between rate of loss of urate and ozone concentration (R2 = 0.97). A novel, non-invasive technique is described to investigate antioxidant compromise and its importance in individual subjects. We conclude that uric acid in nasal lavage samples is scavenged by ozone in a dose and time dependent manner.

Ozone and the lung: a sensitive issue.

Ozone is a powerful oxidant and toxic air pollutant. As a gaseous pollutant, its primary target tissue is the lung and breathing slightly elevated concentrations of ozone results in a range of respiratory symptoms. These include decreased lung function and increased airway hyper-reactivity in 10-20% of the healthy population. Moreover, those with conditions such as asthma and chronic obstructive pulmonary disease (COPD) generally experience an exacerbation of their symptoms. Together, these observations suggest that certain individuals are particularly susceptible to this oxidant gas. The primary goal of this review is to examine the basis of this increased sensitivity. Ozone is a highly reactive gas that is consumed by reactive processes on reaching the first interface in the lung, the lung lining fluid compartment. Reactions between ozone and antioxidants tend to dominate in this compartment and these are generally thought of as beneficial, or protective interactions. In those instances when ozone reacts with other substrates in lung lining fluid such as protein or lipid, secondary oxidation products arise which transmit the toxic signals to the underlying pulmonary epithelium. The rules that govern the balance between beneficial and detrimental interactions in the lung lining fluid compartment are not well established but these may contribute, in part, to sensitivity. On reaching the lung surface, secondary oxidation products arising from ozone initiate a number of cellular responses. These include cytokine generation, adhesion molecule expression and tight junction modification. Together, these responses lead to the influx of inflammatory cells to the lung in the absence of a pathogenic challenge. Moreover, lung permeability is increased and oedema develops. The nature and extent of these responses are variable and often not related within an individual. Thus, although an improved appreciation of the general mechanism of action of ozone has been attained in recent years, the basis for individual susceptibility is still unclear.

Differences in basal airway antioxidant concentrations are not predictive of individual responsiveness to ozone: a comparison of healthy and mild asthmatic subjects.

The air pollutant ozone induces both airway inflammation and restrictions in lung function. These responses have been proposed to arise as a consequence of the oxidizing nature of ozone, depleting endogenous antioxidant defenses with ensuing tissue injury. In this study we examined the impact of an environmentally relevant ozone challenge on the antioxidant defenses present at the surface of the lung in two groups known to have profound differences in their antioxidant defense network: healthy control (HC) and mild asthmatic (MA) subjects. We hypothesized that baseline differences in antioxidant concentrations within the respiratory tract lining fluid (RTLF), as well as induced responses, would predict the magnitude of individual responsiveness. We observed a significant loss of ascorbate (ASC) from proximal (-45.1%, p <.01) and distal RTLFs (-11.7%, p <.05) in healthy subjects 6 h after the end of the ozone challenge. This was associated (Rs, -0.71, p <.01) with increased glutathione disulphide (GSSG) in these compartments (p =.01 and p <.05). Corresponding responses were not seen in asthmatics, where basal ASC concentrations were significantly lower (p <.01) and associated with elevated concentrations of GSSG (p <.05). In neither group was any evidence of lipid oxidation seen following ozone. Despite differences in antioxidant levels and response, the magnitude of ozone-induced neutrophilia (+20.6%, p <.01 [HC] vs. +15.2%, p =.01 [MA]) and decrements in FEV(1) (-8.0%, p <.01 [HC] vs. -3.2%, p <.05 [MA]) did not differ between the two groups. These data demonstrate significant differences between the interaction of ozone with RTLF antioxidants in MA and HC subjects. These responses and variations in basal antioxidant defense were not, however, useful predictive markers of group or individual responsiveness to ozone.

Differential depletion of human respiratory tract antioxidants in response to ozone challenge.

The toxicity of ozone, the major component of photochemical smog, is related to its powerful oxidising ability, and many of its deleterious effects are mediated through free radical reactions. As the majority of ozone oxidation events are thought to be confined to the pulmonary epithelial lining fluid, we studied the interaction of ozone with a range of small molecular weight antioxidants found within this compartment: ascorbic acid (AH2), uric acid (UA), and reduced glutathione (GSH). Epithelial lining fluid obtained as bronchoalveolar lavage (BAL) fluid, was taken from 16 male subjects and the antioxidant concentrations determined for each subject. BAL fluid samples from nine of these subjects were then exposed, using an interfacial exposure system, to a range (50-1000 ppb) of ozone concentrations. Both AH2 and UA were consumed by ozone in a time and ozone concentration dependent manner, with mean consumption rates of 1.7 +/- 0.8 and 1.0 +/- 0.5 pmol L-1 s-1 ppb-1, respectively. Considerable intersubject variation was however observed. The individual rates of consumption for each antioxidant were significantly correlated with the respective initial antioxidant concentration. In contrast, although GSH was consumed at 50 ppb ozone, the rate of consumption did not change with increasing ozone concentration. We conclude that there is differential depletion of BAL fluid antioxidants, suggesting a reactivity hierarchy toward ozone in human ELF of AH2 > UA > > GSH.

Sensitivity to ozone: could it be related to an individual's complement of antioxidants in lung epithelium lining fluid?

Ozone, though not a free radical species, mediates its toxic effects through free radical reactions as a consequence of its high redox potential. Upon inspiration the first physical interface encountered by ozone is a thin layer of aqueous material, the epithelium lining fluid (ELF) which overlays, and is partially derived from, the underlying pulmonary epithelium. ELF is the first physical interface encountered by ozone and the majority of its primary actions are confined to this compartment. ELF contains a range of antioxidants, including the small molecular weight antioxidants: uric acid (UA), ascorbic acid (AH2) and reduced glutathione (GSH). These compounds are present in large quantities and display high intrinsic reactivities toward ozone, consistent with their role as sacrificial substrates in this setting. In this paper we examine the concept that antioxidants, in ELF, represent the first tier of defence against the oxidizing effects of ozone. Since the concentration of these antioxidants appears to differ between individuals, we propose that these protective substances may dictate, in part, an individual's sensitivity to oxidizing air pollutants such as ozone.

Effect of ozone on bronchial mucosal inflammation in asthmatic and healthy subjects.

Epidemiological studies suggestthat asthmatics are more affected by ozone than healthy people. This study tested three hypotheses (1) that short-term exposure to ozone induces inflammatory cell increases and up-regulation of vascular adhesion molecules in airway lavages and bronchial tissue 6 h after ozone exposure in healthy subjects; (2) these responses are exaggerated in subjects with mild allergic asthma; (3) ozone exacerbates pre-existent allergic airways inflammation. We exposed 15 mild asthmatic and 15 healthy subjects to 0.2 ppm of ozone or filtered air for 2 h on two separate occasions. Airway lavages and bronchial biopsies were obtained 6 h post-challenge. We found that ozone induced similar increases in bronchial wash neutrophils in both groups, although the neutrophil increase in the asthmatic group was on top of an elevated baseline. In healthy subjects, ozone exposure increased the expression of the vascular endothelial adhesion molecules P-selectin and ICAM- 1, as well as increasing tissue neutrophil and mast cell numbers. The asthmatics showed allergic airways inflammation at baseline but ozone did not aggravate this at the investigated time point. At 6 h post-ozone-exposure, we found no evidence that mild asthmatics were more responsive than healthy to ozone in terms of exaggerated neutrophil recruitment or exacerbation of pre-existing allergic inflammation. Further work is needed to assess the possibility of a difference in time kinetics between healthy and asthmatic subjects in their response to ozone.

Antioxidant defenses in lung lining fluid of broilers: impact of poor ventilation conditions.

Lung lining fluid antioxidants represent a potentially important protective barrier of lung epithelial cells to damaging effects of air pollutants, yet no information is apparently available concerning lung lining fluid antioxidants in broilers. Therefore, goals of this study were to establish uric acid, ascorbic acid, reduced (GSH) and oxidized (GSSG) glutathione, and protein concentrations in lung lining fluid obtained from male broiler chickens maintained for 6 to 7 wk within environmentally controlled rooms (Control) or chronically exposed to high levels of dust and ammonia within a broiler rearing house (House). The entire respiratory tract was carefully removed following an overdose of anesthetic and lavage fluid was collected after flushing the lungs with heparin-saline (10 mL per lung). There was no difference in GSH, but GSSG, uric acid, and protein concentrations were higher in House birds than in Controls. An increase in the GSSG to total glutathione (GSx) ratio, an indicator of oxidative stress, was also observed in birds maintained in the House environment. Ascorbic acid was not detected in House-reared birds and detected in only 4 of 12 Controls. Regression analysis revealed positive correlations between lung lining fluid protein and uric acid (r = 0.71; P < 0.01), protein and GSSG (r = 0.73; P < 0.01), and uric acid and GSSG concentrations (r = 0.69, P < 0.01). Additionally, GSSG was positively correlated (r = 0.66; P < 0.01) with the right ventricular weight ratio, an index commonly used in identifying the development of pulmonary hypertension syndrome in broilers. These data, the first to document lung lining fluid antioxidants in avian species, indicate an oxidative stress can be detected in fluid of broilers exposed to high levels of dust and ammonia in a simulated poultry house environment.

Respiratory tract lining fluid antioxidants: the first line of defence against gaseous pollutants.

All tissues are vulnerable to oxidant damage, but by virtue of its location, anatomy and function, the epithelial surface of the lung is one of the most vulnerable targets in the body. Recent studies have shown that epithelial lining fluid (ELF), a thin layer of fluid which covers the epithelial surface of the respiratory tract, contains an interesting complement of antioxidants, some of which, like glutathione, are present in concentrations much higher than those found in plasma. It is likely that ELF forms the first line of defence against inhaled toxins such as ozone and nitrogen dioxide. By employing an ex vivo exposure system we have demonstrated that when lung lining fluid is in contact with environmentally relevant concentrations of ozone or nitrogen dioxide, there is differential consumption of the water-soluble antioxidants in the order, uric acid > ascorbic acid >> glutathione. Given that the majority of ozone and nitrogen dioxide reacts within the ELF compartment, the antioxidant composition of this fluid is critically important in determining an individual's sensitivity to gaseous pollutants.

Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans.

Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.

Modeling the interactions of ozone with pulmonary epithelial lining fluid antioxidants.

Water soluble antioxidant--ascorbate (AA), urate (UA), and reduced glutathione (GSH)--consumption by ozone (O3) was investigated in a range of pulmonary epithelial lining fluid (ELF) models. Antioxidants were exposed individually and as a composite mixture, with and without human albumin to a range of ambient O3 concentrations: 0-1500 ppb using a continually mixed, interfacial exposure setup. We observed the following: (1) UA constituted the most o3-reactive substrate in each of the models examined. Reactivity hierarchies in each were as follows: UA > AA >> GSH (individual antioxidant), UA > AA > GSH (composite antioxidant), and UA >> AA approximately equal to GSH (composite antioxidant + albumin). Consumption of GSH as a pure antioxidant solution was associated with a 2:1 stoichiometric conversion of GSH to GSSG. This simplistic relationship was lost in the more complex models. (3) Consumption of antioxidants by O3 occurred without alteration of sample pH. (4) Protein carbonyl formation was observed when albumin alone was exposed to O3. However, in the presence of the composite antioxidant solution no evidence of this oxidative modification was apparent. These data indicate that GSH does not represent an important substrate for O3. In contrast, UA displays high reactivity consistent with its acting as a sacrificial substrate in the ELF. As UA concentrations are highest in the ELF of the proximal airways, its localization, allied to its reactivity, suggesting that it plays important roles, both in conferring protection locally and also by "scrubbing" O3, from inhaled air, limiting its penetration to the more sensitive distal lung.

Protein oxidation at the air-lung interface.

Whilst performing its normal functions the lung is required to deal with a range of toxic insults. Whether these are infectious agents, allergens or air pollutants they subject the lung to a range of direct and indirect oxidative stresses. In many instances these challenges lead to oxidative alterations of peptides and proteins within the lung. Measurement of protein oxidation products permits the degree of oxidative stress to be assessed and indicates that endogenous antioxidant defences are overwhelmed. The range of protein oxidation products observed is diverse and the nature and extent of specific oxidation products may inform us about the nature of the damaging ROS and NOS. Recently, there has been a significant shift away from the measurement of these oxidation products simply to establish the presence of oxidative stress, to a focus on identifying specific proteins sensitive to oxidation and establishing the functional consequences of these modifications. In addition the identification of specific enzyme systems to repair these oxidative modifications has lead to the belief that protein function may be regulated through these oxidation reactions. In this review we focus primarily on the soluble protein components of within the surface liquid layer in the lung and the consequence of their undue oxidation.

Air pollution and the elderly: oxidant/antioxidant issues worth consideration.

The elderly are frequently classified as being particularly susceptible to air pollution. The basis of this increased sensitivity is not known but it is likely that it is linked to age-related impaired function of the lung. However, given this uncertainty and increased impact of air pollution of this section of the community there is a need to explore the mechanisms involved. Gaseous air pollutants such as ozone and nitrogen dioxide, or many of the components adsorbed onto the surface of respirable particles, are either powerful oxidants or capable of generating free radicals. If unabated, oxidants can cause injury to the delicate cells that line the respiratory tract. Small molecular weight antioxidant defences present in respiratory tract lining fluid (RTLF) represent the first line of defence against a range of oxidants that enter the lung. The quantity and quality of the RTLF airways antioxidant network are, therefore, likely to be important determinants of the impact of the oxidant challenge on the underlying respiratory epithelium. As yet, comprehensive information on the distribution and variability of respiratory tract lining fluid antioxidant defences is only available in young, mainly healthy volunteers. Studies undertaken in patients with a range of respiratory diseases suggest that marked changes in the distribution of respiratory tract lining fluid antioxidants can occur. Information is not currently available on the impact of ageing on the respiratory tract lining fluid antioxidant defence network. As several respiratory tract lining fluid antioxidants are of dietary origin, the elderly, who often have different dietary patterns to younger individuals, may have decreased availability of important antioxidants. Given these possibilities, a better understanding of respiratory tract lining fluid antioxidant defences in the aged lung is warranted.

Altered lung antioxidant status in patients with mild asthma.

Lung lining fluid ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) concentrations are low in patients with mild asthma even though blood levels are normal or increased. These findings, along with the presence of increased amounts of oxidised glutathione in their airways, indicate that patients with asthma are subject to increased oxidative stress.