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ABSTRACT |
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To determine whether antioxidants can influence human susceptibility to ozone (O3)-induced changes in lung function and airway inflammation, we placed 31 healthy nonsmoking adults (18 to 35 yr
old) on a diet low in ascorbate for 3 wk. At 1 wk, subjects were exposed to filtered air for 2 h while exercising (20 L/min/m2), and
then underwent bronchoalveolar lavage (BAL) and were randomly assigned to receive either a placebo or 250 mg of vitamin C, 50 IU
of 
-tocopherol, and 12 oz of vegetable cocktail daily for 2 wk.
Subjects were then exposed to 0.4 ppm O3 for 2 h and underwent a second BAL. On the day of the O3 exposure, supplemented subjects were found to have significantly increased levels of plasma
ascorbate, tocopherols, and carotenoids as compared with those
of the placebo group. Pulmonary function testing showed that
O3-induced reductions in FEV1 and FVC were 30% and 24% smaller,
respectively, in the supplemented cohort. In contrast, the inflammatory response to O3 inhalation, as represented by the percent
neutrophils and the concentration of interleukin-6 recovered in
the BAL fluid at 1 h after O3 exposure was not different for the two
groups. These data suggest that dietary antioxidants protect
against O3-induced pulmonary function decrements in humans.
Keywords: antioxidants; ozone; human; inflammation
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INTRODUCTION |
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INTRODUCTION
METHODS
RESULTS
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Ozone (O3) is a highly reactive gas that is commonly found as a major constituent of photochemical smog. Exposure to tropospheric O3 is a ubiquitous public health problem. It is estimated that over 130 million Americans reside in areas where ambient O3 levels exceed the revised 1996 National Ambient Air Quality Standard of 80 ppb averaged over 8 h, which is not to be exceeded more than three times annually (1).
Both controlled human exposure studies and field studies have shown that levels of O3 found in ambient air induce transient functional and inflammatory changes in the lung. The functional responses have been extensively studied and are characterized by transient airway hyperreactivity and decrements in FEV1 and FVC (2). The inflammatory effects of O3 inhalation include neutrophil infiltration into the airway mucosa (9), elevated levels of neutrophil and of inflammatory mediators (e.g., cytokines and eicosanoids) in bronchoalveolar lavage fluid (BALF), and increased epithelial and vascular permeability (10).
Despite intensive study, the mechanisms through which O3 exposure induces adverse responses in the lung are only partly understood. O3 is a strong nonradical oxidant capable of reacting with virtually any biomolecule, including proteins, nucleic acids, carbohydrates, and membrane lipids (14). It is believed that the effects of O3 are mediated through oxidant damage to cell structures (15), with a possible role for oxidant-initiated activation of cell signaling processes (16). Thus, it has been hypothesized that antioxidant compounds present in the lung may serve to reduce O3-induced lung injury by counteracting oxidative stress.
The lung is protected by a number of enzymatic and nonenzymatic antioxidant defenses present intracellularly and in epithelial lining fluid (17). Among these are the antioxidant
nutrients ascorbate, -tocopherol, and carotenoids. Ascorbate
is a water soluble vitamin capable of reacting as a reductant
O3 directly with or with O3-derived secondary oxidants such as
superoxide anion, hydrogen peroxide, or organic radicals (14,
15, 20). Once oxidized, extracellular ascorbate can be transported intracellularly, reactivated at the expense of reducing
equivalents in the cell, and exported as reduced ascorbate
(21). Ascorbate is also a major reductant used in the regeneration of oxidized -tocopherol, a lipid soluble vitamin that provides a first line of defense against membrane oxidation (22,
23). Aside from the vitamin A-forming activity of some members of the carotenoid family, the physiologic roles of most of
these lipophilic compounds have not been identified. However, certain carotenoids have been implicated as potent antioxidants that may inhibit oxidant damage to cells (24).
Ascorbate has been reported to play an important role in
pulmonary health. National health surveys have found that serum levels of ascorbate are positively correlated with pulmonary function and negatively associated with bronchitis and
wheezing (27, 28), and ascorbate may also have a protective
effect against asthma (29, 30)). A number of studies have suggested that both ascorbate and a-tocopherol are antioxidants
capable of ameliorating in vitro oxidant injury to lung cells induced by cigarette smoke, the main risk factor for the development of lung cancer (31). Similarly, in vitro and animal
studies also suggest that ascorbate and -tocopherol are effective in blunting the toxicity of environmental oxidants such as
O3 and NO2 (32). Considerably less clear is the role of carotenoids in pulmonary health, with some studies suggesting
that 
-carotene may actually enhance the carcinogenic effect
of cigarette smoking and others proposing that other carotenoids, such as lutein and lycopene, are potent antioxidants
that may counteract oxidant-induced lung injury (24, 37, 38).
A series of studies have examined the effect of antioxidant
dietary supplementation with ascorbate and -tocopherol on
decrements in pulmonary function associated with O3 exposure in humans. Chatham and colleagues showed in a controlled exposure study that a combination of ascorbate and
-tocopherol diminished O3-induced decrements in FEV1 and
FVC (39). In a study of asthmatic subjects, those given supplemental ascorbate and -tocopherol before O3 exposure had
better peak flows when subsequently challenged with the
bronchoconstrictive agent SO2 than did control subjects given
placebos (40). More recently, two separate Dutch studies of
cyclists exposed to ambient O3 reported protective effects of a
combination of ascorbate and -tocopherol, with (41) or without -carotene (42), on lung function parameters. Similarly,
Romieu and coworkers showed an inverse relationship between ambient O3 levels in Mexico City and FVC, FEV1 and
FEF25-75 in street workers given placebos but not in those who
were supplemented with a combination of ascorbate, -tocopherol, and -carotene (43).
To date, there have been no controlled human studies of
the role of dietary antioxidants on inflammatory responses in
the lung. In the present study we investigated the effect of dietary antioxidant supplementation on pulmonary function and
inflammatory responses to O3 inhalation. Dietary restriction and
supplementation protocols were used to generate two groups
of subjects, one depleted of and one relatively well supplemented in ascorbate, -tocopherol, and carotenoids. The subjects were then exposed to O3 under controlled conditions,
and pulmonary function endpoints and inflammatory endpoints obtained by assay of BALF were measured. We report
here that supplementation with dietary antioxidants diminished O3-induced decrements in lung function without altering
the inflammatory effects of O3 exposure.
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METHODS |
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METHODS
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DISCUSSION
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Subjects
Thirty one healthy, 18- to 35-yr-old male and female nonsmoking subjects were recruited. A descriptive timeline of events in the study protocol is shown in Figure 1.
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Controlled Exposures
After 7 d of dietary antioxidant restriction, each subject was exposed
to filtered room air at 20° C and 40% relative humidity for 2 h while
intermittently resting and exercising for 15-min periods on a recumbent bicycle or a treadmill (Figure 1). The exercise load was adjusted
for each subject to produce a minute ventilation (
E) of 20 L/min/m2
body surface area. Spirometry was performed before and immediately after the exposure, as described earlier (4). Fourteen days after air exposure, each subject was exposed to 0.4 ppm O3 under the same conditions used for the air exposure (Figure 1). Venous blood was sampled from an antecubital site immediately before and immediately
after the exposure. Subjects answered a subjective questionnaire that
sampled their respiratory symptoms immediately before entering and
after exiting the chamber.
Bronchoalveolar Lavage
According to a standard protocol, the volunteers underwent bronchoscopy within 1 h of completion of exposure to either air or O3, as described previously (44).
Dietary Antioxidant Restriction and Supplementation
At the time of enrollment, subjects completed a food frequency self-assessment questionnaire and received nutritional counseling from a registered dietitian. Subjects were issued a microcassette recorder and were given additional counseling and instructions to keep a recorded log of all of their food and drink intakes, including estimations of portion size, for the duration of the study.
The ascorbate-restricted diet was developed at the U.S. National Institutes of Health (NIH) and is designed to restrict vitamin C intake to less than 60 mg/d (the current U.S. Department of Agriculture [USDA]-recommended daily allowance [RDA] for vitamin C) (45).
For the first week of dietary recording, subjects were instructed to consume their customary diet. During the remaining 3 wk of the study, all subjects were placed on a vitamin C-restricted diet that essentially limited their intake of most fruits and vegetables to no more than one serving per day. Plasma levels of vitamin C in the placebo and supplemented groups were 45.0 ± 4.8 (mean ± SEM) nmol/ml and 37.5 ± 3.6 nmol/ml, respectively.
At 2 wk into the study (Day 7 in Figure 1), subjects were assigned
to a placebo or supplementation group in a double-blind, randomized
fashion. Daily supplementation consisted of 250 mg of ascorbate, 50 IU of -tocopherol, and 12 oz of a commercially available vegetable
cocktail beverage containing primarily carrot and tomato juices. Subjects in the placebo group received corn oil capsules and 12 oz of artificially flavored orange soda that was not fortified with ascorbate.
Supplements or placebos were taken for the 14-d interval between the
air and O3 exposures. Subjects were required to give weekly blood
and urine samples for antioxidant analyses in order to monitor compliance with the diet.
Statistics
Groupwise comparisons were made with two-tailed unpaired t tests. Spirometric data were analyzed with the Mann-Whitney nonparametric t test. Unless indicated otherwise, data are shown as mean ± SEM (n). Statistical significance was taken to be p < 0.05.
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RESULTS |
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Subject characteristics for the 31 subjects who completed the
study are listed in Table 1. Also shown in Table 1 are the reported mean antioxidant intakes for carotenoids, -tocopherol, and ascorbate during the dietary restriction phase of the
study for 23 of the subjects in both groups. In addition, the effect of the dietary regimen on total nutrition was assessed
from self-reported data for 22 of the subjects. Relative to values recorded before dietary restriction, subjects in the placebo
and supplemented groups reported mean daily energy intakes
that were decreased by 323 and 301 calories, respectively, during the week preceding O3 exposure. Despite the decrease in
caloric intake, there was no apparent change in body weight in
either group of subjects after 3 wk of dietary restriction (+0.17 ± 1.1 [mean ± SD] kg and +0.14 ± 1.3 kg for the placebo and
supplemented groups, respectively.
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After 3 wk of dietary restriction, with the last 2 wk including either supplement or placebo administration, subjects in the two study groups had distinct levels of plasma antioxidants. Subjects who were given supplements had serum concentrations of ascorbate, total tocopherols, and total carotenoids that were higher by 85%, 28%, and 27%, respectively, than those in the placebo group (Table 2). There were no statistically significant differences between the two groups in plasma levels of glutathione or uric acid. These findings showed that the restriction/supplementation protocol effectively generated two different populations of study subjects, one supplemented with and the other relatively depleted of antioxidants.
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Pulmonary function testing of subjects after sham exposure
to filtered air showed only small, nonsignificant mean decrements in FEV1 or FVC when compared with values obtained
before the subjects entered the exposure chamber (
= preexposure 
postexposure) (Table 3). There were no differences
between the placebo and supplemented groups in responsiveness of pulmonary function parameters to air exposure. As expected, exposure to 0.4 ppm O3 for 2 h with intermittent moderate exercise resulted in a statistically significant reduction in
the mean baseline-normalized () FEV1 and FVC in both
groups of subjects. The exercise (E) rates for supplemented and placebo subjects were 18.6 ± 2.9 L/min·m2 and 17.3 ± 3.1 L/min·m2, respectively, showing no significant differences between the two groups.
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However, as shown in Figure 2, the magnitude of the effect
of O3 exposure on lung function was blunted in the supplemented subjects relative to their placebo-group counterparts,
as evidenced by O3-induced decreases in normalized FVC and
FEV1 values () in the supplemented group that were 24%
(p = 0.046) and 30% (p = 0.055) smaller, respectively, than in
the placebo group. Similar results were obtained when the
lung function data were expressed either as percents of the respective baseline measures (i.e., divided by the mean of
the pre-air and pre-O3-exposure values) or as the percent
change of the pre-O3-exposure values (i.e., O3 divided by
the O3 preexposure values) (data not shown). A total of four
subjects (Subjects 3, 7, 15, and 17) had a FVC after air exposure that exceeded |0.33| L, suggesting suboptimal reproducibility of spirometric performance by these subjects. Exclusion
of these subjects from analyses yielded O3-induced decreases in mean normalized FVC and FEV1 values () in the supplement group that were 15% and 33% smaller, respectively,
than in the placebo group. Regression analyses showed no significant correlations between individual values of O3-induced
changes in lung function and corresponding levels of plasma
ascorbate, -tocopherol, or carotenoids within either the placebo or supplemented groups (ascorbate versus FVC: r = 0.13, p = 0.49; ascorbate versus FEV1: r = 0.0094, p = 0.96; tocopherol versus FVC: r = 0.22, p = 0.24; tocopherol versus FEV1: r = 0.12, p = 0.28; carotenoids versus FVC: r = 0.12, p = 0.50; carotenoids versus FEV1: r = 0.24, p = 0.19).
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Subject responses to a symptom questionnaire administered before and after O3 exposure showed increased cough,
shortness of breath, and pain on deep inspiration after exposure. With the use of an arbitrary scoring system normalized for
sham exposure, the average severity of these O3-induced respiratory complaints ranged from "trace" (1 arbitrary unit) to
"mild" (2 arbitrary units), with some subjects rating their
symptoms as "moderate" (3 arbitrary units). There were no
statistically significant differences between placebo and supplemented subjects in their ranking of the severity of their respiratory symptoms after O3 exposure (values, presented as
air O3 [mean ± SEM], were as follows: shortness of
breath 0.91 ± 0.34 [n = 12] placebo versus 0.46 ± 0.27 supplemented (n = 13); cough 1.1 ± 0.34 [n = 12] placebo versus 0.92 ± 0.21 [n = 13] supplemented; pain on inspiration
1.0 ± 0.29 [n = 12] placebo versus 1.8 ± 0.26 [n = 13] supplemented).
In accord with results obtained in previous studies, exposure to O3 resulted in pulmonary inflammation that was apparent in the BALF obtained within 1 h after exposure. Levels of polymorphonuclear leukocytes (PMN) neutrophils recovered in the BALF immediately after O3 exposure were significantly elevated (~ 3- to 5-fold) after O3 exposure as compared with those after air exposure for both the supplemented and placebo groups (Figure 3A). In contrast to the pulmonary function effects, the magnitudes of these O3-induced inflammatory increases in percent PMN in BALF were not significantly different in the two groups (Figure 3A). Mean BALF %PMN values were within normal limits (~ 1%) after air exposure.
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Similarly, there was a clear increase in the mean concentration of the inflammatory cytokine interleukin (IL)-6 in the BALF in response to O3 exposure as compared with the values upon air exposure (Figure 3B). As was the case with the PMN data, levels of BALF IL-6 in the supplemented group after O3 exposure were not significantly different from those in the placebo group (Figure 3B). BALF levels of IL-8, total protein, prostaglandin (PG)E2 and fibronectin were not increased by O3 exposure, nor was there a significant effect of antioxidant supplementation on their baseline concentrations (data not shown). Essentially the same findings were obtained when the concentrations of IL-6, IL-8, PGE2 and fibronectin were measured in the first wash fluid as in the BALF (data not shown).
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DISCUSSION |
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RESULTS
DISCUSSION
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This study examined the effect of antioxidant supplementation on pulmonary function and inflammatory responses induced by a controlled exposure to O3 in young healthy subjects consuming an ascorbate-restricted diet. We found a
protective effect of supplementation with a mixture of ascorbate, -tocopherol, and carotenoids on decrements in pulmonary function, but not on the accompanying inflammatory response, caused by acute exposure to a moderate level of O3.
The rationale for selecting ascorbate as the primary target antioxidant for dietary restriction in this study was based on several factors. First, several lines of evidence have shown ascorbate to play an important role in pulmonary health in general, in addition to being an important component of the antioxidant defense mechanism that protects against oxidant injury in the lung. Second, ascorbate intake is relatively safe and simple to manipulate in the diet. Because ascorbate is water soluble, its levels respond quickly to restriction or supplementation. Third, ascorbate was one of the antioxidants that had previously been shown to be effective in diminishing the decrement in pulmonary function induced by O3 inhalation in field studies. Since many food sources of ascorbate can also contain carotenoids, an additional advantage of using an ascorbate-restricted diet was that it may also have had a restrictive effect on carotenoid intake.
The incorporation of an ascorbate depletion regimen in the
study design was influenced by pharmacokinetic evidence that
plasma ascorbate levels vary widely in response to the ascorbate intakes provided by the typical diet in the United States
(45). The concern was that large fluctuations in plasma levels
of ascorbate would obscure any potential effect on O3-induced
lung injury. Thus, the study design attempted to maximize the
difference in plasma ascorbate levels between two groups of
subjects through the combined use of a restrictive diet and dietary supplements. Using this strategy, we generated two populations of subjects with substantially different plasma ascorbate concentrations, although with lesser differences in levels
of plasma carotenoids and -tocopherol. It is difficult to ascertain whether the magnitude of the protective effect observed
in the supplemented group in our study would have been affected without the depletion/supplementation feature of the
study design. However, the dietary restriction did not completely eliminate ascorbate from the subject's diet. In fact, the
diet provided a maximum of 60 mg, which is the current USDA RDA for ascorbate. Furthermore, it must be noted
that previous studies were able to show a protective effect of
dietary antioxidants in nondepleted subjects (39).
Our findings show that antioxidant supplementation of ascorbate-depleted subjects blunted O3-induced decrements in pulmonary function but had no effect on markers of the inflammatory response induced by O3 inhalation. Analysis of lung lavage fluid showed that antioxidant supplementation was effective in raising lung concentration of the antioxidants examined in the study (Hatch and colleagues, in preparation), which could explain the difference between the two study groups in the functional response to O3. It should also be pointed out that the plasma levels measured in the study suggest that although they were depleted of ascorbate, the subjects in the placebo group were not starved of this nutrient, since their dietary restriction allowed a daily consumption of up to 60 mg of ascorbate, which is the current USDA RDA.
The possibility exists that the exposure parameters (i.e., actual O3 concentration, E ventilation, etc.) used in the study were inadequate to induce sufficient pulmonary inflammation
for detection of a protective effect of antioxidant supplementation. The absence of significant O3-induced alterations in the
levels of IL-8 or PGE2, two mediators whose levels have been
previously shown to increase with O3 exposure (12, 13, 46),
may support this possibility. However, the extent of the functional responses observed after O3 exposure were consistent
with, and may even have exceeded, those reported in other
studies that used the same exposure regimen (12, 48). Thus,
the magnitude of the pulmonary function decrements induced
by O3 exposure seen in our study is evidence that the dose of
O3 delivered to the lungs was sufficient to induce inflammation.
An alternative explanation may be found in the observation that dietary restriction appears to have had the unintended effect of restricting the daily caloric intake of the subjects during their participation in the study. Caloric restriction has been shown to protect against O3-induced lung injury in rodents (47). Kari and colleagues fed rats ad libitum or gave them a diet that restricted calorie intake by 25% for 20 d before exposure to O3. They reported that calorie-restricted rats exhibited a markedly diminished inflammatory response to O3 inhalation, including reduced levels of IL-6 and percent PMN in BALF as compared with the animals fed ad libitum. Kari and colleagues attributed the mechanism responsible for this effect in part to an observed increase in ascorbate in the BALF of the calorie-restricted rats (47). Although these findings in rats might lead one to speculate that caloric restriction mitigated the inflammatory response to O3 observed in the subjects in the present study, the magnitude of this caloric restriction was small, and did not result in a change in body weight over a 3-wk period. Moreover, unlike rats, humans do not synthesize ascorbate in the liver, and are therefore entirely dependent on dietary sources for ascorbic acid. In addition, any effect of caloric restriction in this study would have been superimposed on the ascorbate-restriction and supplementation regimens used in the study. Thus, additional study will be needed to explain the lack of an effect of antioxidant supplementation on O3-induced inflammatory endpoints in humans, and the role, if any, of caloric restriction.
Lack of concordance between pulmonary functional responses and inflammatory responses to O3 inhalation has been previously observed. Balmes and coworkers reported no correlation between the level of inflammation or severity of respiratory symptoms and the magnitude of acute decrements in FEV1 and FVC induced by a 4-h exposure of human subjects to 0.2 ppm O3 (49). Hazucha and colleagues showed that pretreatment of subjects with ibuprofen blunted O3-induced decrements in FEV1 by about 70% but did not alter the accompanying BALF neutrophilia found at 1 to 2 h after exposure (51). These findings provide a precedent for our observation that dietary antioxidant status can influence the functional but not the inflammatory response to O3 inhalation, and support the validity of our data.
The mechanism(s) for the protective effects of antioxidants is not completely understood. However, the pulmonary functional effect of O3 exposure is believed to be mediated through neurogenic mechanisms (51) that may originate as an interaction of O3 with cellular components. Antioxidants may preferentially interact with O3 or with secondary oxidants, thereby preventing cell activation. In this regard, the use in this study of a mixture of ascorbate, tocopherol, and carotenoids does not permit an assessment of the relative efficacy of each of these antioxidants in diminishing the functional response to O3 inhalation.
Interestingly, there was one subject in the placebo group (Subject 3) and two subjects in the supplemented group (Subjects 26 and 36) whose pulmonary functional decrements in response to O3 exposure exceeded their respective group means by more than 2 SD. The exclusion of these subjects would result in an enhancement of the protective effect of antioxidant supplementation against O3-induced functional decrements (by 58% for FEV1 and 56% for FVC). Subjects who appear to respond strongly to O3 exposure have been noted in previous studies, and it is unclear whether individuals who appear to be "outliers" should be viewed as being in a separate class of hyperresponders or should be considered to be within the normal range of distribution of O3-induced effects (52). Thus, there is no sound basis for excluding these subjects, and the data reported in the RESULTS section include values for all subjects. However, for the purpose of extrapolating our findings to the general population, it is nonetheless noteworthy that this study may underestimate the magnitude of the protective effect of antioxidant supplementation on the functional response to O3.
Another drawback of the present study was the lack of a
crossover design in the depletion/supplementation regimen.
Although this would have been desirable, it was preempted by
logistical problems, the principal one being the inordinately
long washout period that would have been required to reduce
levels of lipid-soluble -tocopherol and carotenoids to their
baseline values. To achieve an equivalent level of statistical
power, the study compensated for the lack of a crossover by
using a larger number of subjects.
The use of the dietary depletion feature in the study design raises the question of whether differences between the two groups are attributable to increased sensitivity in the placebo group or to increased resistance in the supplemented group. Although robust, the magnitude of the pulmonary function response to O3 in the placebo-group subjects did not suggest a frank hyperresponsiveness. The significant, albeit incomplete, reduction of the response in subjects who were well supplemented therefore supports a protective effect of antioxidant supplementation.
When combined with those of previously published studies (39), the findings we report in the present study show a modest but significant effect of dietary antioxidant supplementation in blunting O3-induced changes in lung function. Antioxidant supplementation may therefore represent a safe and effective strategy with which to decrease pulmonary function responses to this common air pollutant, although without an apparent effect on the severity of the inflammation provoked by O3 exposure.
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Footnotes |
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Correspondence and requests for reprints should be addressed to James M. Samet, Ph.D., EPA Human Studies Facility CB#7315, 104 Mason Farm Rd., Chapel Hill, NC 27599. E-mail: samet.jim{at}epa.gov
(Received in original form August 2, 2000 and in revised form November 13, 2000).
The research described in this article has been reviewed by the Health Effects and Environmental Research Laboratory of United States Environmental Protection Agency and has been approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names constitute endorsement or recommendation for their use.This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments:
The authors gratefully acknowledge the technical and
medical assistance of Sa'id Abdul-Salaam, Andrew J. Ghio M.D., Kay Crissman, Ralph Slade, Lisa A. Dailey, Joleen Soukup, Debbie Levine, R.N., and
Mary Ann Bassett, R.N. We are also indebted to Drs. Frank Kari and Milan
Hazucha for their critical review of the manuscript.
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References |
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