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Department of Environmental Health Sciences, Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland 21205
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ABSTRACT |
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 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exposure of humans to ambient levels of ozone (O3) causes inflammatory changes within lung tissues. These changes have been reported for the "initial" (1- to 3-h) and "late" (18- to 20-h) postexposure periods. We hypothesized that at the late period, when protein and cellular markers of inflammation at the airway surface remain abnormal and the integrity of the epithelial barrier is compromised, bronchial reactivity would be increased. To test this, we measured airway responsiveness to cumulative doses of methacholine (MCh) aerosol in healthy subjects 19 ± 1 h after a single exposure to O3 (130 min at ambient levels between 120 and 240 parts/billion and alternate periods of rest and moderate exercise) or filtered air. Exposures were conducted at two temperatures: mild (22°C) and moderate (30°C). At the late period, bronchial reactivity to MCh increased, i.e., interpolated dose of MCh leading to a 50% fall in specific airway conductance (PC50) was less after O3 than after filtered air. PC50 for O3 at 22°C was 27 mg/ml (20% less than the PC50 after filtered air), and for O3 at 30°C it was 19 mg/ml (70% less than the PC50 after filtered air). The forced expiratory volume in 1 s (FEV1) at the late time point after O3 was slightly but significantly reduced (2.3%) from the preexposure level. There was no relationship found between the functional changes observed early after exposure to O3 and subsequent changes in bronchial reactivity or FEV1 at the late time point. These results suggest that bronchial reactivity is significantly altered ~1 day after O3; this injury may contribute to the respiratory morbidity that is observed 1-2 days after an episode of ambient air pollution.
specific airway conductance; methacholine
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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OZONE (O3), a highly reactive gas, is a natural constituent of the upper atmosphere and is a major component of ambient smog formed by the reaction of primary air pollutants (hydrocarbons and oxides of nitrogen) in the presence of sunlight. An edemagenic lung irritant, O3 affects the conducting airways and alveolar regions. Toxicity of O3 to epithelial surfaces is primarily attributed to reactive oxygen species and ozonation of unsaturated fatty acids present in lung lining fluids (29). Early (3-h) and late (18- to 20-h) responses in the human after whole lung exposure to O3 include an influx of protein, inflammatory cells, and mediators into airway and alveolar surface fluids (2, 4, 35). The presence of these cellular and biochemical markers of injury at the epithelial surface and the increased diffusivity of small molecules within the submucosa postexposure (14) have led to speculation that exposure to O3 modulates bronchial smooth muscle tone and responsiveness to nonspecific challenge (24).
Airway hyperresponsiveness is present in all humans with asthma, at
least when symptomatic. The long-term effect(s) of increased airway
responsiveness are unknown, although it may be a risk factor for the
development of chronic obstructive lung disease (34). Increased airway smooth muscle tone can lead to nonhomogeneous ventilation and limit the maximum oxygenation of pulmonary blood; both
of these physiological responses may be exacerbated by O3 (13, 33). The extent to which O3 affects
airway responsiveness is unclear. Whereas an ambient level of
O3 does not provoke airway hyperresponsiveness either
immediately or 24 h postexposure (26), increases in
airway responsiveness have been observed in the immediate postexposure
period when O3 has been combined with heavy exercise (22) or after high effective concentrations [400-600
parts/billion (ppb)] (21, 25, 32). The duration of
changes in airway reactivity after exposure to high concentrations
(
400 ppb) of O3 has not been determined. A recent study
of asthmatic and healthy subjects exposed to 400 ppb O3 has
reported that airway hyperreactivity was present at a time point at
least 12 h postexposure (20). Moreover, an earlier
investigation reported that, even with high levels of O3,
provocative responses to nonspecific aerosol challenge return to
baseline responsivity (preexposure) by 24 h (21). However, in several chamber studies, inflammation is present in airway
and pulmonary tissues 24 h postexposure (2, 35), and many epidemiological studies have documented that a lag time of 1-2 days follows acute episodes of oxidant air pollution before morbidity effects are observed (28, 36).
The purpose of our study was to test the hypothesis that ambient levels of O3 when combined with ambient temperature conditions can induce a state of airway hyperresponsiveness ~1 day postexposure. As a first step, we used a crossover design to expose healthy, nonasthmatic subjects to filtered air (FA) and O3 at mild- and moderate-temperature conditions. Approximately 1 day after exposure, we evaluated nonspecific hyperresponsiveness of the subjects to cumulative challenge doses of methacholine (MCh) aerosol.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject description and characterization.
Nine healthy subjects (4 women and 5 men) were recruited for the study.
All were nonsmokers, without a history of lung disease, and not
receiving medications for any other disease. Age, anthropometric characteristics, and spirometric lung function values of the subjects are listed in Table 1. The subjects had a
mean age of 26 ± 2 (SD) yr and were free of respiratory infection
at the time of the evaluations. Subjects' mean values of the forced
vital capacity (FVC), the forced expiratory volume in 1 s
(FEV1), and the midmaximal expiratory flow rate
(FEF25-75) were >92 ± 11% (SD) of predicted. Consent was obtained from the subjects before admission to the study,
and the research had the approval of the University Human Research
Review Board.
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Experimental protocol. An initial (baseline) evaluation of pulmonary function and the treadmill (model Q55, Quinton Instruments, Seattle, WA) exercise required to attain cumulative ventilation per minute during exercise that was approximately equal to eight times the volume of the FVC was conducted on each subject. On 4 additional study days, the subjects returned to the laboratory at an appointed time and were exposed for a 130-min period to either FA or O3 in a walk-in chamber facility (14.2 m3). For each exposure (FA and O3), chamber air was held at 45-55% relative humidity and at a mean temperature of either 22 or 30°C. Exposure of a given subject commenced at the same time of the day; the order for crossover of the exposures (FA at 22°C, FA at 30°C, O3 at 22°C, O3 at 30°C) was randomized with a minimum 10-day interval between the reexposure study days. Spirometry (at least 3 determinations) was measured before exposure, at midexposure, and at 10 min postexposure, and measurements of specific airway conductance (sGaw) and thoracic gas volume were accomplished at the before-exposure and 10-min postexposure assessment times by using a body plethysmographic method (Sensor Medics, Anaheim, CA) (7); spirometric and plethysmographic measures were repeated 18-20 h (~1 day) postexposure. Immediately after these functional measures at ~1 day postexposure, the measurement of airway hyperresponsiveness to cumulative MCh aerosol challenge was assessed.
Methods of exposure. The chamber exposure facility has been described previously (14). Air transport to the chamber was prefiltered and had a one-pass design with 30 changes of chamber air/h. Chamber O3, which was continuously monitored by an ultraviolet O3 photometer (model 1003-AH, Dasibi, Glendale, CA), was generated from a 100% O2 source by a high-frequency electric field (model G1-L, PCI Ozone, West Caldwell, NJ) and mixed with the FA supply before being added to the chamber. During the O3 exposures, a standard concentration regimen was used, i.e., initiated at 120 ppb, ramped to 240 ppb, and then returned to the starting concentration by the conclusion of the exposure regimen. A ramped or pyramid-shaped profile of O3 concentrations during exposure has been utilized previously (11, 14, 16) and is selected as an exposure plan that realistically resembles urban conditions (product of concentration × time for our exposure plan would be equivalent to 130 min of O3 exposure at a single concentration of 175 ppb). For the initial 120 min of each exposure, a subject alternated between 10-min periods of rest and mild treadmill exercise; exposures concluded with an additional 10 min of exposure under rest conditions. The treadmill speed and grade necessary to obtain the targeted minute ventilation, i.e., cumulative ventilation per minute during exercise that was approximately equal to eight times the volume of the FVC, were predetermined on the baseline visit before commencement of exposures. Exercise is frequently used during chamber exposures to increase minute ventilation to mimic an individual performing light activity under ambient conditions.
During exposure a subject could freely choose between nasal, oral, or oronasal breathing modes except for a 2-min period to assess minute ventilation during exercise periods when oral breathing and expiration into a dry-gas meter (American Meter, Philadelphia, PA) was obligatory.MCh challenge. Approximately 18-20 h postexposure, the subjects returned to the laboratory for assessment of airway responsiveness to buffered MCh aerosol. For bronchoprovocation testing with MCh aerosol, the subjects were initially challenged with saline (0.9%) aerosol, followed by increasing doses of MCh diluted in 0.9% saline. MCh chloride (Sigma Chemical, St. Louis, MO) solutions were made up fresh for each test challenge. For saline and each MCh dose, the subjects inhaled five aerosol breaths starting at rest (functional residual capacity) position and inhaling an inspiratory capacity breath, followed by a 5-s breath hold at full inspiration and then a slow exhalation. To favor aerosol delivery, the subjects were assisted in maintaining the inspiratory flow at <0.4 l/s during the aerosol inhalation by a visual airflow indicator (model Elektro-2, Respiratory Care Center). MCh aerosol was generated by a jet nebulizer (model 646, DeVilbiss) powered with FA at 30 psi; nebulization of MCh for each challenge breath commenced after the subjects inspired a 150-ml volume and lasted for 0.6 s. The starting dose level of MCh was 2.5 mg/ml, which was then increased on each subsequent challenge to a maximal level of 22.5 mg/ml. After the fifth aerosol breath at each MCh dose, subjects relaxed for 3 min and then had spirometric and plethysmographic responses measured for each cumulative MCh dose inhaled. The subjects did not demonstrate changes in spirometric flows, and therefore airway responsiveness was determined as the cumulative MCh dose leading to a decrease in the sGaw of at least 50% from the value of the sGaw observed after the saline challenge.
Statistical analysis.
Pulmonary function volume measurements were corrected to body
temperature and pressure of gas saturated with water vapor
(BTPS), and the trials with the highest FVC and
FEV1 for preexposure, midexposure, end exposure, and ~1
day postexposure were utilized for statistical analysis. Means ± SE were calculated for spirometric function and plethysmographic
measures with standard statistical methods. On the basis of the percent
decrease from the reference value (0.9% saline) of the sGaw after each
succeeding concentration of MCh, the following equation
(1) was used to calculate the interpolated
PC50 (aerosol concentration of MCh leading to a 50% fall
in the sGaw)
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Measures of functional response.
By design, during the exercise periods of each chamber exposure, a
targeted minute ventilation was achieved. The mean minute ventilation
attained by the subjects for the exercise periods are presented in Fig.
1. Mean minute ventilations ranged
between 36.40 ± 0.5 (SE) and 38.7 ± 1.0 l/min and were not
significantly different between exposures. In general, during exposures
to O3, the subjects reduced the depth of the tidal volume
with a compensatory increase in the frequency of respiration, i.e.,
mean tidal volume during exercise periods for exposures to
O3 at 22 and 30°C were 1.84 and 1.72 liters compared with
the mean tidal volumes of 2.02 and 1.89 liters for exposures to FA at
the respective temperatures. The mean changes (before MCh challenge) in
pulmonary function of the subjects after exposures to O3
and FA for the different temperature conditions are presented in Fig.
2. For the FVC and FEV1, the
responses at midexposure and end exposure and at ~1 day postexposure
are compared with the functional values observed preexposure.
Reductions in the FVC and the FEV1 were significant at midexposure and end exposure to O3 (mean decrements were
on the order of 2-7%) for both ambient temperature conditions (22 and 30oC) compared with responses after FA exposure at the
respective temperatures. The FEV1 remained reduced at the
1-day-postexposure time point compared with the preexposure value;
although the change was small, i.e., a mean decrease of 2.3% from the
preexposure level, this reduction was significant. The FVC (Fig. 2) had
recovered to baseline by the 1-day-postexposure time point.
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Measures of response to MCh challenge.
At the 1-day-postexposure time point, the change in sGaw of the
subjects to cumulative concentrations of MCh aerosol was a sensitive
index for the assessment of airway responses. Measures of the FVC and
the FEV1 were not sensitive in our healthy subjects for
assessing airway responsiveness to MCh challenge. Mean values of the
change in the sGaw are compared in Fig. 4
for each exposure condition, and responses to succeeding doses of MCh
are expressed as a percent change from the response to diluent, i.e.,
0.9% saline. At the starting point of each MCh challenge, the sGaw was
not significantly different from the preexposure value of the sGaw (see
Fig. 3). Compared with the responses after exposure to FA, the airways
were clearly more responsive to MCh after exposure to O3.
sGaw at the highest MCh challenge concentration (22.5 mg/ml) for
O3 exposures and ambient temperature conditions of 22 and 30°C were significantly reduced compared with the corresponding FA
exposures. There was the tendency for the sGaw response to MCh to be
enhanced when O3 was combined with the warmer exposure condition.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study in healthy adult nonsmokers demonstrates that airway hyperresponsiveness can be induced by O3 exposure and measured ~1 day postexposure. Nonspecific aerosol challenge clearly demonstrated that the airways were hyperresponsive 1 day after exposure to O3 compared with FA (P < 0.01). There was a tendency for the warmer exposure condition, i.e., 30 vs. 22°C, to enhance this response. As expected, mean spirometric indexes of airway function (e.g., FEV1) were decreased significantly during and acutely after exposure to O3 (P < 0.05), and on average the FEV1 at 1 day postexposure had almost completely recovered (97.7% of the preexposure value; P < 0.05).
This is the first human study to characterize an O3-induced increase in airway responsiveness ~1 day postexposure. The subjects were exposed for 130 min to a ramped O3 concentration (mean level of 175 ppb) at two ambient temperatures (22 and 30°C) and with a mild level of treadmill exercise. An additional functional index that was abnormal ~1 day postexposure was the FEV1, and although the response data were not included in the RESULTS, the FEF25-75 was similarly slightly and significantly reduced (mean decrease of 4.0%; P < 0.05) below the baseline values of the FEF25-75 recorded ~24 h earlier, preexposure to O3.
Our laboratory previously noted the failure of spirometric indexes of expiratory airflow to fully recover ~1 day postexposure to O3 (15, 16). In the present study, O3-induced changes in sGaw during cumulative MCh aerosol challenge did not correlate with delayed recovery in the FEV1 or FEF25-75. It has been suggested that changes in lung function during and immediately postexposure to O3 are related to irritant and neural mechanisms (19, 27), whereas the delayed changes in the FEV1 and FEF25-75 1 day postexposure may represent epithelial injury, receptor dysfunction, and inflammation at distal airway sites (14, 25).
Increases in nonspecific airway responsiveness have been observed
acutely postexposure (immediately to 12 h after exposure) in
healthy subjects exposed to O3. These changes in airway
reactivity have been reported for both low ambient (120-240 ppb)
and high effective (400-600 ppb) chamber concentrations of
O3 (5, 21, 32). The acute development of
airway hyperreactivity may be vagally mediated, and the responsiveness
can be reversed with atropine premedication (18, 21).
Investigations have utilized single- or multiple-exposure plans
(9, 22); however, assessments of hyperreactivity were not
usually conducted at later time points (i.e., 1 day postexposure) when
O3-induced inflammation of the airways and lung parenchyma
have been well characterized (11). In one study of healthy
subjects, an O3 concentration of 200 ppb did not provoke
airway responsiveness either immediately or 1 day postexposure
(26), although hyperresponsive airways have been reported
after exposure to high concentrations (400-600 ppb) of
O3 (18, 32). The duration of changes in airway
reactivity after exposure to high effective concentrations (400 ppb)
of O3 is also not certain. Airway hyperreactivity was found
at a time point at least 12 h postexposure in asthmatic and
healthy subjects exposed to 400 ppb O3 (20);
however, an earlier investigation suggested that, even at high
concentrations of O3, airway responsiveness to either
histamine or MCh aerosol returns to baseline responsivity (preexposure)
within 24 h (18). Our results in healthy subjects demonstrate that airway hyperresponsiveness to MCh was clearly present
1 day postexposure. Airway conductance measures in our subjects had
returned to baseline values at the start of the MCh challenge.
Airway responsiveness to cumulative MCh challenge was significantly
increased by exposure to O3 at both the 22 or 30°C exposure temperatures, and there was a tendency for O3 in
combination with warmer exposure conditions to induce a greater degree
of airway responsiveness. Similar to other phenotypic markers of O3 exposure (2, 16, 31), a range in
sensitivity of the airway response to O3 was present from
no change in airway reactivity (subject 9) to a >50%
decrease of the PC50 (subject 4). We are uncertain why our results using ambient levels of O3
(120-240 ppb) induced responsiveness 1 day postexposure, whereas
investigations using higher effective concentrations of
O3 did not find airway hyperreactivity to be increased at a
similar time postexposure (18). Differences in protocol
design existed because our protocol evaluated airway reactivity by
using cumulative doses of an agonist at a single time point, ~1 day
postexposure, whereas prior investigations may have assessed reactivity
immediately and 1 day postexposure. A potentially confounding factor in
serial measurements to assess airway responsiveness is that an initial
provocative challenge may alter the response to a subsequent challenge
(3).
It has been previously demonstrated that exposure to FA at moderate differences in ambient temperature (20-30°C) did not alter spirometric indexes of airway function; however, when normal subjects exercised under hot, humid conditions (37°C and 60% relative humidity), lung function improved significantly (8). However, the benefit of ambient heat on airway function appears to be lost when heat stress is combined with a high effective concentration of O3. For example, similar to our results with ambient levels of O3, exposure to an O3 concentration of 500 ppb at temperatures of 25 and 31°C induced significant but similar decrements in the FEV1 (decreased by 8% from preexposure value); however, at still warmer temperatures, i.e., 40°C, the O3-induced decrease in the FEV1 was even greater, with an average decrement of 13% (10). For healthy subjects, heat stress alone would not be expected to cause these functional changes, but a warmer exposure condition would cause an increase in ventilation during exercise periods of the exposure. An increase in minute ventilation during exposure to O3 would increase the O3 dose delivered to the respiratory tract. As part of our experimental design, we controlled the level of treadmill exercise and monitored minute ventilation to attain and duplicate the levels of minute ventilation under the four exposure conditions (Fig. 1). Thus the effects on airway responsiveness we observed with O3 were not related to differences in minute ventilation during exercise periods of the exposures.
A number of mechanisms could initiate the O3-induced airway
hyperreactivity we observed ~1 day postexposure. First, there may be
an immediate effect of O3 and the airways. Inasmuch as O3 is highly reactive, it interacts immediately with the
tissue or fluids with which it comes into contact, i.e., epithelial
lining fluid or membranes of resident airway cells (macrophages and
epithelial cells) (11). Because O3 does not
penetrate cells, it can lead to several pulmonary and nonpulmonary
events, and a cascade mechanism has been proposed to account for its
toxicity (29). For example, O3 reacts with
unsaturated fatty acids at the air-tissue barrier to form lipid
ozonation products that include aldehydes, hydroxyhydroperoxides, and
Creigee ozonide; lipid by-products in turn can activate epithelial membrane lipases and release additional mediators onto the airway surface. Support for this sequence includes increased levels of mediators such as PGF2
, proinflammatory cytokines, and
reactive oxygen intermediates in airway fluids sampled ~24 h
postexposure to O3 (11). These by-products and
mediators may also upregulate transcription factors such as nuclear
factor-
B and proinflammatory genes (6) as well as
modulate airway reactivity to nonspecific stimulation
(24).
In addition, desquamation and disruption of airway epithelial membranes by O3 would increase accessibility of MCh and other inhaled irritants and cellular mediators to epithelial sensory nerves and the bronchial musculature (8). In support of this mechanism, our laboratory previously reported that ~1 day after exposure of healthy subjects to O3 there is a loss of epithelial integrity and an increase in airway permeability (14). Other than a temporal association of the two responses (changes in airway responsiveness and epithelial permeability) being present at the same time point postexposure to O3, we do not have additional evidence linking the duration of airway responsiveness to the loss of epithelial integrity. In a large-animal model, however, we have found that O3-induced changes in airway permeability can persist for up to 7 days postexposure (12). In addition, there is increasing evidence in animal models that O3-induced airway hyperreactivity is modulated in part by neuronal effects and impairment of M2 muscarinic autoreceptors that are present on parasympathetic nerves in the lung and normally function to attenuate vagally induced bronchoconstriction (17).
In summary, our study has shown that an increase in airway reactivity to nonspecific stimulation occurs ~1 day postexposure to O3 in healthy subjects. There was a tendency for the airway responses to MCh to be enhanced by an elevation in temperature during exposure, and although significant, but slight, decrements in indexes of forced expiratory flow were also apparent ~1 day postexposure to O3, these spirometric changes were not associated with alterations in airway hyperresponsiveness. Effects of inhalable irritants on the pattern of breathing, i.e., rapid and shallow breaths, may be enhanced by hotter exposure conditions and shift regional deposition of O3 into dependent airways (23). Because frequently O3 generation occurs during periods of increasing ambient temperature (30), our study suggests that O3-induced airway responsiveness may be exacerbated during summer heat waves and causal to an increase in respiratory morbidity during episodes of oxidant air pollution.
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ACKNOWLEDGEMENTS |
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We express appreciation to Dr. Clarke Tankersley for comments and guidance with statistical measures.
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FOOTNOTES |
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This research was supported by National Heart, Lung, and Blood Institute Grant HL-62641 and National Institute of Environmental Health Sciences Grant ES-03810.
Address for reprint requests and other correspondence: W. M. Foster, Pulmonary and Critical Care Medicine, DUMC PO Box 2629, Durham, NC 27710 (E-mail: foste028{at}mc.duke.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 17 May 2000; accepted in final form 15 June 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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E) measured
during exercise periods of the exposures to filtered air (FA) and ozone
(O3). Values are the means ± SE of 
