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Physiology Division, Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205
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ABSTRACT |
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 Top
 Abstract
 Introduction
Methods
Results
Discussion
References
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The influence of local exposure to ozone (O3) on respiratory epithelial permeability of sublobar lung segments was studied by using aerosolized 99mTc-diethylenetriamine pentaacetic acid (DTPA; mol wt, 492). Two bronchoscopes were inserted through an endotracheal tube in anesthetized, mechanically ventilated, mixed breed dogs and were wedged into sublobar bronchi located in the right and left lower lobes, respectively. Segments were ventilated via the bronchoscope with 5% CO2 in air delivered at 200 ml/min, and an aerosol of 99mTc-DTPA was generated and delivered through the scope and into the sublobar segment over a 30-s period. Clearance of 99mTc-DTPA was measured simultaneously from right and left lower lung segments at baseline and 1, 7, and 14 days after a 6-h sublobar exposure to filtered air or 400 parts per billion O3. O3 treatment significantly decreased the clearance halftime (t50) of 99mTc-DTPA by 50% from the baseline mean of 32.3 to 16.0 min at 1 day postexposure. After 7 days of recovery, t50 was still reduced by 28.8%; however, by 14 days postexposure, clearance of 99mTc-DTPA had recovered, and the t50 had a mean value of 30.0 min. 99mTc-DTPA clearance was not altered by exposure to filtered air, and t50 values were comparable to baseline at 1, 7, and 14 days postexposure. These results reveal that a single local exposure to O3 increases transepithelial clearance, but only for epithelia directly exposed to O3, and that 7-14 days of recovery are required before permeability to small-molecular-weight solutes returns to normal.
respiratory epithelial integrity; peripheral airway resistance; 99mtechnetium-diethylenetriamine pentaacetic acid
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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. The injurious effects of O3 on respiratory tissues of humans and animal models have been studied from various perspectives (23). O3 is an edemagenic lung irritant that affects both the airways and alveolar regions. Toxicity of O3 to pulmonary tissues 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 of humans to whole lung exposure to O3 include an influx of protein, inflammatory cells, and mediators into airway and pulmonary surface fluids (5, 32). The presence of these cellular and biochemical markers has suggested that the integrity of cellular membranes of respiratory epithelia is impaired by O3. Pulmonary permeability to small solutes placed on the epithelial surfaces, e.g., 99mTc-labeled diethylenetriamine pentaacetic acid (Tc-DTPA; mol wt 492), increases in the acute period immediately after whole lung exposure to O3 (21).
Direct evidence of an increase in respiratory epithelial permeability in humans was also found to be present ~1 day postexposure, and alterations in epithelial barrier function did not occur uniformly throughout the lower respiratory tract (10). Differences in regional impairment may reflect inherent variations in sensitivity of respiratory epithelial tissues to O3 and/or nonhomogeneous regional ventilation and delivery of O3 to these tissues during whole lung exposures (9). In addition, the time course of recovery of respiratory epithelial integrity after a single exposure to O3, beyond the 1-day postexposure time point, is unknown. Information on the reversibility and the time course for tissue repair is essential to the understanding of the mechanisms of action and evaluation of strategies that may limit or moderate epithelial injury from exposure to oxidant gases such as O3. Thus the main objectives of the present investigation were 1) to investigate O3-induced lung injury in an in vivo animal model, in which exposure was homogeneous with delivery of O3 gas limited to an isolated lung segment, and 2) to establish the time course of recovery after a single O3 challenge. Radiolabeled aerosols were utilized to quantitate epithelial barrier function and regional clearance of Tc-DTPA. The clearance of radiolabeled chelate DTPA across epithelial surfaces of distal airways and the lung parenchyma was assessed noninvasively by external detection. The clearance rate of small radiolabeled solutes from pulmonary tissues under normal conditions is linear, with clearance halftimes (t50) of <100 min. It has been generally assumed that the clearance of solute, e.g., radiolabeled chelate 99mTc-DTPA, follows a simple first-order process and that solute clearance through the respiratory epithelium and into the blood and lymphatic channels is complete within a few hours (34).
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Dogs were handled and maintained in accordance with the standards set forth in the Policy and Procedures Manual published by the Animal Care and Use Committee of The Johns Hopkins University School of Hygiene and Public Health. The Animal Care and Use Committee is sanctioned by the American Association of Accreditation for Laboratory Animal Care.
Experimental protocol.
Conditioned, male, mixed breed dogs (n = 7) with a mean weight of 18.1 ± 0.8 (SE) kg and 1-3 yr of
age were studied. Each animal was evaluated once with the protocol.
However, one dog in the series was studied twice, with a 60-day
interval between each experimental protocol. An initial evaluation
(baseline study) of regional lung clearance of Tc-DTPA was performed by
gamma-camera imaging of the dogs in a supine position and from the
ventral aspect. Animals were lightly anesthetized with a thiopental
sodium infusion (4-6
mg · kg
1 · h1)
supplemented with fentanyl citrate (25-50 µg iv every 15-20 min) and intubated with a cuffed endotracheal tube. Dogs were ventilated by a mechanical volume respirator (tidal volume: 17 ml/kg
body weight). Alveolar ventilation was monitored by using end-tidal
levels of respiratory gases. A fiber-optic bronchoscope (5.5 mm OD;
Olympus BF type P10; Olympus, New Hyde Park, NY) was placed through the
endotracheal tube and visually guided and wedged within a bronchial
airway (lumen diameter = ~5 mm) in the left lower lobe (LLL) of the
lung. A second fiber-optic bronchoscope was passed through the
endotracheal tube and positioned within a bronchial airway (lumen
diameter = ~5 mm) of the right lower lobe (RLL) of the lung (14). A
map of the airway branching pattern was made and used at various times
throughout the study to relocate each sublobar location. A polyethylene
catheter (PE190; 1.2 mm ID, 1.7 mm OD) attached to a pressure
transducer was threaded through the port of the bronchoscope and was
used to record sublobar pressure (Pb). The wedged segment was
ventilated with 200 ml/min of 5%
CO2 in air, which was delivered
around the catheter and through the port of the bronchoscope (15).
Peripheral airway resistance (Rp) of each wedged segment was determined
at functional residual capacity, when Pb reached a plateau and the
pressure in the surrounding noninstrumentated lung equaled zero. At
that time, Rp (in cemtimeters water per milliliter per second) is
calculated and equal to Pb divided by 200 ml/min (14, 15).
1 · h1
iv). Two bronchoscopes were again passed through the endotracheal tube
and wedged within the same sublobar segments that had been evaluated
for Rp and Tc-DTPA clearance at baseline. Filtered air and
O3 [400 parts per billion
(ppb)] were delivered simultaneously via bronchoscopes to
contralateral sublobar lung segments over a 6-h period, after which the
animals were permitted to recover. At 1, 7, and 14 days after the 6-h
exposure periods, Rp and Tc-DTPA clearances were repeated, with
anesthesia, radio-aerosol, and Xe techniques identical to those
described above for the baseline assessments of Tc-DTPA clearance. One
animal in the series (dog 1) was studied twice, with the full
experimental protocol. For this animal, the exposure assignment for
filtered air and O3 to the
respective sublobar segments was reversed in the second study from the
assignments utilized in the first study.
Acute sublobar exposure to O3. Filtered room air [23°C, ~55% relative humidity (RH)] was pumped via a Harvard ventilator through a computer-controlled valve that directed a stream of air into a stainless steel flow-through chamber containing a low-pressure mercury lamp (the O3 generator). O3 output from the generator was mixed with 5% CO2 in air to provide a final O3 concentration of 400 ppb. The O3 concentration to the delivery channel of the bronchoscope was sampled every 30 s with an O3 monitor (model 1003-AH, Dasibi Environmental, Glendale, CA). For the local sublobar exposure to filtered air, a stream of air from the filtered room air supply was mixed with 5% CO2 in air and directed to the delivery channel of the second bronchoscope. Temperature and RH of inspired gas and delivered mixtures were maintained at 21-23°C and 55-60% RH, respectively.
Pulmonary clearance measurement. Aerosolized low-molecular-weight solutes have been commonly used to gauge the permeability of the respiratory epithelium (6). The Tc-DTPA used to assess lung clearance of small solutes was freshly prepared as 99mTc-labeled DTPA (Medi-Physics, Arlington Heights, IL). Tc-DTPA sampled from the reservoir postnebulization was assayed for unbound 99mTc with silica gel media and thin-layer chromatography to verify the labeling procedures (2).
Immediately after deposition of the Tc-DTPA aerosol, the initial distribution and clearance of aerosol were measured with the dog supine and imaged from the ventral aspect by gamma camera. The camera was set with an 18% window around the peak energy of 99mTc and shielded by a parallel-hole collimator. Clearance of Tc-DTPA from the lung was then monitored over a 30-min period, and lung images were stored by computer (Sopha Med, Columbia, MD) for subsequent analysis.Analysis of radioimages.
Tc-DTPA deposition and clearance were analyzed by using techniques
described previously by our laboratory for both humans and the dog
model (10, 11). For the clearance of Tc-DTPA, activity time plots for
regions of interest, as demarcated by the Xe scans, were constructed
for the respective LLL and RLL segments. The retention of Tc-DTPA
activity within the regions of interest during the washout (30 min) was
corrected for radioactive decay and expressed as a percentage of the
radioactivity deposited in the lung segment immediately after
inhalation. The natural logarithm of the proportion of radioactivity
remaining within a sublobar segment was plotted as a function of time.
The semilogarithmic regression line for the interval from peak
radioactivity after deposition to the end of the observation time point
was determined by least squares fit. The slope of the line is
determined according to the equation A = Aoekt,
where Ao is the y intercept, and
A is the count rate at any time
t. The slope of the line is the rate
constant (k) for the clearance of
Tc-DTPA from the lungs, and it can be converted to half-life of
retention (t50,
clearance index) by
t50 = 0.693/k (27, 35). For one of the dogs
(dog 5) the baseline clearance plots
of Tc-DTPA for contralateral LLL and RLL sublobar segments are shown in
Fig. 1. Corrections to the analysis of
Tc-DTPA clearance were not made for nonpulmonary epithelial
radioactivity, because it has been demonstrated that such corrections
over the 30-min time period do not significantly affect the measured
clearance rate (3, 26, 31).
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Statistical analysis. Comparisons of treatment (filtered air and O3 exposures) on the Rp and Tc-DTPA clearance data were accomplished by a paired t-test analysis. Effects of treatment and recovery time on Rp and Tc-DTPA clearance were analyzed with analysis of variance for repeated measures and a Newman-Keuls post hoc test for significance of the differences. A P value <0.05 was considered significant. Analysis of associations between the changes in Rp and alterations in Tc-DTPA clearance at similar time points after exposure were performed by using a linear regression and method of least squares.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Control.
At baseline, the clearance index
t50 for Tc-DTPA
from wedged regions of the sublobar lower lobes
(n = 12, 2 segments per animal) had a
mean value of 23.62 ± 2.6 (SE) min. However, the LLL was found to
exhibit significantly slower clearance
(P < 0.01) than the sublobar segment
of the contralateral RLL. The paired values of
t50 for right and
left sublobar segments and their respective means are presented in Fig.
2. On average, the clearance
t50 of the sublobar segments in the LLL had a value
of 33.50 ± 4.1 (SE) min, ~20 min slower than the mean clearance
t50 observed in the sublobar segments of the RLL
(13.73 ± 1.9 min).
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O3 and filtered air.
Tc-DTPA clearance after localized exposure to
O3 and filtered air was restudied
at 1, 7, and 14 days postexposure. In five dogs, a sublobar segment in
the LLL was treated with O3, and
the RLL was exposed to filtered air. In an additional three dogs, this
assignment was reversed, with respect to the lower sublobar segments
being challenged with O3 or
filtered air. The results for Tc-DTPA clearance posttreatment are
listed along with the baseline clearance values in Table
1. Localized
O3 treatment speeded the clearance
of Tc-DTPA; i.e., when reevaluated 1-day postexposure, the mean
t50 of the
O3-exposed sublobar segments was
faster on average by 50.5% (P < 0.01) when compared with the mean
t50 at baseline.
At 7 days postexposure to O3, the
permeability of the epithelium had still not returned to normal, and
Tc-DTPA clearance was still ~29% faster when compared with the
baseline t50
(P < 0.01). However, by 14 days
postexposure, the epithelium had recovered, and permeability
t50 for Tc-DTPA were now comparable to the baseline
values of t50.
For comparison, the clearance t50 for the
filtered-air-treated lung segments are also included in Table 1. After
exposure to filtered air, permeability of the exposed segments to
Tc-DTPA remained virtually unchanged, with mean clearance
t50 of 27.3, 25.6, and 24.3 min at 1, 7, and 14 days postexposure, respectively.
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1 · s.
The individual and mean values of Rp are within the range of Rp values
reported previously. For example across six different lobes of the
mixed breed dog the baseline Rp has been found to vary from 0.4 to 0.7 cmH2O · ml1 · s
and the differences in Rp between lobes are not statistically significant (14).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study demonstrates that permeability of the peripheral airway epithelium is altered by a local O3 challenge and can require from 7 to 14 days postexposure to recover. As a control, local exposure of a contralateral sublobar segment to filtered air did not influence the barrier function of the epithelium. This is based on the subsequent clearance and permeability of radiolabeled Tc-DTPA aerosol that serves as an indicator of epithelial integrity of the sublobar segment. Permeability of Tc-DTPA is repeatable within a given lung segment, but it is location dependent and is not homogeneous throughout the lung. We also observed that Rp within sublobar lung segments was significantly increased by a localized O3 challenge, and this response appeared to be direct, without any influence on contralateral segments exposed to filtered air and thus confined to the O3-challenged segment. Recovery was more rapid from O3-induced changes in Rp (Fig. 3) than from O3-induced alterations in epithelial permeability (Table 1).
The present investigation, in which O3 was delivered to an isolated sublobar lung segment at a concentration of 400 ppb, is the first to characterize directly the localized injury of the respiratory epithelium and to follow the time course of recovery. We hypothesize that the increase in 99mTc-DTPA clearance of the lung segment represents a change in epithelial membrane permeability as a result of O3-induced damage to cellular membranes and sterol-dependent materials lining peripheral airway surfaces of the lung (20, 30). Oxidant-mediated injury of cellular membrane components and epithelial lining fluids probably leads to repair mechanisms and subsequent upregulation of lung sterol metabolism, but the time course of these events has been unknown (19, 33). Both of these O3-related effects [loss of cellular membrane integrity and destruction of surfactant (28)] can increase lung clearance of 99mTc-DTPA (7, 27). A number of animal models have been evaluated to monitor recovery of pulmonary tissues after short exposures to O3. These have usually relied on samples of lung lavage fluid to estimate permeability changes of the epithelium (1, 18). For example, in investigations of rats at 0, 1, 3, and 8 days after single exposures to 1.8 parts/million O3, increased levels of albumin in lavage fluids had returned to baseline by 8 days (1). Human lung lavage, when collected 1-18 h after a single exposure to O3, similarly substantiates an increase in lavageable protein and is suggestive of O3-induced changes in epithelial permeability (4). O3 increases permeability of the lung epithelium to Tc-DTPA when assessed at 24 h postexposure (10), but the time course of recovery for epithelial tissues is unknown. Chronic exposure to cigarette smoke can also increase pulmonary epithelial permeability, but permeability recovers toward normal within 7 days of smoking cessation (25).
Changes in lung volume have been induced in both humans and dog models to show that hyperexpansion can accelerate lung clearance of DTPA. This effect is generally attributed to an expansion in the surface area for diffusion or to stretching of intercellular pores with a resultant increase in permeability (24, 31). In our experiments, we did not have a direct measurement of the anesthetized animals' resting lung volume, although the dogs were maintained on a constant-volume respirator while 200 ml/min of gas were delivered to the wedged segment throughout the delivery and measurement periods of DTPA clearance. At 1 day after exposure to O3, when Rp was significantly elevated, a volume change caused by slow emptying of gas distal to the wedged segment may have influenced DTPA clearance from the segment. However, at later points (7 and 14 days after exposure), the changes in Rp were not significant, and any volume effects on DTPA clearance as a result of emptying and Rp would not have influenced our results.
The size and amount of DTPA aerosol delivered to the lung can influence the clearance rate of the DTPA (17). This effect was not influential in our measurements because the size, volume, and delivery time of DTPA aerosol were controlled with equal amounts of aerosol consistently delivered to the wedged segments at baseline and during retesting of permeability (1, 7, and 14 days postexposure). After whole lung delivery of Tc-DTPA aerosol, apical-to-basal differences in DTPA clearance have been observed (26). However, if Tc-DTPA is instilled directly onto a specific airway surface in the dog, epithelial permeability is uniform between airway sites [i.e, trachea, and 5th and 10th generation airways (36)]. Thus our observation of right-to-left differences in epithelial permeability of sublobar segments, using an isolated aerosol delivery technique, is unique. In human studies that used spatial resolution techniques, we have noted an association between permeability of radiolabeled DTPA and aerosol penetration, whereby the more peripherally deposited Tc-DTPA exhibited the fastest clearance (10). In the present dog study, although we assessed ventilation to the isolated sublobar segments by using 133Xe gas, we did not acquire steady-state or equilibrium 133Xe scans that are required for estimating penetration of the radiolabeled aerosol (9, 10). Thus we are uncertain of the mechanism for the right-to-left differences in sublobar epithelial permeability, but the differences may be related to several factors, such as lung and airway morphology and aerosol penetrance that have been proposed previously as explanations for regional differences in Tc-DTPA clearance from the dog lung (26).
During exposure to O3, neural afferents in the lung and the bronchial musculature (16) may be stimulated by products of reactive oxygen species (generated by ozonolysis of unsaturated fatty acids), such as hydrogen peroxide, and lead to the development of airway bronchoconstriction. In addition, recent histological studies in humans have demonstrated that O3 alters subepithelial sensory nerves within the bronchial mucosa and enhances the local release of bronchoconstrictive mediators, such as tachykinins and neurokinins (22). O3 can also lead to cellular and biochemical changes in the lower respiratory tract that are characteristic of an acute inflammatory response. For example, lung lavage fluid that is sampled ~1 day postexposure to O3 contains increased levels of polymorphonuclear leukocytes and soluble markers of inflammation, as well as markers of epithelial permeability (5). Airway inflammation and mechanical damage to the bronchial epithelium are likely to be contributory factors to the loss of epithelial integrity and the increase in permeability to Tc-DTPA that we observed, and they would explain in part the association of clearance of Tc-DTPA to Rp at the 1-day-postexposure time point. Impairment and leakage within the epithelial barrier leading to submucosal passage of inflammatory mediators, loss of peripheral airway stability, and increased airflow Rp are tenable as a hypothesis. However, linkage between these injuries may be coincidental, because after the first day postexposure, these responses had separable time courses of recovery. In the dog model, a single whole lung exposure to a high level of O3 leads to the development of nonspecific airway hyperreactivity, and subsequent recovery over a 7-day period is closely linked to the resolution of an airway inflammatory response involving neutrophils and desquamation of airway epithelial cells (8). We did not acquire information on airway responsivity to nonspecific challenge; thus we do not know if it was present regionally or related to the loss of epithelial integrity. We are not aware of any prior studies which investigated the time course of recovery for peripheral airway conductance after O3. In studies in humans, after either a single or an intermittent exposure to O3, impairment of both large and regional airway function is apparent (9, 12). Follow-up measures suggest that these changes can persist for at least 1 day postexposure but that they dissipate soon thereafter (13).
In summary, our study has revealed that exposure to an effective dose of O3 increases transepithelial clearance, but only for epithelia directly exposed to O3. In the initial recovery period, e.g., 1 day postexposure to O3, impairment of epithelial integrity appears to be correlated to decreases in peripheral airway conductance. Although peripheral airway tone returned to normal within 7 days, epithelial permeability to small-molecular-weight solutes of peripheral airway and alveolar surfaces required in excess of 7 days to recover.
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ACKNOWLEDGEMENTS |
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We express appreciation to Kristen Macri, Teresa Myers, and Sharron McCulloch as well as to Drs. Yong Wang and Michael Davis for assistance with the research.
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FOOTNOTES |
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The research was supported by National Institute of Environmental Health Sciences Grant ES-03810 and by National Heart, Lung, and Blood Institute Grant HL-50579.
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. §1734 solely to indicate this fact.
Address for reprint requests: W. M. Foster, #7006 Hygiene Bldg., Physiology, Johns Hopkins Univ. Sch. Of Hygiene & Public Health, 615 N. Wolfe St., Baltimore, MD 21205 (E-mail: mfoster{at}welchlink.welch.jhu.edu).
Received 12 May 1998; accepted in final form 13 October 1998.
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Abstract
Introduction
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Discussion
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) and left (
) lower lung
are represented for baseline measurements made simultaneously in 1 dog.
Tc-DTPA retention points are expressed as logarithm of %Tc-DTPA
activity deposited in respective sublobar segments at
time 0. Solid line, retention points
fitted to linear regression.
with SE bars) are
expressed as t50,
i.e., time required to clear 50% of Tc-DTPA delivered directly to the
isolated sublobar segment. Significant difference between means of left
and right lower segments, P < 0.01.
). * Mean of
O3-exposed segment is
significantly different from preexposure mean Rp,
P < 0.01.