Vol. 88, Issue 3, 821-826, March 2000
Lung function and ventilation inhomogeneity in rat lungs after
allergen challenge
M. Victoria
Sánchez-Cifuentes1,
Maria L.
Rubio1,
Mercedes
Ortega1,
German
Peces-Barba1,
Manuel
Paiva2,
Sylvia
Verbanck3, and
Nicolás González
Mangado1
1 Laboratorio de Fisiopatología
Respiratoria Experimental, Servicio de Neumología,
Fundación Jiménez Díaz, Universidad Autómona,
28040 Madrid, Spain; 2 Biomedical Physics
Laboratory, Université Libre de Bruxelles, 1070 Brussels; and
3 Akademisch Ziekenhuis, Vrije Universiteit
Brussel, 1090 Brussels, Belgium
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ABSTRACT |
We studied the early response to ovalbumin challenge in
sensitized Brown-Norway rats through its effect on N2, He,
and SF6 phase III slopes of the single-breath washout and
on indexes of lung function. Sensitized rats showed
varying degrees of response in terms of pulmonary pressure
(PL), with increases ranging between 125 and 225% of
baseline. The sensitized rats presented decreased quasistatic
compliance, forced vital capacity, and end-expiratory flow, with all
three lung function indexes showing a significant negative correlation
with corresponding PL values. They also showed significant
positive correlations of PL with the N2, He,
and SF6 phase III slopes, reflecting
diffusion-convection-dependent inhomogeneities generated by
conformation changes throughout the entire rat lung. In addition, the
rats showing the most marked PL increases (>150% baseline PL) also revealed a reversal of the
SF6-He slope difference because of a more marked
SF6 than He slope increase. This latter finding suggests
that the degree of structural heterogeneity during early response is
even more marked in the most peripheral rat lung generations.
Brown-Norway rats; early response; diffusion-convection-dependent
inhomogeneity
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INTRODUCTION |
IT HAS BEEN SUGGESTED theoretically (9) and
experimentally (2) that, in human lungs, a large portion of the phase
III slope in the single-breath washout (SBW) is caused by a mechanism of diffusion-convection-dependent ventilation inhomogeneity (DCDI) in
the lung periphery. Theoretically, DCDI generates concentration differences between lung units that are asymmetric by their different volume and/or unequal airway narrowing when units subtend from branch
points situated along the so-called diffusion front (9). In human
subjects, DCDI is thought to occur at the level of the acinus, and the
DCDI component of the phase III slope is expected to reflect
intra-acinar structure. In addition, phase III slopes obtained from
gases with differing diffusivities (He, SF6) can be used to
assess conformation changes at the level of their respective diffusion
front (the diffusion front for SF6 being situated more peripherally than that for He).
Recent experimental studies of DCDI with the use of single- and
multiple-breath washout techniques have shown the potential of
detecting acinar airway alteration in both asthmatic and chronic obstructive pulmonary disease patients (10, 20, 21).
Whereas these studies clearly indicated that through DCDI it is
possible to detect acinar structure abnormalities under a given
baseline condition, its potential to detect relatively dynamic changes, such as during bronchoprovocation testing, remains obscure. In a
previous study on hyperresponsiveness in normal subjects (21), for
instance, no significant changes in acinar ventilation inhomogeneity were observed during histamine challenge, despite earlier reports of a
possibility that histamine could also affect the peripheral airways.
This observation suggested either that histamine really did not affect
the acinar airways or that it was impossible to pick up any such
alteration through the DCDI mechanism.
It was the aim of this study to investigate quantitatively whether DCDI
can be affected by bronchoprovocation at all. For this purpose we chose
the rat lung as the model for DCDI and tested its response to allergic
bronchoconstriction. In rat lungs, DCDI is indeed the predominant
mechanism of ventilation distribution (5, 17, 22). Experimental phase
III slopes can be quantitatively reproduced by simulations of diffusion
and convection in a lung geometry based on the detailed morphometric
description of rat lung structure down to the alveolar end (13). These
simulations indicated that DCDI is operational over most of the rat
lung, with the He diffusion front extending from generations
3-4 out into the periphery and the SF6 front
starting off approximately eight generations more peripherally. In
particular, the simulations mimicked the experiments by reproducing the
larger He than SF6 phase III slopes (i.e., negative
SF6-He slope difference). In the absence of lung disease,
negative SF6-He slope difference in rats contrasts with
observations in any other species, including humans. This is a direct
consequence of the respective lung structures in which the DCDI
mechanism is operational, i.e., the whole rat lung or the human lung
acinus. For a detailed description of the different characteristics,
such as acinar distribution along the bronchial tree and volume
asymmetry in subsequent lung generations, which actually lead to He and
SF6 phase III slope inversion between rat and human lungs,
we refer to the simulation study in which DCDI in both species are
compared (22).
Despite the different baseline condition of He and SF6
slopes with respect to humans, DCDI theory predicts that any
conformation change at the level of a given diffusion front will affect
the corresponding phase III slope. In both the human acinus and the whole rat lung, the SF6 diffusion front is situated several
generations more peripherally than the He front, and, therefore, a
preferential increase of, for instance, SF6 phase III
slopes reflects a more peripheral alteration (in the human acinus or
the whole rat lung). Our laboratory previously studied the differential
behavior of He and SF6 phase III slopes in rats with
induced panacinar and centriacinar emphysema (4, 14). We now apply the
same technique to study allergen challenge in rats that were first
sensitized to ovalbumin (OA). During the early response, a combination
of functional and ventilation distribution measurements was performed.
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MATERIALS AND METHODS |
Experimental protocol.
A total of 28 inbred male Brown-Norway rats was selected for this study
when they were 14-16 wk old and weighing 292 ± 9 (SD) g. Twenty
rats were submitted to the sensitization procedure, whereas the
remaining eight were used as controls. The sensitization consisted of a
subcutaneous injection of 1 ml sterile solution containing 1 mg OA
(grade V, Sigma Chemical, St. Louis, MO) and 200 mg hydroxide aluminum
(Aldrich Chemical, Milwaukee, WI) in saline. In addition, a peritoneal
injection of 0.25 ml of Bordetella pertussis vaccine, containing 7.5 × 109 heat-killed bacilli, was given as coadjuvant
(1). The control rats also underwent subcutaneous and peritoneal
injections but with the use of saline instead of OA. A period of 15 days followed until the study day, when functional and ventilation
tests were carried out in both groups.
On the study day, the rats were anesthetized with pentobarbital sodium
(50 mg/kg ip), paralyzed with pancuronium bromide (1 mg/kg ip), and
tracheotomized in the cervical region. A tubing (40 mm long, 2.3 mm OD,
1.6 mm ID) was used to connect the trachea to a breathing assembly
consisting of a differential pressure transducer, a mass spectrometer
(Marquette Electronics, Milwaukee, WI), a gas reservoir, and a stopcock
valve that allowed communication either to a ventilator (model S-4833,
Harvard Apparatus, Edenbridge, UK) or to a syringe. The rat was placed
into a 1.6-liter volume displacement plethysmograph, with a
pneumotachograph (8 mm of maximum internal diameter) coupled to a
differential pressure transducer (MP45-871, ±2
cmH2O; Validyne, Northridge, CA). This pneumotachograph was
used for all the tests except for the recording of the flow-volume
curves. In this case, a second pneumotachograph (11 mm of maximum
internal diameter) was used that was more efficient for high flows.
Volumes were obtained by hardware integration of flow (FV 156-871,
Validyne). Data acquisition of volume and gas concentrations was done
at 62 Hz and stored on a personal computer (IBM). For on-line
monitoring of flow and volume signals, an oscilloscope was used (model
BS-601, Aaron), while pulmonary pressure (PL) was
continuously registered on a four-channel recorder (Rikadenki, Kogyo,
Japan). Flow-volume curves were performed by using an additional X-Y
recorder. The above-described instrumentation was identical to the one
used in our laboratory's previous rat ventilation studies (4, 5, 14),
except for the aerosol delivery system. The ventilator was used here to
aspire the aerosol from the nebulizer (Updraft II, Hudson, Temecula,
CA) and deliver it directly to the trachea in a tidal respiration
pattern (4 ml tidal volume, 58 beats/min). The solutions to be
nebulized were either OA solution (5% OA in saline) or saline.
Figure 1 depicts the test sequence for all
OA-sensitized rats. The control rats underwent exactly the same
procedure but with saline substituted for OA during both sensitization
and aerosol challenge. The entire test sequence was monitored by the
tracheal pressure at end inspiration of the tidal volume breathing.
This pressure is also referred to as PL
(P1-P10 in Fig. 1). The sequence started with
three inspiratory capacity (IC) inhalations, i.e., up to the volume
corresponding to 30 cmH2O, to standardize volume history in
all animals. Then all rats were exposed to a saline aerosol for 3 min
after which they reached the so-defined baseline condition
(P2). Functional measurements (i.e., IC, pressure-volume and flow-volume curves) were recorded, after which the OA aerosol (sensitized rats) or saline (control rats) was administered for 5 min.
Immediately after the OA or saline challenge, PL
corresponded to P5. After that, when either PL
had reached a plateau or 30 min had elapsed, this value was defined as
P6, and a second set of functional measurements was
initiated. Over the course of these functional measurements, the
average PL was termed P7. The rats were then
killed with N2 IC expansions immediately followed by another PL measurement (P8). Within a time span
of ~30 min postmortem, two rebreathing and four SBW tests were
performed. Because of the large contribution of gas exchange to phase
III slope in rats, ventilation distribution tests should be performed
postmortem. The exact contribution of gas exchange, depending on the
maneuver performed, and the effect of rigor mortis, which necessitates that the SBW tests be done within 1 h postmortem, can be found elsewhere (4). Before the first and immediately after the fourth SBW
test, PL was recorded as P9 and
P10, respectively. Before each SBW, the lung was inflated
to IC for 30 s to standardize volume history. Before each SBW test, the
breathing assembly was flushed with the washout gas mixture to limit
the instrumental dead space to 0.15 ml.
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Fig. 1.
Protocol of study. IC, inspiratory capacity; OA, ovalbumin aerosol
challenge; FRC, functional residual capacity; RV, residual volume; SBW,
single-breath washout test; P1-P10, pulmonary
pressures (PL) 1-10 (see text for details).
P1, PL after IC; P2, PL
after saline inhalation (baseline); P3, PL
after functional measurements; P4, PL just
before OA inhalation; P5, PL at end of OA
inhalation; P6, maximal PL during early
response (within 30 min); P7, PL during lung
function; P8, PL after death; P9
and P10, PL measured before and after,
respectively, the 4 SBW tests.
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Lung function and ventilation distribution.
Pressure-volume curves were obtained by manually inflating the lung
with air up to 30 cmH2O, after which the mass spectrometer emptied the lung down to residual volume (RV) at a constant flow of 1.2 ml/s. Lung compliance was calculated as the maximal slope in the
deflation limb of the pressure-volume curve.
Forced expiration maneuvers were carried out by inflating the lung to
30 cmH2O and rapidly deflating to RV by using the vacuum reservoir with a negative pressure of 
40 cmH2O.
Forced vital capacity (FVC), expiratory flow after 75% exhalation of
FVC (F75), and specific F75
(F75/FVC) were derived directly from the expiration flow-volume curves.
Static lung volumes, i.e., functional residual capacity (FRC) and
expiratory reserve volume (ERV), were determined immediately after
death with the use of a rebreathing test in which a N2-free gas mixture was rebreathed for 30 s by a tidal airway pressure change
between 0 and 20 cmH2O and a final expiration to 20
cmH2O. The relation between initial N2 and
final N2 concentration was used to determine the initial
lung volume at 0 cmH2O, i.e., FRC. The difference between
the last rebreathing expiration and inspiration volume was computed to
represent ERV, and RV was calculated by subtracting ERV from FRC.
SBW tests were performed by slowly inflating the lung (~1 ml/s),
starting from FRC with 4 ml of a gas mixture containing 5% He, 5%
SF6, and 90% O2 and emptying the lung down to
RV by the mass spectrometer (1.2 ml/s). In the SBW tests, phase III
slopes were computed by linear regression over the portion of the curve between 40 and 80% of expired volume. The negative slopes resulting from phase III of the inspired gases (He, SF6) were
considered in absolute value. Finally, phase III slopes were normalized
by dividing the N2 slope by mean expired N2
concentration and by dividing He or SF6 phase III slopes by
inspired minus mean expired He or SF6 concentration (5).
Statistical analysis.
Most comparisons in this study involved three groups, and analyses of
variance were used to check for differences among them. Within each
group, we checked for differences between pre- and post-OA challenge
(or pre- and postsaline) by means of a nonparametric pairwise
comparison (Wilcoxon). Spearman rank correlations were evaluated among
PL, phase III slopes, and functional parameters. All
statistical analyses were performed by using StatGraphics Plus software
(Manugistics, Rockville, MD), and statistical significance was accepted
at the P = 0.05 level.
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RESULTS |
Figure 2 shows the PL
throughout the test sequence in the control group and in two subgroups
of the OA-sensitized rats classified as nonresponders (NR) and
responders (R) as follows. Early response to OA was quantified in terms
of change in PL between P2 (baseline condition)
and P6 (maximum 30-min post-OA challenge), as indicated by
the arrows in Fig. 2. A significant early response to OA was confirmed
when P6 was 
150% P2, analogous to the 150%
baseline pulmonary resistance cutoff previously used by others (1). According to this criterion, the sensitized rats separated into 8 NR
and 12 R rats.
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Fig. 2.
PL (means ± SD) in subsequent stages of test sequence in
Fig. 1. Significant increases or decreases between subsequent
PL values within each group are indicated by solid line
segments. R, responders; NR, nonresponders. Significantly different
from * control and  NR at any given PL level
(P < 0.05).
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After the three initial IC expansions and saline challenge,
P2 (in absolute value) was similar in control [7.91 ± 0.70 (SD) cmH2O], NR (8.10 ± 1.95 cmH2O), and R groups (8.41 ± 1.51 cmH2O). Over the 5-min period of OA challenge, both groups showed significant PL increases (P4-P5), and, in the
30-min interval after OA challenge, both NR and R groups separated from
the control group in terms of P6. This maximal
PL value P6 appeared in a significantly shorter time interval after OA challenge in the R group (7 ± 2 min) than in
the NR group (18 ± 4 min) (P < 0.05). In the OA-sensitized rats, the second set of functional measurements (after the OA challenge) induced a transient PL decrease
(P6-P7). However, by the time SBW testing was
initiated, PL had increased again (P9 was even
slightly above the P6 level) and stabilized over the course
of SBW testing (no significant changes between P9 and
P10). The fact that the significant PL increase
between P8 and P9 in NR and R groups was also
observed in the control group indicates that at least the portion of
P9 increase above the P6 level was due to the
animal death itself.
Lung function and ventilation distribution.
Table 1 lists the static lung function
parameters obtained in the three groups pre- and post-OA challenge (NR
and R groups) and pre- and postsaline (control group). Before OA
challenge, the only lung function parameter that differed between R and
NR groups was F75. With the OA challenge, lung compliance,
FVC, F75, and F75/FVC values significantly
decreased in both OA-challenged groups, and all these decreases were
greater in the R group. IC only decreased significantly after OA
challenge in the R group.
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Table 1.
Lung function parameters before and after ovalbumin challenge in the
sensitized rats (R and NR groups) and before and after saline
challenge in the control group
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Figure 3 shows the phase III slopes derived
from the postmortem SBW maneuvers (4-ml inspiration from FRC and
exhalation to RV) in all three groups. In the NR group, the slightly
increased N2, He, and SF6 slopes and
SF6-He slope difference with respect to the control group
did not reach statistical significance. By contrast, in the R group,
N2, He, and SF6 phase III slopes were significantly different with respect to NR and control groups (all
P < 0.01). In addition to the larger slopes in the R group, the SF6-He slope difference actually changed signs. This
reversal of SF6-He slope difference was due to the larger
increase of SF6 phase III slope than of He phase III slope.
Lung volumes corresponding to these SBW tests showed significant
differences in terms of ERV between R (0.81 ± 0.58 ml) and NR groups
(1.51 ± 0.55 ml) and between R and control groups (1.22 ± 0.58 ml).
FRC values were not significantly different among groups (control: 3.79 ± 0.37 ml; NR: 4.41 ± 0.35 ml; R: 4.39 ± 0.84 ml).
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Fig. 3.
N2, He, and SF6 phase III slopes and
SF6-He slope differences in control, NR, and R groups.
Values are means ± SD. * Significantly different from control
(P < 0.001); significantly different from NR
(P < 0.001).
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Table 2 shows potential correlations among
functional parameters and corresponding PL (i.e., PL
= P7) and between phase III slopes or lung volumes
and corresponding PL (in this case PL is the
average of P9 and P10). All of
these correlations correspond to measurements during early response
(before or after death), including only data from NR and R groups. The
correlation between lung function and PL is highly
significant, but for F75 this correlation disappears when
it is normalized to FVC. The good correlation between PL
and phase III slopes contrasts with the absence of correlation with the
SF6-He slope difference. Of the lung volumes, ERV is the
only one correlating with PL. In fact, ERV also correlated significantly with phase III slopes of all three gases (N2:
P = 0.0001; He: P = 0.0002; SF6: P = 0.002) but not with the SF6-He slope difference
(P = 0.1; not shown in Table 2). The relation between ERV and
N2 phase III slope is illustrated in Fig.
4, where, in addition to NR and R groups,
data from the control group are shown for comparison.
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Table 2.
Spearman rank correlations among lung function, static lung volumes,
and phase III slopes and corresponding pulmonary pressures during early
response (using R and NR groups)
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Fig. 4.
N2 phase III slope vs. expiratory residual volume (ERV) for
NR ( ), R ( ), and control groups (×).
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| |
DISCUSSION |
This study clearly shows that it is possible to detect alterations in
response to antigen challenge at a level of the lung at which the
mechanism of DCDI predominates, as is thought to be the case in the
whole rat lung. Inherent to the way the DCDI mechanism generates phase
III slopes, a conformation change at any given lung depth will be most
reflected in the phase III slope of the gas that has its diffusion
front located at this particular lung depth. In the case of the rat
lung, the SF6 diffusion front is located approximately
eight generations more peripherally than is the He front. In this
respect, the fact that early response to OA (in terms of increased
airway pressure) induced marked increases in N2, He, and
SF6 phase III slopes (Fig. 3) suggests lung conformation changes throughout the entire rat lung. In addition, the reversal of
the SF6-He slope difference, which in this case is mainly
due to the SF6 slope increasing more than the He slope,
suggests an even more marked response to OA in the more peripheral rat
lung generations.
It has been suggested that, in rat lungs, metacholine can elicit a
response in both airways and tissue mechanics (11). We shall, however,
limit the comparison of our ventilation distribution results to reports
of early response during allergen challenge in the same breed of rats,
also sensitized with OA (3, 7, 8). These reports suggested that, in
vitro, both airway and tissues can react to antigen challenge (8) and
that, in vivo, the observed increase in resistance during early
response can be partly attributed to airways and partly to the
parenchyma (3, 7). Morphometry showed airway narrowing, the effect
being most marked in the larger airways (3), which is compatible with He slope increases, and the parenchyma was shown to be distorted (7),
which could in part explain the SF6-He slope reversal through an even more marked SF6 slope increase. The early
response in terms of increased PL was also associated with
changes in lung function parameters (Table 2), in agreement with the
above-mentioned morphological alterations as well (3, 7). The fall in
FVC and F75 can be attributed to the airway narrowing (3),
whereas the diminished compliance is compatible with the increased
tissue resistance and parenchymal distortion (7).
One effect that appears to be determinant of N2, He, and
SF6 phase III slopes is ERV (Spearman rank correlations
using NR and R groups), bearing in mind, however, that all phase III
slopes reported here derive from SBW tests starting inhalation at FRC. In fact, Fig. 4 illustrates that, for a wide range of ERV values in
control and NR groups, N2 slopes are hardly affected. Only in the R group are the generally smaller ERV values accompanied by
larger N2 phase III slopes. This result suggests that only when RV becomes sufficiently close to FRC may some neighboring units
develop severe cross-sectional and/or volumetric heterogeneity and, as
a result, produce significant phase III slope increases. In addition,
the absence of correlation between ERV and SF6-He slope
difference suggests that such a mechanism of structural heterogeneity
has no preferential site of action and in fact affects the entire lung.
In the case of rat lungs, in which acinar units are widely distributed
over most lung generations, one could indeed imagine that such
heterogeneity could occur throughout all generations of the rat lung.
In humans, DCDI is only one of the contributors to the phase III slope,
because gravity (12) and inhomogeneous volume expansions among
gravity-independent lung units may also generate a sloping alveolar
plateau. In humans, one way to isolate the DCDI component, i.e., the
acinar component, of ventilation inhomogeneity is to consider the
SF6-He slope difference, because, in humans, all effects
involving units larger than acini are expected to affect He and
SF6 phase III slopes in the same way (and leave
SF6-He slope difference unaltered) as they operate at
branch points proximal to both diffusion fronts. Van Muylem et al. (16)
were able to correlate SF6-He slope differences with
indexes of acinar airway inflammation obtained in patients selected for
lung resection. Another study by the same group showed a negative
SF6-He slope difference in lung transplant patients only
during a rejection phase and a return to a positive SF6-He
slope difference during the recovery, which was mainly attributed to
alterations in the first acinar generations (15). A negative
SF6-He slope difference and its modification to zero slope
difference after bronchodilatation were observed by Peces-Barba et al.
(10) in five asthmatic patients, pointing to severe intra-acinar
alterations that were, at least in part, reversible.
Note that, in the absence of lung disease, the SF6-He slope
difference may be positive (as in the human acinus) or negative (as in
the whole rat lung), depending on the particular details of each lung
structure as indicated by corresponding model simulations (19, 22).
Experiments in normal pig lungs have even shown a zero
SF6-He slope difference (6), a result that as yet has not
been simulated in a model with realistic lung geometry. Whatever the
normal baseline SF6-He slope difference in a given species, the deviation from this baseline is what actually matters in detecting abnormal ventilation inhomogeneity through the DCDI mechanism, as long
as it is clear in which part of the lung DCDI is operational. Also,
irrespective of the baseline SF6-He phase III slope
difference, a preferential increase of, for example, the He slope (with
respect to SF6) will always reflect a preferential response
from the more proximal lung generations (because the He diffusion front
is always more proximally located than the SF6 front).
In conclusion, we have shown that the DCDI mechanism that dominates the
phase III slope in the rat lung does respond to the dynamic situation
of lung distress such as the early response to OA challenge. The phase
III slope increases observed for the different density gases He and
SF6 suggested that conformation changes, involving
cross-sectional and/or volumetric heterogeneity, occurred over most of
the rat lung generations. In addition, the significantly larger
SF6 than He phase III slope increase after OA challenge
suggests that the degree of structural heterogeneity increases toward
the lung periphery. Part of the origin of the observed structural
heterogeneity throughout the rat lungs may be associated with
substantial reductions in ERV during early response to OA.
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ACKNOWLEDGEMENTS |
This study was supported by Fondo de Investigaciones Sanitarias de
la Seguridad Social contract 93/0619, by the Belgian Federal Office for
Scientific Affairs (program PRODEX), and by the Fund for Scientific
Research-Flanders.
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FOOTNOTES |
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 and other correspondence: N. G. Mangado,
Servicio de Neumología, Fundación Jiménez
Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain
(E-mail: neumoexp{at}fjd.es).
Received 6 October 1998; accepted in final form 25 October 1999.
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