Vol. 86, Issue 2, 725-731, February 1999
SPECIAL COMMUNICATION
Aerosol probes of lung injury in a 28-wk longitudinal study of mild
experimental emphysema in dogs
Frank S.
Rosenthal
School of Health Sciences, Purdue University, West Lafayette,
Indiana 47907
 |
ABSTRACT |
After baseline measurements of lung mechanics,
effective air space diameter (EAD), and aerosol dispersion (AD), three
dogs were exposed to two treatments of aerosolized papain (3 ml of a
4% solution), and measurements were repeated during a 28-wk follow-up
period. EAD and AD were measured with boluses of 0.7-µm particles of
di-2-ethylhexl sebacate, with Pen (i.e., volumetric bolus
penetration/total lung capacity) between 0.1 and 0.4. After papain
exposure, EAD increased a mean of 28%
(P < 0.0001) and AD (Pen = 0.3, 0.4)
increased 4-7% (P < 0.03). The
progression of injury was indicated by increasing trends in total lung
capacity (P < 0.05), residual volume
(P < 0.05), and EAD
(P = 0.06) through week 18. There was no evidence of
disease progression between weeks 18 and 28, whereas some of the data for
individual dogs suggested partial recovery from lung injury at
week 28. The results show that aerosol
probes can detect and characterize mild lung injury in experimental emphysema.
air space size; lung function; aerosol dispersion; effective air
space diameter; papain
| |
INTRODUCTION |
THE DETECTION OF LUNG injury in its early or mild
stages is important to clinical, epidemiologic, and experimental
studies of chronic lung disease. Traditional diagnostic techniques in detecting the lung injury associated with chronic obstructive pulmonary
disease (COPD) have been limited in sensitivity and specificity. This
is clearly true with respect to emphysema and pulmonary function
testing. For example, airflow obstruction seen in forced expiratory
measurements identifies only a fraction of subjects who have anatomic
evidence of emphysema (22). Furthermore, lung function testing cannot
specifically identify emphysematous changes in the lung.
Recently, high-resolution computed tomography and aerosol inhalation
studies have shown promise in detecting and characterizing the lung
injury associated with human emphysema (2, 3, 6, 8, 9). Two types of
aerosol-based techniques have been used. In one technique, aerosol
deposition measurements are analyzed to estimate an effective air space
diameter (EAD), which has been found to be increased in patients with
emphysema. With a second technique, aerosol dispersion (AD), an aerosol
bolus is inhaled and then exhaled; the exhaled bolus is spread over a
larger volume than the inhaled bolus; and the amount and nature of this
spreading are a marker of disease-induced ventilatory disruption.
Methods of quantifying and measuring EAD and AD have been discussed
previously (14, 15, 18). Beinert et al. (2) compared 25 patients with
COPD with 36 controls and found that EAD significantly increased in
patients with COPD. In a subset of 10 patients studied with high-resolution computed tomography, these investigators found a
significant correlation between mean pixel density and EAD. Kohlhäufl et al. (8) found 52% greater AD in 26 patients with pulmonary emphysema than in 19 healthy control subjects. Brand et al.
(3) recently found that EAD discriminated between those patients who
had evidence of emphysema and those who did not. This clinical work is
supported by experimental work showing a correlation between EAD and
morphometric measurements in human autopsied lungs and in a canine
model of emphysema (13, 17, 20). Aerosol methods have also been found
to be sensitive in the detection of lung injury in cystic fibrosis (1)
and with exposure to ozone (7) and cigarette smoke (12).
In a previous study we found that EAD and AD were significantly
increased when emphysema was induced in dogs by exposure to papain
(17). The present work is a follow-up study in which a lower dose of
papain is used and the follow-up period is extended from 9 to 28 wk.
The following questions were posed.
1) Can aerosol methods detect milder
levels of emphysema than previously examined? 2) Does the response of aerosol
probes reflect the severity of lung injury?
3) What are the relationships
between functional changes and air space enlargement after papain
treatment? 4) How do flow rate and
breathing pattern influence the sensitivity of aerosol probes to mild
lung injury? 6) In an extended
follow-up period (28 wk), does lung injury continue to progress,
stabilize, or reverse?
| |
METHODS |
Animal preparation.
The animal preparation and instrumentation system for aerosol and lung
mechanics measurements has been described previously (17). Briefly,
animals were premedicated with acepromazine (1-4 mg) and
glycopyrollate (5 µg/lb). Anesthesia was induced with pentobarbital
sodium (25 mg/kg) and maintained with hourly supplemental doses
(10-20% induction dose/h). Animals were intubated. Spontaneous respiration was suppressed by hyperventilating the animal so that end-tidal CO2 was ~4.0%. The
animals were placed in an airtight Plexiglas whole body chamber with
the endotracheal tube ported outside the chamber. Respiration was
induced by controlling the pressure inside the chamber manually with a
syringe or with a servo-controlled system connected to sources of
positive and negative pressure (19).
Tests of lung mechanics and pulmonary function.
A series of pulmonary function tests was conducted that included
pressure-volume curves, determination of functional residual capacity
(FRC) by helium dilution, forced expiration, single-breath N2 washout (SBNW), and
frequency-dependent lung mechanics. With the exception of SBNW, methods
for performing these tests have been described previously (17). SBNW
was carried out with a breathing pattern induced by changing pressure
in the whole body chamber with a manual air syringe.
First, exhalation to residual volume (RV) was induced. Then the lungs
inspired 100% O2, through a
nonrebreathing valve, to total lung capacity (TLC), defined as the
volume of air in the lung at 25 cmH2O transpulmonary pressure. Then exhalation to RV was induced, during which
N2 content was measured with a
MedScience N2 analyzer. The
percent N2 in exhaled air was
plotted against exhaled volume with an
X-Y chart recorder, and the slope of
phase III (designated
"slope3") was determined by
fitting a straight line to the data between one- and two-thirds exhaled
vital capacity (VC). TLC was computed as the sum of inspiratory capacity (IC) and FRC. FRC was determined using the steady-state closed-system helium dilution method, with 20 breaths of 10% helium at
1 l/s. RV was determined by subtraction of expiratory reserve volume
from FRC. For the determination of RV, expiratory reserve volume was
measured immediately after the last of the multiple breaths used to
determine FRC.
Measurement of aerosol deposition and dispersion.
Data for aerosol parameters were obtained from single-breath
experiments with an aerosol measurement system previously described (17). An oil droplet monodisperse aerosol of di-2-ethylhexl sebacate
particles with mean diameter of ~0.7 µm was generated using a MAGE
(Lavoro y Ambiente, Bologna, Italy) aerosol generator. Particle size
was determined several times during each experiment from
1) sedimentation rate in a
convection-free channel and 2) particle size spectrum obtained with an optical particle counter (Climet, Reading, CA). EAD was determined from the fractional deposition of aerosol boluses during pauses between inspiration and
expiration of 0.2 and 5 s, respectively (17). Bolus penetration (Pen)
was defined as volumetric bolus penetration (17) divided by TLC as
measured in baseline measurements. EAD was determined with 400-ml
boluses inspired with Pen of 0.38-0.44
(EAD400) and with 800-ml boluses
inspired with Pen of 0.57-0.73
(EADdeep). Pen was kept constant
for all EAD measurements in a single dog.
The data of aerosol concentration vs. inhaled or exhaled volume were
used to compute parameters of AD: the coefficient of AD (CD) and the
skewness (SK) of the exhaled bolus (18). For each dog, AD parameters
were measured with 200-ml boluses at four values of Pen in the range
0.11-0.48. For dogs 2 and
3, in which the Pen values were
~0.1, 0.2, 0.3, and 0.4, the measured values were designated CD1,
CD2, CD3, and CD4. For dog 1 in which
CD was measured at Pen of 0.12, 0.25, 0.37, and 0.48, the measured value at the lowest Pen was designated CD1, and values of CD
corresponding to Pen of 0.2, 0.3, and 0.4 were estimated by linear
interpolation between the measured values and designated CD2, CD3, and
CD4. The measured values of SK were designated SK1, SK2, SK3, and SK4 in order of increasing Pen for all dogs.
The AD measurements were done with several different patterns of
inspired and expired flow rate. Flow rates of 0.25 ("L") and 0.5 l/s ("H") were used. Breathing patterns were identified by a
sequence of two letters indicating the flow rate during inspiration and
expiration, respectively. AD was measured with LL, HH, LH, and HL
breathing patterns. For example, CD1LH is the CD measured at the lowest
value of penetration, with an inspired flow rate of 0.25 l/s and an
expired flow rate of 0.5 l/s.
Morphometry.
While under anesthesia, dogs were heparinized (220 U/kg) and
exsanguinated via the femoral artery. Lungs were excised, inflated with
air to a pressure of 25 ± 2 cmH2O, and dried for 18-24 h in a convection oven maintained at 60 ± 3°C. After drying, each lobe (right apical, right medial, right diaphragmatic, left apical, left medial, left diaphragmatic, auxiliary) was sliced at 1 cm, from
apex to base, with a rotary "deli" slicer. From the medial slice
of each lobe, except the auxiliary lobe, three blocks with dimensions
of ~5 × 5 × 3 mm were obtained. Two of these blocks were
from near the periphery (i.e., pleural surface) of the slice, and one
of these blocks was selected from the central region of the slice. Two
blocks were obtained from the auxiliary lobe. Each block was embedded
with glycol methacrylate, sectioned at 4 µm, and stained with
Polysciences Multiple Stain. Photomicrographs of the sections were
analyzed, as described previously, to determine the mean linear
intercept (Lm)
(15). Lungs excised from three dogs that were not exposed to papain
were similarly prepared and analyzed.
Schedule of experiments.
Three dogs were studied with respective identifiers of 95-5
(dog 1), 95-6
(dog 2), and 96-1
(dog 3). To establish their baseline values of lung mechanics and aerosol parameters, animals were first
studied in three or four sessions 
1 wk apart. Animals were then
exposed to aerosolized papain in two treatments 1 wk apart, each
treatment consisting of a dose of 3 ml of a 4% solution of papain
(30,000 USP U/mg; Calbiochem, La Jolla, CA). This dose was chosen as
one-half of the dose used in a similar previous study. The system for
papain exposure has been described previously (17). Briefly, the dog
was anesthetized, intubated, and ventilated on a Bennett respirator so
that end-tidal CO2 was ~4%. To
minimize any acute airway reaction to the exposure, the dog was first
treated with a bronchodilator consisting of 3 ml of albuterol sulfate (0.14 mg/ml) nebulized with a Bird nebulizer in the breathing circuit
of the respirator. Then the dog was exposed to papain aerosol by using
the same nebulizer. Tidal volume was 500-600 ml. Additional
studies of lung function and aerosol parameters were done at 2, 4, 8, 12, 18, and 28 wk after the second papain exposure. For
dog 1, additional studies were done at
6 and 10 wk after exposure. On the last study date for each dog, the
lungs were excised for morphometry. Three dogs that had not been
exposed to papain were studied with aerosol and lung mechanics tests on two occasions, then lungs were excised for morphometry.
Statistical analysis.
To determine whether aerosol or lung function parameters were affected
by the lung injury caused by papain exposure, the pooled data for the
three experimental dogs were fit with general linear models of the form
where
y is an aerosol or lung function
parameter, dog is a categorical variable identifying the dog from which
the data were obtained, treatment is a categorical variable identifying
whether the data were obtained before or after treatment with papain, and b0,
b1, and
b2 are the fitted
parameters of the statistical model.
To determine whether there was a trend with time in the postexposure
period, the postexposure measurements were fit with models of the form
where
week post is a continuous variable indicating the number of weeks after
papain exposure when the data were obtained.
To determine whether there was a difference between aerosol parameters
measured with different breathing patterns, the data were fitted with
models of the form
where
flow is a categorical variable indicating which of the four breathing
patterns was used to obtain the data (e.g., LL).
The effect of breathing pattern was analyzed on three different data
sets: 1) all observations before
papain exposure, 2) all observations
after papain exposure, and 3) all observations.
To determine the correlation of parameters of lung injury in the
postexposure period, the percent change from baseline of the first
parameter was regressed against the percent change from baseline for
the other parameter (measured at the same time point for the same dog)
for the pooled data of all dogs and all time points in the postexposure period.
To determine differences in morphometry between exposed vs. unexposed
lungs, a two-tailed t-test assuming
unequal variances was applied.
| |
RESULTS |
Lung injury in the postexposure measurements was demonstrated by
significant changes from baseline values in many of the lung function
and aerosol parameters (P < 0.05;
Table 1). These changes ranged from 2% in
the ratio of forced expired volume in 1 s to forced vital capacity to
46% in RV (Table 1). EAD400
changed by a mean of 29% (P < 0.0001). CD values for tests with more deeply penetrating boluses
increased from 4 to 7% (P < 0.05).
There was no statistically significant effect of papain exposure on SK, although these values tended to increase after papain exposure.
Of the lung mechanics and aerosol parameters changed significantly by
papain exposure, only IC, VC, and TLC showed a significant trend with
the number of weeks after exposure when the complete 2-28 wk
postexposure data were analyzed (Table 2).
To control for the possibility of recovery from lung injury near the
end of the follow-up period, the trend analysis was repeated for
2-12 and 2-18 wk after exposure. For the data obtained
2-18 wk after exposure, significant trends were found for IC, VC,
TLC, and RV (P < 0.05), whereas the
trends for FRC and EAD400 were
marginally significant (P = 0.05 and
P = 0.06, respectively).
In general, the data showed no evidence of progression of lung injury
between weeks 18 and
28 (Figs.
1 and
2). Individual dogs showed some
evidence of reversal of papain-induced changes between
weeks 18 and
28 for the following variables: RV
(dogs 2 and
3), FRC (dog
3), and EAD400
(dog 1; Figs. 1 and 2).
Dog 3 showed an almost continuous
improvement in forced expiratory flow at 25% VC
(FEF25) throughout the follow-up
period. Dog 1 showed an almost
continuous improvement throughout the follow-up period in SBNW
(Fig. 2). Consistent with a lack of progression between
weeks 18 and
28 was the fact that, for variables
that showed a significant or marginally significant trend in time, the
P values for the trend were generally
smaller when the analysis was carried out through week
28 vs. week 18 (Table
2).
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Fig. 1.
Percent change from baseline of lung volumes in 3 papain-exposed dogs
followed for 28 wk after exposure. VC, vital capacity; TLC, total lung
capacity; FRC, functional residual capacity; RV, residual volume.
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Fig. 2.
Percent changes from baseline in aerosol and lung mechanics parameters
in 3 papain-exposed dogs followed for 28 wk after exposure.
EAD400, effective air space
diameter determined with 400-ml bolus inspired with penetration of
0.38-0.44; EADdeep, effective
air space diameter determined with 800-ml bolus inspired with
penetration of 0.57-0.73; CD3, coefficient of aerosol dispersion
at penetration of 0.3; LL, low (0.25 l/s) inspired flow and low expired
flow; HH, high (0.50 l/s) inspired flow and high expired flow;
FEF25, forced expiratory flow at
25% vital capacity; slope3, slope
of phase 3.
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In the pooled set of all postexposure measurements, the percent change
in TLC was strongly correlated with the percent change in
EAD400
(r2 = 0.75, P < 0.0001; Fig.
3). The magnitude of the percent change in
FEF25 was negatively correlated
with the percent change in EAD400
(r2 = 0.26, P < 0.03; Fig.
4). The percent change in SBNW was also negatively correlated with the percent change in
EAD400
(r2 = 0.25, P < 0.03, data not shown). The
percent change in FEF25 was
negatively correlated with the percent change in TLC
(r2 = 0.33, P < 0.01, data not shown).
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Fig. 3.
Percent change from baseline of
EAD400 vs. percent change from
baseline of TLC for pooled postexposure measurements.
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Fig. 4.
Percent change from baseline of
FEF25 vs. percent change from
baseline of EAD400 for pooled
postexposure measurements.
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CD values for experiments done at 0.5 l/s were generally lower than CD
values for experiments done at 0.25 l/s whether all data, prepapain
data, or postpapain data were considered. SK was also generally reduced
at higher flow rates, although not significantly for baseline values
(Table 3). Measurements obtained with the HL breathing pattern were different from those obtained with the LH
pattern for CD4, SK1, SK2, SK3, and SK4 in the prepapain measurements and for CD4, SK1, SK2, and SK4 in the postexposure measurements. For
the overall data set, there was no significant effect of flow rate or
breathing pattern on the percent increase in CD or SK after papain
exposure (P > 0.05, data not shown).
Consistent with lung injury, the mean
Lm in the exposed
lungs [225 ± 25 µm (SD)] was 24% greater than the
mean Lm in the
unexposed lungs (182 ± 9 µm, P = 0.07). The mean of the final measurements of
EAD400 in the exposed lungs (211 ± 38 µm) was 32% greater than the mean of EAD400 in
the unexposed lungs (160 ± 18 µm,
P = 0.13), whereas the mean of
EADdeep in the exposed lungs (164 ± 13 µm) was 38% larger than the mean of
EADdeep in the unexposed lungs (119 ± 13 µm, P = 0.01). In the
set of six exposed and unexposed lungs,
Lm was
significantly correlated with the final measurements of
EAD400
(r2 = 0.71, P = 0.03, data not shown) and
EADdeep
(r2 = 0.81, P = 0.02, data not shown).
| |
DISCUSSION |
Although only three dogs were exposed to papain, the longitudinal
nature of this study made it possible to observe significant effects of
papain exposure on lung mechanics and aerosol parameters. The air space
enlargement associated with experimental emphysema was observed by EAD
measurements and confirmed by lung morphometry. This study replicated
many of the experimental measures in a previous study in which
identical papain exposure conditions but twice the papain dose was
used. When the magnitude of exposure-induced changes in lung mechanics
and aerosol parameters is compared between the two studies, at an
equivalent point in time of 8 wk after exposure, a highly consistent
pattern emerges, with the changes in the present study being two to
five times less than in the previous study (Table
4). This provides evidence that aerosol probes reflect the severity of lung injury.
The time course of aerosol parameters and lung mechanics after exposure
provides some insights into the relationships of structural and
functional changes in experimental emphysema: the strong correlation between changes in TLC and EAD400
(Fig. 3) after papain exposure suggests that these changes are caused
by a common mechanism, presumably enzymatic degradation of lung
elastin, which breaks down alveolar walls and reduces lung elasticity.
In contrast, the negative correlation between changes in
FEF25 and
EAD400 and between
FEF25 and TLC suggests a complex
relationship between airflow obstruction and structural lung
destruction. This is particularly seen in the case of
dog 3, where
FEF25 showed an initial large decrement in FEF25, which almost
continuously lessened during the postpapain period, whereas
concurrently EAD400 and TLC were increasing or remaining unchanged (Figs. 1 and 2). Thus, rather than
indicating a causal connection between
FEF25 and
EAD400, their negative correlation
may simply reflect opposite trends with time after exposure.
EAD400 and
EADdeep were sensitive to the
induced lung injury; however,
EAD400 demonstrated progressive
lung injury, whereas EADdeep did
not. This difference was surprising, since it was expected that, with a
larger bolus volume and deeper penetration, EADdeep would be a more reliable
measure of pulmonary air space size. However, in some cases, part of
the deeply inspired boluses used to measure
EADdeep may have been lost to
residual air in the lung and not recovered on exhalation, thus causing
error in the determination of true aerosol deposition. This potential
error may have contributed to variability in determination of
EADdeep and, in turn, lower
correlations of EADdeep with time and TLC as compared with
EAD400.
AD and SBNW are thought to detect changes in convective airflow
distribution due to lung injury. Although both were sensitive to
papain-induced injury in this study (Table 1), their response was
somewhat different: AD parameters (e.g., CD3LL, CD3HH) were consistently increased in all three dogs after papain exposure, whereas
SBNW increased in dogs 1 and
3 and decreased in
dog 2. In addition,
dog 1 showed a marked continuous
recovery from an initial large increase in
slope3 during
weeks 2-12 after papain exposure,
which was not clearly apparent in the data for CD parameters in this
dog (Fig. 2). The reasons for the differences in the response to lung
injury of AD vs. SBNW are not clear. However, a theoretical model has
related AD to heterogeneous ventilatory time constants (16), whereas
N2 washout has been related to
heterogeneity of regional lung volumes at the start of inhalation (10).
Furthermore, because of the low CD of the aerosols used to measure AD,
diffusional transport is not a factor in AD, whereas it may be in SBNW.
Thus AD and SBNW may reflect different aspects of the uneven
ventilation caused by lung injury.
Although not consistent for all dogs and all measures of lung injury,
portions of the data indicate a partial recovery from the effects of
lung injury in this disease model. Although recovery has not generally
been reported in studies of experimental emphysema, it is consistent
with a study by Martorana et al. (11) of papain-induced emphysema in
dogs. These investigators found an increase in postfixation lung
volumes in exposed animals at 3 mo relative to control animals but a
decrease at 6 mo relative to 3 mo (P < 0.05) (11). The mechanism for recovery is unclear, although it
could be related to the resynthesis of elastin known to occur after
elastase-induced lung injury (21).
Similar to the previous study of aerosol probes of papain-induced
emphysema (17), CD values were lower when measured at higher flow rate
in baseline and postexposure measurements. This effect has been
previously attributed to 1) a
reduction in time available for intrinsic particle transport and
2) a blunting of radial flow
gradients (18). The data indicating that CD4HL is lower than CD4LH
suggest that these mechanisms are more effective during inspiration
than during expiration. SK parameters also tended to be reduced at
higher flow rate; however, their dependence on breathing pattern was
complex, with SK being greater for HL than for LH at shallow
penetrations and less for HL than for LH at deeper penetrations. The
source of these differences is unknown but may relate to differences
between inspiratory and expiratory flow profiles, which vary with lung depth.
The previous, higher dose study found that the mean percent increases
in CD and SK parameters after papain exposure were consistently greater
for measurements at higher flow rates. This phenomenon was explained by
a theoretical model that attributed changes in AD to increased
heterogeneity of ventilatory time constants in the injured lung (16).
In the present study, no consistent effect of flow rate on the mean
percent increases in AD parameters after papain exposure was seen. This
suggests that an alternative mechanism, independent of time constants,
may contribute to the increased AD resulting from milder lung injury.
AD is thought to arise from an irreversibility of convective flow
between inspiration and expiration (21). Irreversibility of alveolar
motion and alveolar flow has been shown by model studies to occur even
under quasi-static conditions (4, 5). It is possible that, in mild lung
injury, damage to alveoli increases this irreversibility, thereby
increasing AD.
Conclusions.
Overall this study demonstrated that EAD and AD can detect milder
levels of lung injury than previously examined and that these probes
quantitatively reflect the degree of lung injury. In contrast to a
previous study, with a higher papain dose, there was no apparent effect
of flow rate on the sensitivity of AD to lung injury. The use of EAD as
an in vivo marker of air space enlargement provided insight into the
relationship between functional and structural change after papain
exposure. For example, the data demonstrated a link between air space
enlargement and reduced lung elasticity after papain exposure. As
measured by TLC and EAD, there was a progressive increase in lung
injury between weeks 2 and
18 after exposure, with no evidence of
further progression at week 28. The
data also suggested the possibility of a partial recovery from lung
injury in some animals in experimental emphysema.
| |
ACKNOWLEDGEMENTS |
The author thanks Dr. George McCabe for assistance in
planning and implementing the statistical analysis and Drs. Walter
Weirich, Ralph Richardson, Brad Schmidt, and Mark Suckow for advice and assistance on veterinary medical aspects of the work. Mary Haley, Changhong Li, Lee Ann Grote, and Cheryl Anderson provided excellent laboratory assistance during the experiments. Dr. Gary Carlson provided
helpful critical comments on the manuscript.
| |
FOOTNOTES |
This work was supported by National Heart, Lung, and Blood Institute
Grant R01 HL-36530.
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: F. S. Rosenthal, School of Health
Sciences, Civil Engineering Bldg., Purdue University, W. Lafayette, IN
47907.
Received 27 July 1998; accepted in final form 13 October
1998.
| |
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Abstract
Introduction
