Airway wall dimensions during carbachol-induced
bronchoconstriction in rabbits
F. SASAKI, Y. SAITOH, L. VERBURGT, AND M. OKAZAWA
Respiratory Health Network of Center of Excellence, University of British Columbia, Pulmonary
Research Laboratory, St. Paul’s Hospital, Vancouver, British Columbia V6Z 1Y6, Canada
airway narrowing; smooth muscle shortening; lung
THE THICKNESS of the airway wall internal to the airway
smooth muscle is an important determinant of airway
narrowing. In a theoretical analysis, Moreno et al. (23)
proposed that thickening of the inner wall could result
in exaggerated airway narrowing during bronchoconstriction. By using morphometric measurements, James
et al. (15) also suggested that hyperresponsiveness in
asthmatic patients could be partially explained by an
increase in airway wall thickness internal to the smooth
muscle layer. In these studies, an assumption has been
that the inner wall area (WAi ) in cross-sectioned airways remains constant during bronchoconstriction; this
was partly supported by previous studies (13, 14).
However, the interstitial pressure probably increases
in the inner wall and decreases in the outer wall (17,
19) during bronchoconstriction and, since there are rich
communications between the vascular networks in the
inner wall and adventitia across the smooth muscle
layer (9, 12), it is possible that blood, lymph, or
interstitial fluid could relocate during bronchoconstriction. We therefore hypothesized that WAi would decrease and adventitial area would increase during
bronchoconstriction. To test this hypothesis, we mea-
1578
sured airway wall dimensions during acute and sustained carbachol-induced bronchoconstriction in rabbit
peripheral airways by using morphometric techniques.
METHODS
Animal Peparation
Twenty-four New Zealand White rabbits weighing 2.56 6
0.32 kg were anesthetized with a-chloralose (100 mg/kg) and
urethan (1,000 mg/kg) intravenously and paralyzed with
pancuronium bromide (0.1 mg/kg). Animals were ventilated
with pure oxygen at a tidal volume of 7 ml/kg, respiratory rate
of 40 breaths/min, and positive end-expiratory pressure of
2 cmH2O through a tracheostomy tube. The chest was opened
widely by splitting the sternum. Systemic arterial pressure
was measured via a catheter placed in the carotid artery.
Tracheal pressure was measured through a side port of the
tracheal tube by using a piezoresistive transducer (model
FPM-02PG, Fujikura, Tokyo, Japan) and compared with
atmospheric pressure to give transpulmonary pressure (PL ).
Airflow was measured with a pneumotachometer (Fleisch
no. 00) and a differential pressure transducer (model MP45,
Validyne; 65 cmH2O). All pressure and flow tracings were
displayed continuously on a monitor and recorded as necessary by using a digital recording system (Raytech). Pulmonary resistance (RL ) was estimated with a data analyzing
system (Anadat) that uses the recursive least square method
by fitting data points to PL 5 EL · VT 1 RL · V̇ 1 P0, where EL is
lung elastance, VT is tidal volume, V̇ is air flow, and P0 is a
constant end-expiratory pressure of 2 cmH2O (20).
Experimental Protocol
Acute bronchoconstriction experiment. Six rabbits were
used for each of the saline and carbachol groups. After
baseline RL was measured, saline or carbachol (100 mg/ml)
was nebulized with a model 646 DeVilbiss nebulizer for 3 min.
One minute after the end of nebulization, RL was measured
again.
Sustained bronchoconstriction experiment. Six rabbits were
used for each of the saline and carbachol groups. After
baseline RL was measured, saline or carbachol (100 mg/ml)
was nebulized for 30 s. This nebulization was repeated every
5 min for a period of 40 min. RL was measured 1 min after
each nebulization.
Freeze substitution technique. After the last measurement
of RL, the heart base was snared to trap the vascular blood in
the lung and the heart and lung were quickly dissected en
bloc. The lung was frozen by showering it with liquid nitrogen
until it was rigid and then submerging it in liquid nitrogen for
20 min. During these procedures, the lung was kept inflated
at a PL of 2 cmH2O.
A freeze substitution technique was used to process the
lung for morphometric study. Briefly, the frozen lungs were
stored in precooled acetone at 270°C for 18 h, 220°C for 6 h,
and 4°C for 24 h. Three coronal sections of each lung were
0161-7567/96 $5.00 Copyright r 1996 the American Physiological Society
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Sasaki, F., Y. Saitoh, L. Verburgt, and M. Okazawa.
Airway wall dimensions during carbachol-induced bronchoconstriction in rabbits. J. Appl. Physiol. 81(4): 1578–1583,
1996.—Airway wall area is an important determinant of
airway narrowing. We hypothesized that in cross-sectioned
peripheral airways, the wall area internal to the outer smooth
muscle border (inner wall area) would decrease and the
airway wall area external to the outer smooth the muscle
layer (adventitial area) would increase during bronchoconstriction because of the relocation of blood and/or fluid between
these compartments. To test this hypothesis, we used anesthetized open-chest rabbits and measured airway wall dimensions and smooth muscle shortening of membranous airways
after carbachol-induced bronchoconstriction using morphometric techniques. Acute (3-min) and sustained (40-min)
bronchoconstriction was induced by aerosol nebulization of
carbachol and compared with saline treatment. After physiological measurements, the heart base was snared, and the
lung and heart were excised en bloc and frozen by using liquid
nitrogen while a transpulmonary pressure of 2 cmH2O was
maintained. The lung was processed for light-microscopic
examination by using a freeze substitution technique. Results
show that adventitial area was significantly decreased after
sustained but not acute bronchoconstriction. The mechanism
of this change, which contradicts our hypothesis, is unclear.
However, the decrease of adventitial area could increase
rather than decrease the effect of lung parenchymal tethering
and attenuate airway narrowing.
AIRWAY WALL DIMENSIONS DURING BRONCHOCONSTRICTION
P*mo 5 Œ4p(WAi 1 A *i )
(1)
A*i was calculated based on the assumptions that Pi does not
change and that Pi conforms to a perfect circle in the relaxed
and dilated state, using
A *i 5
P2i
(2)
4p
Percent smooth muscle shortening (PMS) was calculated
by using
PMS 5
P*mo 2 Pmo
P*mo
3 100
(3)
Statistical Analysis
Data are expressed as means 6 SD. Physiological data for
the saline and carbachol groups were analyzed by using a
two-tailed unpaired t-test. The frequency distributions of Pi
were compared between groups using the KolmogorovSmirnov test (11). The relationships between Pi and the
square root of each component of the wall area were analyzed
by using a random effects regression analysis as described by
Feldman (10). The technique minimizes the within- and
between-subject variabilities of slope and intercept of regression lines in each group after weighting the data from each
animal for number of data points and goodness of fit. The
differences in the regression lines between the two groups
were analyzed by comparing both slope and intercept by
using the chi-square test and by plotting the mean and 95%
confidence interval of the difference vs. Pi. To determine
whether there was a relationship between the magniture of
smooth muscle shortening in individual airways and changes
in wall area (DWA) in this airway, we calculated DWA caused
by constriction. To calculate a predicted wall area, we used
the relationship between Pi and wall area for saline-treated
animals and assigned a predicted wall area for each constricted airawys on the basis of its Pi. DWA was the difference
between predicted wall area and actual wall area and could
be positive or negative. The relationship between PMS and
DWA was also analyzed using random effects regression
analysis (10). A two-way analysis of variance was used to
compare PMS between groups and between experiments. The
differences between groups and between experiments were
tested by multiple comparisons with a Bonferroni correction.
P , 0.05 was considered significant.
RESULTS
Table 1 shows the physiological measurements at
baseline and after inhalation of saline or carbachol in
each experiment. Inhalation of saline did not change
the baseline RL in either the acute or sustained experiments. Inhalation of carbachol significantly increased
RL in both the acute and sustained experiments. In the
sustained experiment, RL plateaued after three or four
inhalation periods. RL after inhalation of carbachol was
not different between the acute and sustained experi-
Fig. 1. Schematic diagrams of cross section of airway. Dl
and Ds, long and short diameters, respectively, of outer
border of smooth muscle perimeter; WAi and WAo, inner
and adventitial wall areas, respectively; Po and Ao,
airway outer perimeter and area, respectively; Pmo and
Amo, outer muscle perimeter and area, respectively; Pi
and Ai, airway internal perimeter and area, respectively.
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made, and eight blocks were excised from both lungs and
fixed in formalin for 24 h. Each block was embedded in the
paraffin, sectioned at 5 µm, and stained with Masson’s
trichrome for morphometric analysis. The shrinkage factor of
the sampled tissue was calculated by comparing the surface
dimensions of the tissue and the surface dimension of the
histological section.
Morphometric measurements. All membranous airways
that were cut in reasonable cross section (a short vs. long
diameter ratio at the smooth muscle border of $0.6) were
examined. Measurements were made by using a Nikon
microscope equipped with a camera lucida attachment and a
digitizing tablet coupled to an IBM-compatible computer. The
measurements (Fig. 1) included 1) the long and short diameters of the outer border of the smooth muscle perimeter, 2)
airway internal perimeter (Pi ) and area (Ai ), where Pi is the
perimeter of the luminal border and Ai is the area enclosed by
Pi, 3) outer muscle perimeter (Pmo ) and area (Amo ), where Pmo
is the perimeter of the outer border of the smooth muscle and
Amo is the area enclosed by Pmo, and 4) airway outer perimeter
(Po ) and area (Ao ), where Po is the perimeter of outermost
adventitial border and Ao is the area enclosed by Po. In cases
in which the airway was attached to an adjacent vessel, an
imaginary line was drawn half way between the two structures to estimate Po. Airways in which over one-third of Po
was attached to an adjacent vessel were omitted from the
analysis. WAi, adventitial wall area (WAo ), and total wall area
(WAT ) were calculated as WAi 5 Amo 2 Ai, WAo 5 Ao 2 Amo,
and WAT 5 Ao 2 Ai. Pmo of the theoretical fully dilated airway
(P*mo) was calculated by adding WAi to the theoretical fully
dilated area (A*i ) and using
1579
1580
AIRWAY WALL DIMENSIONS DURING BRONCHOCONSTRICTION
Table 1. Physiological data
Acute Experiment
Saline
Baseline
Sustained Experiment
Carbachol
After
Baseline
Saline
After
Baseline
Carbachol
After
Baseline
After
RL, cmH2O · ml21 · s 0.033 6 0.008 0.033 6 0.007 0.034 6 0.004 0.082 6 0.020* 0.035 6 0.007 0.036 6 0.005 0.030 6 0.004 0.080 6 0.028*
EL, cmH2O/ml
0.301 6 0.089 0.284 6 0.056 0.238 6 0.091 0.511 6 0.301* 0.321 6 0.221 0.308 6 0.096 0.292 6 0.082 0.602 6 0.204*
BP, mmHg
32.1 6 10.1
25.6 6 6.3*
36.1 6 9.8
25.3 6 5.7*
30.3 6 8.4
24.4 6 5.8*
32.2 6 11.8
20.5 6 6.0*
HR, beats/min
219 6 69
199 6 59*
200 6 49
114 6 54*
210 6 27
173 6 23*
221 6 12
125 6 24*
Values are means 6 SD; n 5 6 rabbits. RL, pulmonary resistance; EL, lung elastance; BP, blood pressure; HR, heart rate. * Significantly
different compared with baseline values, P , 0.05.
tained carbachol experiment was significantly less than
PMS in the acute carbachol experiment. To test whether
the magnitude of PMS was related to the difference in
outer wall area, DWAo was plotted against PMS (Fig. 6).
There was significant positive relationships between
PMS and DWAo.
DISCUSSION
In previous studies from our laboratory, James and
co-workers (13, 14) reported that Pi and WAi are
relatively constant despite smooth muscle contraction
or change in lung volume. These studies have provided
a methodology to calculate PMS and airway narrowing
Fig. 2. Cumulative frequency distributions of internal perimeter for
saline (solid line) and carbachol (dashed line) groups. Top: values in
acute bronchoconstriction experiment. Bottom: values in sustained
bronchoconstriction experiment.
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ments. Systemic arterial blood pressure (BP) and heart
rate (HR) significantly decreased after inhalation of
saline or carbachol in both experiments. The decrease
in BP after acute carbachol treatment was not different
from that after sustained carbachol treatment. However, the change in HR was significantly greater in
carbachol-treated than in saline-treated animals in
both experiments. Although HR after carbachol nebulization tended to be lower in the acute experiment than
in the sustained experiment, there was no statistical
difference between them.
Seven hundred seventy-four airways were selected
for analysis. In the acute experiment, 176 were salinetreated airways and 215 were carbachol-treated airways; in the sustained experiment, 213 were saline
treated-airways and 170 were carbachol-treated airways. The cumulative frequency distribution of Pi for
airways was not different between the saline- and
carbachol-treated animals in either experiment (Fig.
2). The relationships between Pi and the square root of
WAi, WAo, and WAT in each experiment are plotted in
Figs. 3 and 4. These relationships were linear with
mean r2 values for regression ranging from 0.77 to 0.95.
The difference in the regression lines between salineand carbachol-treated groups were expressed as the
mean and 95% confidence intervals in Fig. 5. The
comparison of the regression lines show the following.
1) In the acute experiment (Fig. 3), there were no
difference in the relationships between Pi and square
root of WAi, WAo, and WAT in the saline and carbachol
groups (Fig. 5, A–C). 2) In the sustained experiment
(Fig. 4), there was a significant difference for the Pi vs.
square root of WAo relationship between saline and
carbachol group, indicating that WAo in the carbachol
group was significantly and systematically smaller
than in the saline group over a large range of Pi values
from ,0.3 to 2.7 mm (P , 0.05; Fig. 5E). There was no
significant difference for the Pi vs. square root of WAi
and WAT relationships between saline and carbachol
groups (Fig. 5, D and F), although WAT tended to be
smaller in the carbachol group than in the saline group
(Fig. 5F). 3) In the acute experiment, PMS in the
carbachol group (28.2 6 21.2%) was significantly greater
than in the saline group (10.1 6 12.2%). In the sustained experiment, PMS in the carbachol group (22.026
15.8%) was significantly greater than in the saline
group (6.2 6 5.6%). 4) Although there was no difference
in PMS between the saline groups, PMS in the sus-
AIRWAY WALL DIMENSIONS DURING BRONCHOCONSTRICTION
1581
lary networks in the inner wall and the adventitia
across the smooth muscle layer (9, 12), contraction of
the smooth muscle could cause the relocation of capillary blood and possibly lymph and interstitial fluid.
Therefore, we hypothesized that WAi would decrease
and WAo increases because of relocation of the fluid
during bronchoconstriction.
James and co-workers (13, 14) reported data that
support our hypothesis. They showed that although
there was no significant change, WAi of guinea pig
airways during bronchoconstriction tended to decrease.
In fact, they speculated that relocation of blood or
lymphatic fluid occurred during bronchoconstriction. In
that study, however, they fixed the lung by infusing
formalin through the airway, thus eliminating the
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Fig. 3. Relationship between Pi and square root of different components of airway wall area [WAi, WAo, and total wall area (WAT )] for
saline (s) and carbachol (r) groups in acute bronchoconstriction
experiment. Data were plotted on both log scales. Thin and thick solid
lines, regression lines for these relationships in saline and carbachol
groups, respectively.
by using histological sections and to compare these
variables in similar-sized airways (4, 24). In a theoretical study, Moreno et al. (23) suggested that if conservation of wall area occurs during bronchoconstriction,
then WAi is an important determinant of airway narrowing and that thickening of the inner wall could exaggerate the airway narrowing because of geometric factors.
During smooth muscle contraction, there should be an
increase in stress in the inner wall and a decrease in
stress in the outer wall (17, 19) because the airway wall
is tethered by the elastic recoil through alveolar attachments. This peribronchial and adventitial pressure
should decrease during bronchoconstriction (17). Because there are rich communications between the capil-
Fig. 4. Relationship between Pi and square root of different components of airway wall area (WAi, WAo, and WAT ) for saline (s) and
carbachol (r) groups in sustained bronchoconstriction experiment.
Data were plotted on both log scales. Thin and thick lines, regression
lines for these relationships in saline and carbachol groups, respectively.
1582
AIRWAY WALL DIMENSIONS DURING BRONCHOCONSTRICTION
Fig. 5. Differences of regression lines for relationship between Pi and square root of different
components of airway wall area (WAi, WAo, and
WAT ) between saline and carbachol groups. Solid
lines, mean difference between 2 regression lines;
dotted lines, 95% confidence interval. A–C, acute
experiments; D–F, sustained experiments.
Fig. 6. Relationship between percent smooth muscle shortening
(PMS) and change in outer wall area (DWAo ). Change in wall area is
difference between predicted wall area and actual wall area of
constricted airways (see text). There are significant linear relationships between PMS and DWAo at r2 5 0.3 and P , 0.001.
measure a decrease in the inner wall during bronchoconstriction could be because the bronchial vessels in the inner
wall of rabbits occupy only a small volume (5, 6) or because
the amount of smooth muscle shortening was not enough
to deform the inner wall and cause thinning of it.
The decreased adventitial area in the sustained
carbachol experiment is more difficult to explain, and
we can only speculate. An alteration in airway perfusion (and presumably microvascular pressure) could
change the airway wall thickness by changing capillary
blood volume and/or transcapillary fluid flux (3, 7, 8). It
is possible that a decrease in the bronchial BP could
decrease the adventitial area. Because BP and HR
significantly decreased after carbachol inhalation (Table
1), indicating a decrease in cardiac output, bronchial
blood flow and microcirculatory perfusion would decrease. Carbachol treatment, on the other hand, is
expected to have a vasodilatory effect on the vascular
bed (18, 26), which would tend to balance the decreased
BP and HR. However, the thinning of the adventitia
was only observed in the sustained carbachol experiment although the magnitude of decrease in BP and HR
was comparable in the acute carbachol experiment,
indicating that decreased perfusion of the adventitia
may not be the major cause of airway thinning. Bronchial blood volume can comprise as much as ,20% of
the total tissue volume at the airways (1, 22). In the
present experiment, the average difference of adventitial area between control and sustained carbachol
airways was ,17%. Therefore, it would be difficult to
explain the decrease of adventitia solely by blood
volume shifts. The fact that the thinning of the adventitia was not observed in the sustained saline experiment
despite comparable decreases in BP and HR suggests that
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surface tension in the lung and airways. This procedure
could result in an altered transmural stress distribution and changes in the location of blood or fluid in the
airway wall. They also did not snare the heart base before
fixing; therefore, most of the blood probably drained out of
the lung and the remaining blood could have redistributed
during the long period of Formalin fixation. In the present
study, we attempted to decrease these artifacts by snaring
the heart base to trap the blood in the lung and rapidly
freezing the lung to prevent redistribution of blood and
fluid in the airway wall.
Contrary to our initial hypothesis, the results showed
no change in WAi in the acute and sustained carbachol
experiments and decreased adventitial area in the sustained carbachol experiment. The reasons we did not
AIRWAY WALL DIMENSIONS DURING BRONCHOCONSTRICTION
We thank Dean English for excellent technical assistance.
This work was supported by the British Columbia Health Research Foundation. M. Okazawa is a scholar of the Canadian Lung
Association.
Address for reprint requests: M. Okazawa, Univ. of British Columbia Pulmonary Research Laboratory, St. Paul’s Hospital, 1081 Burrard St., Vancouver, British Columbia V6Z 1Y6, Canada.
Received 22 June 1995; accepted in final form 13 May 1996.
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deformation of the wall by the sustained bronchoconstriction is required for thinning of the adventitia. Another
observation of interest was that there was a significant
linear relationship between change in PMS and DWAo
(Fig. 6). This suggests that airway deformation caused
by smooth muscle shortening is required for thinning of
the adventitia. In addition, thinning of the adventitia
was only observed in the sustained carbachol group
although PMS was significantly less in this group than
in the acute carbachol-treated group, suggesting that if
the ‘‘airway wall thinning’’ mechanism is operable it is
time dependent and reflects a shift of interstitial fluid
or lymph rather than a shift of vascular volume.
A centrifugal gradient of peribronchial pressure could
be another possible reason for thinning of the adventitia in peripheral airways. In the peripheral airways,
the bronchial capillary plexus communicates with the
pulmonary capillaries. During bronchoconstriction, the
peribronchial adventitial pressure should decrease because of the increased tethering force of the lung
parenchyma. However, it is documented that the interstitial pressure is more negative in the hilum than
around the peripheral airways (2, 16). If this pressure
gradient from peripheral to hilar interstitium increases
during bronchoconstriction, peripheral airway adventitial blood and interstitial fluid could shift toward the
hilum through the vascular plexus and along the airway
axis and the peripheral adventitial area could decrease as a
result. Movement of blood, interstitial fluid, and lymph
toward the hilum would cause peripheral airway wall
thinning at the expense of central airway wall thickening. However, we did not observe relatively greater
airway wall thinning in more peripheral airways.
Another possible reason for the thinning of the
airway wall is that hyperinflation of the lung resulting
from long periods of bronchoconstriction could cause
axial lengthening of the bronchial tree. If conservation
of mass is maintained in the airway wall, then the
lengthening of bronchi would induce a decrease in the
cross-sectional wall area of the airways. However, this
mechanism does not explain the unique observation of
the thinning of adventitia and not the inner wall.
It has been suggested that a geometric consequence
of thickening of the adventitial wall is to ‘‘uncouple’’ the
airway-lung parenchymal interdependence (21), unloading the smooth muscle and resulting in exaggerated
airway narrowing (25). If the adventitial area decreases, the opposite effect is expected during bronchoconstriction. Our results show that during sustained
bronchoconstriction, peripheral airways had a significantly smaller adventitial area and smaller PMS than
during acute bronchoconstriction and support this theoretical analysis. Although the mechanisms are still
unknown, the thinning of adventitia could be a natural
defense to attenuate excessive bronchoconstriction.
1583