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Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada V6T 2B5
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Yamato, H., J. P. Sun, A. Churg, and J. L. Wright.
Guinea pig pulmonary hypertension caused by cigarette smoke cannot be explained by capillary bed destruction. J. Appl.
Physiol. 82(5): 1644-1653, 1997.
Chronic exposure
to cigarette smoke is known to produce pulmonary hypertension in humans
and in animal models, but the etiology of this process is
controversial. To evaluate whether alterations in the structure of the
pulmonary capillary bed or the peribronchiolar arterioles could be
correlated with the pulmonary arterial pressure (Ppa), we examined the
pulmonary vasculature in guinea pigs that had developed pulmonary
hypertension after being exposed to cigarette smoke for 6 mo. The
smoke-exposed animals had a significant increased Ppa compared with the
control (air-exposed) animals (14.4 ± 2.4 vs. 9.9 ± 0.9 cmH2O). In the smoke-exposed
animals, there was an increased percentage of muscularized peribronchiolar arterioles (33.5 ± 5.8% smoke exposed vs. 56.1 ± 5.8% control), and the capillary diameter and density were
significantly decreased in both the center and periphery of the lobule
(center diameter 8.8 ± 1.9, periphery diameter 10.0 ± 2.0 µm,
center density 79 ± 5, and periphery density 84 ± 4 in smoked
exposed vs. center diameter 7.7 ± 1.9, periphery diameter 8.6 ± 2.0 µm, center density 73 ± 6, and periphery density 77 ± 6 in controls). Neither group showed any correlation between
these values and the Ppa. We conclude that although chronic exposure to
cigarette smoke produces alteration of the capillary bed and pulmonary
arterioles secondary to emphysematous air-space enlargement, these
structural findings cannot explain the increase in Ppa. It appears that
pulmonary hypertension due to chronic cigarette smoke exposure is a
result of a primary alteration of capillary or muscular arteriolar
vascular structure but instead may be secondary to alterations of the
dynamic properties of the vascular bed with subsequent increase in
vascular resistance.
emphysema
INTRODUCTION THE ASSOCIATION between pulmonary hypertension and
chronic obstructive pulmonary disease is well recognized, but the
mechanism(s) by which pulmonary hypertension develops is controversial.
Several theories exist, including emphysematous destruction of the
vascular bed (19), hypoxic vasoconstriction (13, 15), decreased
vascular caliber and vessel distensibility due to thickening of the
intima and muscular media of the vessels (13), and increased
intrathoracic pressure secondary to airways obstruction (9). In
previous studies from our laboratory, both animal (20, 22, 25) and human (5, 23, 24), it was have found that cigarette smoke-induced pulmonary hypertension is associated with structural alterations in the
pulmonary vascular bed and with physiological evidence of a rigid
vascular bed (see DISCUSSION for
details). Because increased vascular resistance could be
secondary to alterations of the capillary network or of the arteriole
vasculature, the present study was designed so that the capillary bed
could be evaluated by using vascular casting with scanning-electron
microscopy and morphometry and the peribronchiolar arterioles could be
evaluated by using standard light microscopy. We wished to ascertain
whether any structural abnormalities could be identified by these
techniques could explain the pulmonary arterial pressure (Ppa) in
animals chronically exposed to cigarette smoke.
METHODS A group of eight Cam Hartley guinea pigs were exposed to the smoke of
seven commercially available nonfiltered cigarettes each day, 5 days
each week, for a total of 6 mo while seven guinea pigs were exposed to
room air as a control group. The 6-mo time period was selected because
our previous study (22) showed that airflow obstruction and pulmonary
hypertension were well established at this time period. The smoke
exposure utilized a nose-only chamber and was performed according to
our previously published methodology (22, 25). The animals were housed
under a laminar flow hood on paper-pellet bedding and were provided
with unlimited access to standard guinea pig chow and vitamin
C-supplemented water. The control animals weighed 324 ± 11 (SD) g
at the start and 1,039 ± 148 g at the termination of the experiment
while the smoke-exposed animals weighed 320 ± 18 and 901 ± 108 g at these respective time periods [values not significantly
different (NS) from control].
After anesthesia with intramuscular Innovar-vet (1 mg/kg), a
tracheostomy was performed, and the animal was placed on a respirator with a tidal volume of 5 ml at a rate of 70 breaths/min. A PE-90 cannula was inserted into the carotid artery for measurement of systemic pressure, and a Silastic catheter was inserted into the pulmonary artery by using the technique of Rabinovitch and colleagues (11). A thermoprobe was inserted into the arch of the aorta, and
cardiac outputs were measured by duplicate injections of 0.1 ml
ice-cold saline into the pulmonary artery, with output calculated by
the Columbus rat cardiac computer system. Because wedge pressures cannot be obtained, total pulmonary vascular resistance was calculated as Ppa divided by cardiac output. Total lung capacity was
measured according to our usual protocol (21), with functional residual capacity measured according to Boyle's law and residual volume and
vital capacity measured as the respective volumes at After completion of the physiological measurements, vascular casting of
the right lung was performed as described previously (26). Using the
morphometric procedure documented in Yamato et al. (26), we examined
the alveolar baskets in both the center and periphery of the lung
lobule. In brief, capillary density (volume proportion of capillaries)
was calculated as the ratio of direct capillary hits to total number of
points; to correct for volume, the mean value for each case was divided
by the total lung capacity. Capillary diameter was
measured by using a 42-point grid to randomly select the capillaries.
When a polygonal ring was clearly identified, the area and axial
dimensions of the ring center were measured.
The left lungs were inflated with cold paraformaldehyde at 30 cmH2O pressure. After fixation,
the lung volume was measured by displacement, and the lungs were sliced
in a sagittal plane and a midsagittal section was submitted for
paraffin embedding, sectioning, and staining with hematoxylin and eosin
and with aldehyde fuchsin elastic stains. Mean linear intercept, an
index of air-space size, was calculated by using a 42-point morphometry
grid, counting alveolar intercepts in 10 random sites (1). Muscularized
peribronchiolar arterioles were evaluated by examining 20 random
×40 fields and determining the percentage and number per square
millimeter of lung parenchyma of peribronchiolar arterioles, which had
a double elastic lamina for at least 50% of the vessel circumference.
We chose not to analyze the true muscular arteries because our previous study (22) found no evidence of structural alteration in these vessels,
even after 12 mo of cigarette smoke exposure.
All analyses were performed by using the SYSTAT statistical analysis
system (16). The physiological data and the light-microscopic morphometric data were compared between the two groups by using an
analysis of variance. Regression lines between Ppa and air-space size,
number of muscularized arterioles per square millimeter of lung
parenchyma, and percentage of muscularized arterioles were determined
by using the SYSTAT MGLH program, which also supplies the Pearson
correlation coefficient.
The morphometric data accrued from the examination of the vascular
casts were compared by using a Kruskal-Wallis test for nonparametric
data. Bonferroni corrections were performed as appropriate. Histograms
were constructed by using all of the data points in each group to
provide a visual representation of the distribution of the data.
Regressions between Ppa and the capillary data were constructed in two
different ways. We first utilized the mean value for each animal of the
individual indexes; although capillary density was corrected for lung
volume, the diameter and alveolar ring analyses were examined as direct
means. Because the variance between the animals was less than the
within-animal variation, we then constructed regression lines and 95%
confidence limits for each group by using all of the data points in
each animal and compared the slopes of the two regression lines.
RESULTS The physiological data and light-microscopy structural data are shown
in Table 1, which also indicates the
significance values of the comparisons. The smoke-exposed animals had a
significantly raised Ppa and total pulmonary vascular resistance
compared with the control animals. The cardiac output of
the smoke-exposed animals was slightly decreased compared with the
control animals. Heart rate and systemic pressures were similar in the
two groups. The smoke-exposed animals had significantly more
muscularized arterioles per square millimeter of lung parenchyma
compared with those found in the control animals. Because this number
would be affected by alterations of lung volume, we also calculated the
percentage of muscularized arterioles, a value that should not be
affected by lung volume; significant differences between the two groups remained. The total lung capacity (lung volume) and air-space size were
significantly larger in the smoke-exposed animals compared with the
control animals. Figure 1 shows the overall
(P < 0.001; R = 0.77) and individual group
regressions (NS for each group) between the Ppa and the air-space size
while Fig. 2 shows these regressions
between the Ppa and percent muscularized arterioles (P < 0.01, R = 0.73 overall; NS for each
individual group). Figure 3
shows the regressions between the percent muscularized arterioles and
air-space size (P < 0.001, R = 0.82 overall; NS for each
individual group). In Figs. 1, 2, 3, it is obvious that the overall
correlation is totally dependent on the distinct differences of Ppa and
of air-space size that are found between the control and smoke-exposed animals.
Table 1.
Physical and light-microscopy structural data
The structural analysis of the capillary bed is shown in Figs.
4, 5, 6,
A-D, with each panel being a histogram
comprised of all of the data points for the animals in that
group. The histograms provide a visual representation of
the shift of the data distributions between the control and
smoke-exposed animals. In the smoke-exposed animals, the pulmonary
capillary density is decreased (P < 0.001) and the capillaries are narrowed
(P < 0.001). The capillary rings are
larger (P < 0.001) in the
smoke-exposed animals compared with the controls. These findings are
present in both the center and the periphery of the lung lobules.
Figure 7,
A and
B, shows the regression lines for the
overall mean individual animal data (center of lobule:
P > 0.01, R = 0.63; periphery of lobule:
P < 0.02, R = 0.58) and for each individual group (NS) between the Ppa and the capillary density corrected for lung
volume while Fig. 7, C and
D, shows separate regressions and 95%
confidence limits for all of the data points in the control and
smoke-exposed animals. Figure 8,
A-D, shows regression lines between Ppa and capillary diameter for the overall mean individual animal data (center of lobule: P < 0.02, R = 0.72; periphery of lobule:
P < 0.02, R = 0.60) and for each individual
group (NS), as well as the separate regressions and 95% confidence
limits for all of the data points in the control and smoke-exposed
animals. Figure 9,
A-D, shows the regression lines
between Ppa and capillary ring area for the overall mean individual
animal data (center of lobule: P < 0.01, R = 0.65; periphery of lobule:
NS) and for each individual group (NS), as well as the separate
regressions and 95% confidence limits for all of the data points in
the control and smoke-exposed animals. Figures 7-9 demonstrate
that the two groups are distinctly separated because of the Ppa, that
the individual groups have no correlation between Ppa and the mean
animal mean values of the capillary parameters, and that when all of
the data points are utilized, the slopes of the regression lines
between the Ppa and capillary parameters are almost flat.
DISCUSSION We have previously utilized capillary vascular casts derived from a
subset of the present animals to provide a detailed analysis of
capillary vascular structure after chronic cigarette smoke exposure
(26), and we reported that smoke produced decreased capillary density
and capillary narrowing but no clear evidence of capillary destruction.
The present study was designed to ascertain whether a correlation could
be found between structural changes in either the capillaries or the
peribronchiolar arterioles and the Ppa or total pulmonary vascular
resistance. Our data suggest that, although the capillary and
arteriolar structure is markedly altered, there are no correlations of
these parameters with the physiological data.
These conclusions need to be considered in light of the controversies
that surround the mechanisms behind the development of pulmonary
hypertension in smoke-induced chronic obstructive lung disease. As
noted in the introduction, it has been long believed that pulmonary
hypertension is due to emphysematous capillary destruction, but acute
animal studies have shown that approximately two-thirds of the lung
parenchyma had to be removed before the Ppa rose (reviewed in
Ref. 12), suggesting that simple capillary loss is not an
adequate explanation. There is, nonetheless, an association
of pulmonary hypertension with emphysema in animal models;
several laboratories (3, 6, 8, 14, 18) have been able to produce
hypertension by induction of emphysema with papain, and we also
observed increased Ppa and emphysema in guinea pigs after long-term
exposure to cigarette smoke (20, 22, 25). The altered pressure-flow
relationship found by Rubin and colleagues (24) in their model of
papain-induced emphysema in dogs was interpreted as secondary to loss
of cross-sectional area, supporting the idea that emphysema causes
capillary loss. Martorana et al. (6) found a significant
correlation between air-space size and Ppa in papain-induced emphysema,
and this correlation was again identified in the present study.
However, all of these studies examined well-established emphysema
rather than early lesions. By contrast, in our initial study of
smoke-exposed guinea pigs (22), we found an increase in Ppa after 1 mo
of cigarette smoke exposure, but we were unable to find air-space
enlargement, and there was no evidence of airflow obstruction at that
time. Thus, in our model, the increase in Ppa clearly precedes
emphysema.
It is possible that the increase in Ppa in subjects with airflow
obstruction is due to mechanical factors with redistribution of blood
flow. This hypothesis was supported by data (23) indicating that oxygen
administration during exercise reduced the rise in Ppa regardless of
whether the patients were grouped according to the severity of
emphysema or the severity of airways disease. Wilkinson and colleagues
(17) demonstrated a strong negative correlation between Ppa and forced
expired volume in 1 s, and we have previously found a similar negative
correlation between Ppa and forced expiratory flow between 25 and 75%
of vital capacity (23). Mink et al. (8) found altered
vascular pressure-flow curves and interpreted their results as
indicative of an increased vascular critical opening
pressure. Against this hypothesis is a human study by
Magee and colleagues (5), who found that, although resting Ppa
increased with the severity of airflow obstruction, there was no
evidence of a critical closing pressure and suggested instead that the
vascular bed was rigid and nondistensible. This conclusion was also
reached in our previous animal study (20), where we divided
smoke-exposed guinea pigs into two groups based on the Ppa. We found
that, although both groups had similar severity of emphysema, only the
group with pulmonary hypertension had an altered pressure-flow response
to dobutamine, with a relatively small increase in flow with increasing
Ppa.
A rigid vascular bed could be due to alterations in either the arterial
and/or the capillary bed. The precapillary peribronchiolar vessels (arterioles) are normally poorly muscularized and have a single
elastic lamina (10). In several studies of pulmonary hypertension, both
in humans (2, 17, 23) and animals (3, 14, 20, 22, 25), these vessels
have been shown to be extensively altered, with increased
muscularization and the development of a double elastic
lamina. This phenomenon has been termed arteriolar muscularization (7). In the present study, we found an increase in the
percentage of muscularized arterioles in the smoke-exposed animals, all
of which had increased Ppa. However, in our previous study (20), all
groups of smoke-exposed guinea pigs had similar numbers of muscularized
vessels and similar severity of emphysema, regardless of the Ppa. Thus
it is probable that muscularization of the arterioles is indicative of
vascular injury rather than pulmonary hypertension.
In summary, previous studies have found that chronic cigarette smoke
exposure will result in pulmonary hypertension, which may precede
emphysematous air-space enlargement and/or airflow obstruction.
Although there is muscularization of the pulmonary arterioles, this
appears to occur regardless of whether the Ppa is raised. Alterations
of the structure in the larger arteries appear to occur in humans but
have not been identified in animals chronically exposed to cigarette
smoke. The present study demonstrates that pulmonary hypertension is
not a static phenomenon that can be attributed to alteration of the
capillary vascular bed or to muscularization of the arteriolar vascular
bed. Rather, our study provides support for the hypothesis that
pulmonary hypertension in chronic obstructive pulmonary disease is due
to an alteration [possibly endothelial dysfunction (4)] of
the dynamic function of the vasculature, which is quite separate from
emphysematous lung destruction. Whether this occurs
gradually over time or represents an abrupt change is a matter for
further investigation.
30 and +30
cmH2O transpulmonary pressure.
Test
Control
Smoke Exposed
P Value
Pulmonary arterial pressure, cmH2O
9.9 ± 0.9
14.4 ± 2.4
<0.001
Cardiac
output, ml/min
110 ± 27
81 ± 22
<0.05
Heart rate, beats/min
247 ± 25
222 ± 40
Total pulmonary vascular resistance,
cm · ml
1 · min
0.205 ± 0.018
0.348 ± 0.075
<0.001
Systemic pressure, cmH2O
49 ± 8
42 ± 5
Total lung capacity, ml
38.3 ± 4.1
43.3 ± 5.7
<0.001
No. muscularized
arterioles/mm2 lung
3.3 ± 0.7
5.0 ± 1.0
<0.01
Percent muscularized
arterioles
33.6 ± 5.8
56.1 ± 5.8
<0.001
Air-space size, µm
107 ± 11
157 ± 28
<0.001
Values are means ± SD.
Fig. 1.
Regression of pulmonary arterial pressure
(cmH2O) with air-space size (µm)
by using mean values for each animal. 
, Control animals; 
,
smoke-exposed animals. Long-dashed line, overall regression line for
both groups (R = 0.77); solid line,
regression line for control animals [not significant (NS)];
short-dashed line, regression line for smoke-exposed animals
(NS).
[View Larger Version of this Image (12K GIF file)]
Fig. 2.
Regression of pulmonary arterial pressure
(cmH2O) with percent muscularized
arterioles by using mean values for each animal. , Control animals;
, smoke-exposed animals. Long-dashed line, overall regression line
for both groups (R = 0.73); solid
line, regression line for control animals (NS); short-dashed line,
regression line for smoke-exposed animals (NS).
[View Larger Version of this Image (15K GIF file)]
Fig. 3.
Regression of precent muscularized arterioles with air-space size
(µm) by using mean values for each animal. , Control animals; ,
smoke-exposed animals. Long-dashed line, overall regression line for
both groups (R = 0.82); solid line,
regression line for control animals (NS); short-dashed line, regression
line for smoke-exposed animals (NS).
[View Larger Version of this Image (15K GIF file)]
Fig. 4.
Structural analysis of capillary bed illustrating histograms for
complete data set of capillary density (%) in center
(A) and periphery
(B) of lung lobule in control
non-smoke-exposed animals and in center
(C) and periphery
(D) of lung lobule in smoke-exposed
animals. There is a significant difference between control and
smoke-exposed animals in both center and periphery of lung lobule
(P < 0.001).
[View Larger Versions of these Images (26 + 27 + 27 + 28K GIF file)]
Fig. 5.
Structural analysis of capillary bed illustrating histograms for
complete data set of capillary diameter (µm) in center
(A) and periphery
(B) of lung lobule in control
non-smoke-exposed animals and in center
(C) and periphery
(D) of lung lobule in smoke-exposed
animals. There is a significant difference between control and
smoke-exposed animals in both the center and periphery of lung lobule
(P < 0.001).
[View Larger Versions of these Images (26 + 24 + 28 + 28K GIF file)]
Fig. 6.
Structural analysis of capillary bed illustrating histograms for
complete data set of area
(µm2) of central capillary
ring (pillar) in center (A) and
periphery (B) of lung lobule in
control non-smoke-exposed animals and in center
(C) and periphery
(D) of lung lobule in smoke-exposed
animals. There is a significant difference between control and
smoke-exposed animals in both center and periphery of lung lobule
(P < 0.001).
[View Larger Versions of these Images (32 + 29 + 28 + 27K GIF file)]
Fig. 7.
Regression between pulmonary arterial pressure
(cmH2O) and capillary structure
illustrating relationship between pulmonary arterial pressure and
volume-corrected capillary density
(%/ml3) by using mean values
for each animal. , Control animals; , smoke-exposed animals.
A: data for center of lobule.
B: data for periphery of lobule.
Long-dashed line, overall regression line for both groups (center of
lobule: R = 0.63; periphery of lobule: R = 0.58); solid line, regression line
for control animals (NS); short-dashed line, regression line for
smoke-exposed animals (NS). C (center
of lobule) and D (periphery of
lobule): regressions and 95% confidence limits between pulmonary
arterial pressure and all capillary density data points in control
(solid lines) and smoke-exposed (dashed line) animals. Although the 2 plots are clearly separate because of the differences in pulmonary
arterial pressure, slope of line is flat, indicating no correlation
between pulmonary arterial pressure and capillary
density.
[View Larger Versions of these Images (16 + 13 + 14 + 12K GIF file)]
Fig. 8.
Regressions between pulmonary arterial pressure
(cmH2O) and capillary structure
illustrating relationship between pulmonary arterial pressure and
capillary diameter (µm); (A: center
of lobule. B: periphery of lobule) by
using mean data points for each animal. , Control animals; ,
smoke-exposed animals. Long-dashed line, overall regression line for
both groups (center of lobule: R = 0.72; periphery of lobule: R = 0.60);
solid line, regression line for control animals (NS); short-dashed
line, regression line for smoke-exposed animals (NS).
C (center of lobule) and
D (periphery of lobule): regressions
and 95% confidence limits between pulmonary arterial pressure and all
capillary diameter data points in control (solid lines) and
smoke-exposed (dashed line) animals. Although the 2 plots are clearly
separate because of differences in pulmonary arterial pressure, slope
of line is flat, indicating no correlation between pulmonary arterial
pressure and capillary diameter.
[View Larger Versions of these Images (13 + 11 + 14 + 12K GIF file)]
Fig. 9.
Regressions between pulmonary arterial pressure
(cmH2O) and capillary ring
(pillar) area (µm2)
illustrating relationship between pulmonary arterial pressure and
capillary ring area (A: center of
lobule; B: periphery of lobule) by
using mean data points for each animal. , Control animals; ,
smoke-exposed animals. Long-dashed line, overall regression line for
both groups (center of lobule: R = 0.65; periphery of lobule: NS); solid line, regression line for control
animals (NS); short-dashed line, regression line for smoke-exposed
animals (NS). C (center of lobule) and
D (periphery of lobule): regressions and 95% confidence limits between pulmonary arterial pressure and all
capillary density data points in the control (solid lines) and
smoke-exposed (dashed line) animals. Although the 2 plots are clearly
separate because of differences in pulmonary arterial pressure, slope
of line is flat, indicating no correlation between pulmonary arterial
pressure and capillary ring area.
[View Larger Versions of these Images (15 + 12 + 14 + 12K GIF file)]
ACKNOWLEDGEMENTS
This work was supported by a grant from the Heart and Stroke Foundation of British Columbia and Yukon.
FOOTNOTES
Address for reprint requests: J. L. Wright, Univ. of British Columbia, Dept. of Pathology, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 (E-mail: jlwright{at}unixg.ubc.ca).
Received 6 September 1996; accepted in final form 8 January 1997.
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