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THE ANATOMICAL RECORD 252:92–101 (1998)
Computerized Morphometry
of the Pulmonary Vasculature Over
a Range of Intravascular Pressures
JILL A. OHAR,* K.S. WALLER, TANYA J. WILLIAMS, DOUGLAS A. LUKE,
AND DAPHNE E. DEMELLO
Departments of Internal Medicine, Pathology, and Public Health, St. Louis University
School of Medicine, St. Louis, Missouri 63110–0250
ABSTRACT
Recent availability of computerized image analysis has fostered hope
that barium injection and landmarking of pulmonary arteries would be
unnecessary for morphometric assessment when using this technique. We
reasoned that if barium injection altered morphometric variables, it would do
so in a linear fashion correlating with incremental increases in injection
pressure of the barium. The two goals of the present study were to determine
whether barium injection into arteries affected morphometric measurements
and to determine whether incremental increases in injection pressure correlated with alterations in morphometric measurements in a linear fashion.
Computerized image analysis was used to measure the internal elastic
lamina (IEL) and external elastic lamina (EEL). Medial area (MA), luminal
area (LA), percentage of medial thickness, IELÎMA, and idealized LA were
calculated. Barium injection did not alter morphometric variables in a linear
fashion correlating with incremental increases in injection pressure of the
barium except the percentage of arteries that filled with barium. Maximum
recruitment for pre-acinar arteries occurred at 40 mmHg pressure and 60
mmHg distending pressure for intra-acinar arteries. Incremental increases in
injection pressure did not affect IEL, EEL, or calculated morphometric
variables. However, IEL, medial thickness, and MA were all smaller in
injected vessels than in uninjected vessels. IELÎMA and the ratio of
measured vs. idealized LA were both increased in injected lungs. We suspect
that vascular injection selects for evaluation, a population of smaller,
thin-walled vessels, which in the uninjected lungs are collapsed and hence
excluded from analysis. Anat. Rec. 252:92–101, 1998. r 1998 Wiley-Liss, Inc.
Key words: computer-assisted diagnosis; pulmonary artery; pulmonary
circulation; pulmonary hypertension; vascular resistance;
vascular smooth muscle
Computerized interactive morphometric analysis entails measurement of the internal elastic lamina (IEL)
circumference and the outer limit of the media, often
demarcated in larger vessels, by the external elastic
lamina (EEL). The computer then, by using integrals,
calculates the actual area occupied by the media and
lumen. Computer-assisted morphometric analysis is based
on the premise that medial cross-sectional area and IEL
circumference of the vessel wall are independent of intravascular distending pressure, thus raising the hope that
the practice of uniform vascular distension would no
longer be necessary (Cook and Yates, 1972). Traditional
morphometric analysis requires preparation of the lungs
r 1998 WILEY-LISS, INC.
under uniform conditions to ensure accurate comparisons.
Lungs for morphometric evaluation are traditionally fixed
after intravascular injection of a barium sulfate/gelatin
suspension at a standard supraphysiologic pressure (73
mmHg). This method has been used to eliminate indi-
Grant sponsor: American Heart Association, Missouri affiliate.
*Correspondence to: Jill A. Ohar, M.D., Division of Pulmonology, St. Louis University Health Sciences Center, 3635 Vista
Avenue, 7FDT, St. Louis, MO 63110–0250.
E-mail: oharja@wpogate.slu.edu
Received 14 November 1997; Accepted 10 April 1998
COMPUTERIZED PULMONARY MORPHOMETRY
vidual variability and permit measurement under a uniform convention of true structural change caused by
experimental conditions or disease. The viscosity of the
barium–gelatin mixture permits filling of the arterial tree
but not capillaries; thus, it aids in the histologic distinction
of intra-acinar arteries from veins (Elliott and Reid, 1965).
Furthermore, barium sulfate–gelatin solidifies rapidly and
therefore maintains uniform distention of pulmonary arteries at the pressure with which the barium sulfate gel was
injected. Barium sulfate angiograms can be used to evaluate the overall growth pattern of the vasculature and
alterations in flow distribution, as in thromboembolic
disease and Swyer-James syndrome. The growth pattern
or flow distribution of the pulmonary vasculature may also
be assessed in a section of lung by the number of bariumfilled arteries relative to the number of alveoli visible in a
high power field. Traditionally, a ratio is calculated of the
number of alveoli per the number of barium-filled arteries.
This value increases when small arteries become sclerosed, as in pulmonary hypertension, or fail to develop
normally, as in congenital heart disease (Rabinovitch et
al., 1978; Rabinovitch and Reid, 1980). This ratio is also
altered in experimental models of pulmonary hypertension induced by monocrotaline or hyperoxia (Jones et al.,
1985). Theoretically, raising intravascular distending pressure increases pulmonary vascular recruitment and could
influence the findings in this assessment. However, barium
sulfate injection of lung tissue necessitates an intact
pulmonary arterial tree to permit vascular injection and
thus precludes the use of biopsy specimens, thereby limiting its usefulness in humans.
Implicit in computer-assisted morphometric studies of
the pulmonary vasculature is the assumption that the IEL
and EEL do not change length as a consequence of
pathologic remodeling or when fixed at supraphysiologic
pressures. Although several studies using this technique
have been published (Ono and Voelkel, 1991, 1992; Ono et
al., 1992; Sheedy et al., 1996; Zhao et al., 1996), the
assumption that the IEL and EEL do not change has not
been proven by a controlled comparison of computerassisted vs. traditional methods. Cook and Yates (1972)
referred to unpublished data to state that at physiological
pressures no lengthening of the IEL occurs when an artery
is distended, presumably when compared with undistended arteries; they did not comment on the effect of the
supraphysiologic pressures characteristic of pulmonary
hypertension. Further, they discussed systemic rather
than pulmonary arteries and did not refer to disease
states. In contrast, Fernie and Lamb (1985) concluded
that, at supraphysiologic intravascular distending pressure, the IEL of fixed pulmonary arteries vs. undistended
arteries does stretch by a factor of 1.5. They deduced this
by comparing the slope of the linear regression of the IEL
circumference related to the square root of the medial area
(MA) in pulmonary arteries injected at a pressure of 75
mmHg; the arteries were grouped by size rather than by
landmarking to the accompanying respiratory structure.
The lungs used in these studies were obtained at autopsy
from patients who died of obstructive lung disease, heart
failure, and other unrelated conditions (Fernie and Lamb,
1985; Fernie et al., 1985).
Published research has not supported the assumption
that the IEL and EEL are unaffected by pathologic remod-
93
eling. In the normal rat, Davies et al. (1985) showed that
the IEL is longer than EEL in pulmonary arteries more
than 48 µm in external diameter, whereas the EEL is
longer than the IEL in those less than 48 µm. In the
hypoxic rat, this relationship is changed, thus demonstrating unreliability in comparing an elastic lamina in disease
with normal lamina. Furthermore, in an animal model of
pulmonary hypertension produced by platelet activating
factor (PAF) (Ohar et al., 1990, 1991), we showed that at all
levels the IEL and EEL circumferences are reduced under
the experimental conditions. This finding and the reduction in external diameter (ED) of hilar pulmonary arteries
that occurs in chronic hypoxia (Davies et al., 1985) because
of contracture of the arterial wall points to a plasticity of
the vascular wall that is quickly apparent in disease
states.
Also implicit in the applications to date of computerassisted morphometric analysis in the pulmonary vasculature is the assumption that landmarking is not necessary.
However, by definition, a morphometric study is one that
quantifies structural elements. In the pulmonary vasculature, structural characteristics of the arterial wall such as
muscularization are dictated by the level of the artery
within the branching system, and pathologic processes
extend the level to which muscularization is seen. The
level of branching of the pulmonary arteries is by convention ‘‘landmarked’’ by identifying the accompanying respiratory structure (i.e., bronchiole, terminal bronchiole, respiratory bronchiole, alveolar duct, and alveolar wall).
Landmarking of pulmonary arteries by the accompanying
airway and categorization of vessel walls as muscular,
partly muscular, or nonmuscular is an accepted method for
quantification of structural characteristics that permits
comparison of normal with diseased vessels or with vessels
of different species at the same level in the branching
system. Therefore, studies that do not landmark risk
comparison of structurally different populations of pulmonary arteries in diseased vs. normal specimens or among
species from different species.
To evaluate the validity of computerized morphometry
in the analysis of pulmonary vascular structure, we studied the effect of a range of intravascular distending pressures on IEL circumference, medial cross-sectional area,
and the ratio of the number of alveoli per number of
barium-filled arteries per unit area. The two goals of the
study were to determine (1) whether the presence of
barium sulfate injected under pressure into the pulmonary arteries affected morphometric measurements at all
and (2) whether incremental increases in injection pressure
affected incremental alterations in morphometric variables.
MATERIALS AND METHODS
Animal Preparation
Female New Zealand white rabbits weighing 2–3 kg
were killed with a pentobarbital injection. The chest was
immediately opened, the pulmonary artery cannulated,
and the lungs flushed at an intravascular distending
pressure of 20 mmHg with phosphate buffered saline at
room temperature. The left atrium was opened widely to
prevent back-pressure before flushing commenced, and
flushing continued until the left atrial effluent was clear.
The lungs were submerged in normal saline solution and
stored frozen at 0°C until they were injected with barium
94
OHAR ET AL.
Fig. 1. Barium sulfate angiogram. Barium was injected at a pressure of 40 mmHg for 15 min. The
background blush in the periphery of the lung is consistent with adequate filling.
sulfate and fixed with formalin. Freezing eliminated intravascular tone and also allowed injection of the lungs in
batches to reduce variability of injection conditions. Frozen lungs were compared with lungs injected without the
freezing step, and no difference in vascular filling and
structural integrity was noted.
Barium Sulfate Injection and Fixation
Lungs were thawed and warmed to 37°C by submersion
in warmed normal saline solution. The main pulmonary
artery was cannulated (2-mm outer diameter tubing), and
a solution consisting of barium sulfate (70% weight/
volume) suspended in gelatin (7% weight/volume solution
in water warmed in a water bath to 60°C) was injected into
the pulmonary artery at a constant pressure until vessels
underlying the visceral pleura were visible and filled in a
typical snowflake pattern (5–15 min). Distending pressures used were 20, 30, 40, 60, 70, and 80 mmHg. The
snowflake pattern was visible in all lungs, but a longer
injection time was required at lower pressures. For a
seventh, ‘‘zero-pressure group,’’ lungs were not injected
with barium. The trachea of each lung was then cannulated and filled with formalin by gravity. A head pressure
of formalin (20 cm water) was maintained while the lungs
were submerged in formalin for 3 days. The lungs were
then radiographed to visualize filling of the intra-acinar
Fig. 2. Fully and partly muscularized arteries are visible at all airway
levels in the rabbit. The size range, quantified by external diameter, of
muscularized arteries differed widely across airway levels. B, bronchiole;
TB, terminal bronchiole; RB, respiratory bronchiole; AD, alveolar duct;
AW, alveolar wall.
vasculature by the presence of a uniform background
‘‘haze’’ and thus suitability for morphometric studies. In
each group, lungs from four rabbits were selected based on
the radiographs (Fig. 1). In the lower pressure group,
although four angiograms could be included, many more
COMPUTERIZED PULMONARY MORPHOMETRY
95
Fig. 3. The percentage of arteries filled with barium progressively increases with increasing intravascular
distending pressure up to 60 mmHg for intra-acinar arteries and up to 40 mmHg for pre-acinar arteries. No
further recruiting occurs at higher pressures.
injections were rejected as unsatisfactory vs. those in the
higher pressure groups.
Percentage of Arteries Filled by Barium
and the Arterial:Alveolar Ratio
From the angiograms it was apparent that the different
distending pressures did not alter filling of the larger
pre-acinar arteries. To assess recruitment, three features
were analyzed in each high power field (HPF: (1) alveolar
density as a measure of lung distension, (2) the number of
barium-filled vessels per unit area, and (3) the total
number of vessels less than 200 µm and greater than 10
µm in diameter per unit area. The calculated ratio of
feature 2 to feature 3 is a measure of arterial recruitment.
Twenty HPFs from the left lower lobe were analyzed for
each of four animals in each intravascular pressure group.
Using the number of alveoli within an HPF as an index of
lung distension (presuming normal alveolar development
in these adult rabbits), the number of veins included in the
total vessel count should remain constant.
Sectioning and Staining
Five blocks of lung tissue approximately 1.5 cm 3 1.5 cm
were obtained from each animal by slicing along the
lingula and upper and lower lobes parallel to the hilum:
1.0 cm from the hilum for the right upper lobe, 1.4 cm for
the right middle lobe, 1.8 cm for the right lower lobe, 1.4 cm for
the left upper lobe, and 1.8 cm for the left lower lobe. Lung
blocks were embedded in paraffin, sectioned (5 µm thick), and
stained by the Verhoeff–van Gieson method. One stained
slide was examined from each block, yielding a total of five
stained slides that were studied from each animal.
In the rabbit, fully muscularized arteries are present
down to the respiratory bronchiolar level, with a range of
1,000–94 µm, and include a complete IEL and EEL. Distal
to this, partly muscular arteries (150–31 µm) are seen as
far as the alveolar wall and only an IEL is present.
Nonmuscularized arteries can be as large as 150 µm in
diameter (Fig. 2).
Morphometric Analysis
A computer-assisted image analysis system (American
Innovision, San Diego, CA) was used to measure several
variables in cross-sectioned arteries accompanying bronchioli, terminal bronchioli, respiratory bronchioli, and
alveolar ducts and within alveolar walls. Twenty arteries
per airway level per animal were evaluated, resulting in
evaluation of 100 arteries per animal. Morphometric measurements were made directly from the glass slide. Magni-
96
OHAR ET AL.
Fig. 4. Internal elastic lamina (IEL) circumference measurements are
unaffected by intravascular distending pressures. B, bronchiole; TB,
terminal bronchiole; RB, respiratory bronchiole; AD, alveolar duct; AW,
alveolar wall. IEL circumference (inset) is significantly less in injected
intra-acinar (AW and AD) arteries (striped bars) than in uninjected arteries
(solid bars). Barium sulfate injection likely facilitates selection of smaller
arteries for evaluation by the morphometrist. These smaller arteries are
often collapsed in uninjected specimens and thus excluded from the
evaluation.
fied images were relayed from a Nikon Labophot (Model
197873, Japan) light microscope through a Javelin Chromochip II (Model JE3462HR, Javelin Electronics, Japan)
video camera to a standard videoscreen. For vessel morphometry, only barium-filled arteries were measured. Only
arteries that were cut in good cross section (defined as the
lengths of perpendicular diameters differing by ,10%) and
measuring 50–1,000 µm in diameter were analyzed. The
measured parameters included the circumference of the
IEL and EEL when present. The IEL and EEL of each
arterial profile were traced with the computer cursor
(mouse) on the screen to record the circumference. From
these tracings, a computer program using integrals calculated the two areas, the area between the EEL and IEL
(medial area), and the area enclosed by the IEL (luminal
area). The intima was so thinned by the intravascular
distension that the endothelium sat directly on the IEL,
and intimal thickness (area between IEL and endothelium) could not be measured.
Calculated Morphometric Variables
Calculated variables included percentage of medial thickness, IELÎMA, and idealized lumen area (LAideal). Percent
of medial thickness was calculated according to the following formula: medial thickness 5 [(M1 1 M2)/2] diameter 3
100%. The thickness (M1 and M2) was taken as it was cut
at two positions along the shortest ED. The IEL divided by
the square root of the medial area was taken to indicate
the relation of medial thickness to arterial size (Fernie et
al., 1985; Fernie and Lamb, 1985).
LAideal is an idealized circle that the IEL would circumscribe if it were ‘‘smoothed out.’’ LAideal was calculated
from the IEL circumference according to the following
formula:
LAideal 5 p
3 2p 4 .
IEL 2
COMPUTERIZED PULMONARY MORPHOMETRY
97
Fig. 5. External diameter is unaffected by intravascular distending pressure. B, bronchiole; TB, terminal
bronchiole; RB, respiratory bronchiole; AD, alveolar duct; AW, alveolar wall. At the alveolar wall level (AW),
external diameter is significantly smaller in barium-injected arteries (striped bars) than in uninjected arteries
(solid bars in inset).
In idealized, fully distended arteries, LAmeasured/LAideal is
equal to 1 (Davies et al., 1985). In constricted arteries, the
ratio is ,1. The more constricted an artery, the lower the
ratio value.
0.01 was considered to be significant. Data are expressed
as the mean 6 the standard deviation.
Statistical Analysis
RESULTS
Percentage of Arteries Filled by Barium
and the Arterial:Alveolar Ratio
Two separate statistical analyses were conducted. First,
to determine whether morphometric variables measured
in uninjected lungs were comparable to morphometric
variables measured in injected lungs, the means of variables from all injected groups (20–80 mmHg) were compared with the means of variables measured in uninjected
specimens (0-mmHg pressure) by Student’s t-test. Second,
to determine the effect of different distending pressures on
the variables measured from the arteries in each injection
pressure group, the means of the variables measured in
each pressure group (20–80 mmHg) were compared by
analysis of variance followed by a test for linear trend. P ,
At the pre-acinar level, the percentage of barium-filled
arteries, a measure of vascular recruitment, tended to
increase with increasing intravascular distending pressure in a linear fashion. The trend apparent at the
pre-acinar level was not statistically significant. At the
intra-acinar level however, the percentage of arteries filled
with barium increased significantly with increasing intravascular distending pressure (Fig. 3). Full recruitment or
complete filling of pre-acinar arteries occurred at an
intravascular distending pressure of 40 mmHg, whereas
60 mmHg was required for full recruitment of intra-acinar
arteries. As would be expected from these data, the alveolar:
98
OHAR ET AL.
Fig. 6. Medial area is unaffected by increasing intravascular distending pressure. B, bronchiole; TB, terminal bronchiole; RB, respiratory
bronchiole; AD, alveolar duct; AW, alveolar wall. In barium-injected
arteries (striped bars), the medial area is significantly smaller than in
uninjected arteries (solid bars) at all airway levels (inset).
arterial ratio tended to be greater in lung tissues injected
at 20–40 mmHg than in lung tissues injected at 60–80
mmHg (data not shown).
Morphometric Analysis
The IEL circumference tended to be smaller in injected
arteries than in uninjected arteries. This difference in IEL
circumference was significant at the alveolar wall and
alveolar duct levels (Fig. 4). When injected arteries were
evaluated for effect of intravascular distending pressure
on IEL circumference, no linear relationship could be
identified (Fig. 4).
The ED was significantly smaller in the injected than in
the uninjected arteries only at the alveolar wall level (Fig.
5). There was no significant difference in ED between
injected and uninjected arteries at all other airway levels,
and ED was unaffected by distending pressure at all
airway levels (Fig. 5).
The MA was significantly smaller at every airway level
in injected arteries than in uninjected arteries (Fig. 6). A
linear trend between MA and distending pressure was not
identified.
Fig. 7. Luminal area measurements were unaffected by increasing
intravascular distending pressure or by barium injection (inset).
There was no significant difference in lumen area between injected and uninjected arteries at any airway level
(Fig. 7). Further, among injected arteries, no linear trend
was found between distending pressure and measured
lumen area at any airway level (Fig. 7).
Calculated Morphometric Variables
At every airway level the medial thickness was significantly smaller in the injected than in the uninjected
arteries (Fig. 8). When injected arteries were evaluated for
effect of intravascular distending pressure on medial thickness, no linear relationship could be identified (Fig. 8).
The IELÎMA was significantly smaller in uninjected
than in injected arteries at every airway level (Fig. 9).
Among injected arteries, there was no significant linear
trend between IELÎMA and intravascular distending
pressure identified at any airway level (Fig. 9).
The ratio of measured vs. idealized lumen area was
significantly smaller in uninjected than in injected arteries at all airway levels (Fig. 10). However, no significant
linear trend at any airway level could be established
between intravascular distending pressure and lumen
area ratio (Fig. 10).
COMPUTERIZED PULMONARY MORPHOMETRY
99
Fig. 8. Medial thickness is unaffected by increasing intravascular distending pressure. B, bronchiole; TB, terminal
bronchiole; RB, respiratory bronchiole; AD, alveolar duct; AW, alveolar wall. Medial thickness (inset) is significantly
smaller in barium-injected arteries (striped bars) than in uninjected arteries (solid bars) at all airway levels.
DISCUSSION
One goal of the present study was to determine whether
the presence of barium injected into arteries affected
vascular morphometric measurements. We reasoned that
if barium injection did affect measurement of morphometric variables, it would do so in a linear fashion correlating
with incremental increases in injection pressure. Therefore, the second goal of the present study was to determine
whether incremental increases in barium injection pressure correlated linearly with alterations in vascular morphometric measurements, indicating a cause-and-effect
relationship. We found that comparison of injected (injecting pressure 20–80 mmHg) with uninjected arteries showed
significant differences: in injected vessels, IEL circumference, medial thickness, and medial area were all smaller
than those in uninjected vessels. IELÎMA and the ratio of
measured vs. idealized lumen area were both increased in
injected lungs. This result is contrary to our expectation
that increasing intravascular distending pressure would
progressively stretch the IEL and thin the media, thus
producing an incremental increase in IEL circumference
and a decrease in medial thickness and cross-sectional
medial area. Whereas barium-injected arteries did have a
reduced medial thickness and medial area as compared
with uninjected arteries, the IEL circumference was also
decreased. One explanation for this phenomenon is that
vascular injection selects for evaluation, a population of
smaller, thin-walled vessels, which in the uninjected lungs
are collapsed and hence excluded from analysis.
The only measurement that was linearly affected by
increasing intravascular distending pressure was the increased percentage of arteries that filled with barium. For
pre-acinar arteries, maximum recruitment occurred at
40-mmHg pressure; for intra-acinar arteries, this was
achieved at 60-mmHg distending pressure. In injected
vessels, incremental increases in the barium injection
pressure did not affect IEL circumference, external diameter, medial thickness, medial area, or lumenal area.
Today there is widespread acceptance of computerassisted image analysis techniques for morphometric evalu-
100
OHAR ET AL.
Fig. 9. Top: Comparison of the slope of the linear regression of the
internal elastic lamina circumference related to the square root of the
medial area (MA) (IELÎMA) is unaffected by increasing intravascular
distending pressure. B, bronchiole; TB, terminal bronchiole; RB, respiratory bronchiole; AD, alveolar duct; AW, alveolar wall. Bottom: IELÎMA is
significantly smaller in uninjected arteries (solid bars) than in injected
arteries (striped bars) at all airway levels.
ation of pulmonary arteries. The evolution of these techniques was predicated on inflexibility of the circumference
of the IEL and the medial area despite increasing intravascular distending pressures. Our study validates this concept as did the work of Cook and Yates (1972). However,
Fernie and Lamb (1985) claimed that the IEL does stretch
based on the different slopes of the regression lines derived
from IELÎMA in a lung injected with barium sulfate at a
pressure of 73 mmHg compared with the uninjected contralateral lung. However, their study included patients with
known pulmonary pathology, and the vessels analyzed
were not landmarked according to accompanying respiratory structure. In many pathologic conditions, vascular
remodeling occurs, resulting in extension of the muscular
coat to a more distal level in the vascular tree, medial
hypertrophy, and lengthening or shortening of the elastic
laminae (Jones et al., 1985; Ohar et al., 1991). Therefore,
in the study by Fernie and Lamb (1985), it is not clear that
vessels at the same level in the vascular tree were compared. Furthermore, in their study, the medial areas of the
measured vessels were not reported.
Fig. 10. Top: The ratio of measured to idealized lumen area is
unaffected by increasing intravascular distending pressure. B, bronchiole;
TB, terminal bronchiole; RB, respiratory bronchiole; AD, alveolar duct;
AW, alveolar wall. Bottom: The ratio of measured to idealized lumen area
is unaffected by barium injection (striped bars, injected arteries; solid
bars, uninjected arteries).
Computer-assisted image analysis for evaluation of pulmonary arteries represents a technologic advance that
allows rapid measurement of large numbers of morphometric variables that can be easily downloaded for statistical
analysis. It does not circumvent the need for landmarking
of pulmonary arteries to accompanying respiratory structure, and it does not facilitate direct comparison of bariuminjected vessels to uninjected vessels because barium
injection facilitates evaluation of a population of thinwalled vessels that is generally eliminated from analysis
in uninjected specimens because of vessel collapse.
ACKNOWLEDGMENT
We are indebted to Lynne M. Reid, M.D., for her
patience, assistance, and critical review of the manuscript.
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