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Meakins-Christie Laboratories, Montreal Chest Institute Research Centre, Royal Victoria and Montreal General Hospitals, McGill University, Montreal, Quebec, Canada H2X 2P2
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Lei, M., H. Ghezzo, M. F. Chen, and D. H. Eidelman.
Airway smooth muscle orientation in intraparenchymal airways.
J. Appl. Physiol. 82(1): 70-77, 1997.
Airway smooth muscle (ASM) shortening is the central event
leading to bronchoconstriction. The degree to which airway narrowing
occurs as a consequence of shortening is a function of both the
mechanical properties of the airway wall as well as the orientation of
the muscle fibers. Although the latter is theoretically important, it
has not been systematically measured to date. The purpose of this study
was to determine the angle of orientation of ASM (
) in normal lungs by using a morphometric approach. We analyzed the airway tree of the
left lower lobes of four cats and one human. All material was fixed
with 10% buffered Formalin at a pressure of 25 cmH2O for 48 h. The fixed material
was dissected along the airway tree to permit isolation of
generations 4-18 in the cats and
generations 5-22 in the human
specimen. Each airway generation was individually embedded in paraffin.
Five-micrometer-thick serial sections were cut parallel to the airway
long axis and stained with hematoxylin-phloxine-saffron. Each block
yielded three to five sections containing ASM. To determine , we
measured the orientation of ASM nuclei relative to the transverse axis
of the airway by using a digitizing tablet and a light microscope (×250) equipped with a drawing tube attachment. Inspection of the
sections revealed extensive ASM crisscrossing without a homogeneous orientation. The was clustered between 
20° and 20°
in all airway generations and did not vary much between generations in
any of the cats or in the human specimen. When was expressed
without regard to sign, the mean values were 13.2° in the cats and
13.1° in the human. This magnitude of obliquity is not likely to
result in physiologically important changes in airway length during
bronchoconstriction.
morphometry; angle of orientation; cats; human
INTRODUCTION ASTHMA IS CHARACTERIZED by bronchial
hyperresponsiveness, the capacity of the airways to narrow excessively
in response to both specific and nonspecific stimuli (17). Of the many
factors potentially contributing to bronchoconstriction, airway smooth muscle shortening is believed to play the central role (17, 18). The
characteristics of airway smooth muscle are, therefore, of great
interest in the understanding of the pathophysiological basis of
hyperresponsiveness. Although there is evidence to suggest that asthma
is associated with airway smooth muscle hyperplasia and hypertrophy (5,
7, 10, 11), less is known regarding the arrangement of airway smooth
muscle within the airway wall. Bates and Martin (1) reported a modeling
analysis that underscores the potential contribution of airway smooth
muscle arrangement to the mechanics of airway narrowing. Their study
suggests that the bronchoconstrictive effect of airway smooth muscle
shortening is a function of both the material properties of the airway
wall and the way in which airway smooth muscle is arranged around the airway wall. To the extent that airway smooth muscle is arranged obliquely, there is the possibility that shortening of the muscle could
be associated with changes in airway length as well as changes in
caliber.
It has long been known that the arrangement of airway smooth muscle
bundles varies according to location within the airway tree. In the
trachea, smooth muscle is arranged transversely at right angles to the
long axis of the airway. In the periphery of the lung, smooth muscle is
said to be arranged in a helical fashion (16). Relatively little has
been reported regarding the precise geometry of the smooth muscle
despite the theoretical possibility that its arrangement could be of
importance. Ebina et al. (8) reported that smooth muscle is arranged at
an angle of 30° to the long axis of the bronchi by using
three-dimensional reconstruction of intraparenchymal airways. Such a
large angle, if confirmed, would have important implications for the
way in which airway smooth muscle shortening is transduced into airway narrowing (1). Current models of bronchoconstriction (26) ignore this
possibility, in part because of lack of data.
In the present study, we wished to investigate the orientation of
airway smooth muscle in a more systematic fashion. To do this, we
employed a method of directed sampling in which the airway wall is
sectioned parallel to its long axis. This approach permits an
examination of the airway smooth muscle in histological sections "en
face" in a relatively rapid and convenient way that is well suited
to the task of measuring airway smooth muscle orientation. This
approach has been previously used for descriptive purposes at least
since the time of Miller (16), but it has never been applied to
quantitative measurements. We successfully applied this method to the
measurement of airway smooth muscle orientation in both the cat and the
human.
MATERIALS AND METHODS Cats
Histological Preparation
Dissection. After fixation, Formalin was gently expelled from the lung and the airways were reinflated with 2% colored gelatin solution to distinguish between lung parenchyma and the bronchial tree. We used a volume of gelatin sufficient to ~80% of the fixed volume estimated from the weight of the specimen (22). This permitted identification of the airways without altering the airway dimensions. The main bronchus was clamped, and the lobes were cooled to 4°C for 30 min to solidify the gelatin for easy dissection. Once cooled, the first bronchial branch (including bronchi and bronchioles) from the left caudal lobe was dissected free of lung parenchymal tissue.Classification. Relatively little information is available regarding the classification of feline airway generations, but the cat appears to have an analogous anatomic configuration to the human and other large mammals (4, 24, 27). We therefore used the method of Weibel (22) to classify airway generations, setting the trachea as generation 0. Generation numbers then increased at each succeeding branch point. Airway identification proceeded from the lobar airway to the periphery following the principal (larger) daughter branch at each branch point.
Tissue preparation. Airway generations 4-5, which have large cartilage plates, were immersed in Fisher Calex solution for decalcification for 48 h. The bronchial tree from generations 6-18 was placed in a plastic cassette; generations 4-5 were placed in another plastic cassette for tissue processing through graded alcohols, xylene, and paraffin overnight. After dehydration processing, the bronchial tree was infused with paraffin to harden the specimen and to minimize further shrinkage. We could then easily divide the bronchial tree into segments at branch points where each segment represents one generation. Airway generations 4-18 were cut transversely by using a dissecting microscope.
Embedding, slicing, and staining. Segments of airway between branch points were embedded in melted paraffin blocks at 60°C in a longitudinal position. From each block, 5-µm-thick serial longitudinal sections were cut parallel to the airway long axis. Sections were obtained every 5 µm from the outer to the inner aspect of the airway wall. The tissue sections were mounted and stained with haematoxylin-phloxine-saffron. With this stain, the nuclei of smooth muscle cells were stained blue with a red cytoplasm and elastic fibers were stained yellow. Care was taken to ensure that the long axis of the airway could be identified. All sections from each generation were examined for airway smooth muscle content, and those sections containing muscle (3-5 per generation) were used for measurement of smooth muscle orientation.
Human specimen. One adult human left upper lobe was obtained from a surgical excision for lung cancer in a patient without bronchial asthma. There was no evidence of malignancy in the resected lobe. The lobe was fixed in 10% Formalin with the same conditions as above. Airway generations 4-22 were dissected and removed from the lingular division of the upper lobe. Airway generations 4-6 were cut off transversely and immersed in Fisher Calex solution for decalcification for 48 h. Airway identification was carried out as above. The bronchial tree from generations 7-22 was divided into two parts to accommodate the larger size of the airway tree. The remaining processing was carried out in a manner similar to that done with the cat airways.
Morphometry
Measurement reference. A necessary part of studies that concerns directional organization of tissue is the establishment of a reference against which measurements can be compared or evaluated. We attempted several methods, including the placement of markers in paraffin blocks and on slides, but found that the best reference was to use the anatomic organization of the airway wall itself. It has been known, at least since the study of Miller (16), that elastic fibers run parallel to the long axis of the airway between branch points.Measurement of angle of orientation of airway smooth
muscle (). It has been previously
observed that smooth muscle cells are spindle shaped with a single
centrally placed nucleus occupying the wide portion of the cell about
midway along its length and elongated along the long axis of the fiber
(13). Airway smooth muscle cells are rarely multinucleated, and nuclei
have been previously used for verification of the presence of
hyperplasia in the airways (3). Because the nuclei are more easily seen
than the cells themselves but are orientated parallel to axis of the
cells, we chose to use them for measurement of the orientation of
airway smooth muscle fibers.
Sampling. Preliminary studies
suggested that ~100 nuclei per generation needed to be measured to
ensure optimal reproducibility. The following algorithm was used to
sample nuclei. Serial longitudinal sections containing muscle were
examined in a stepwise fashion. A microscope eyepiece cross hair
(effective length 0.1 mm) was superimposed on the middle of the
section, and all nuclei touching this line were measured. With this
approach, typically 20-25 nuclei representing ~10% of the
nuclei on each section were sampled. This was repeated in successive
sections until all 100 nuclei were measured or the specimen was
exhausted. In practice, three to five sections were measured depending
on the thickness of the specimen. For all measurements, the edge of the
airway corresponding to the higher generation, i.e., the periphery of
the lung, was positioned away from the observer. Angles were measured
as positive or negative in the standard counterclockwise way with
respect to a line transverse to the axis of the airway (Fig.
1). Thus a nucleus with a positive angle
was positioned on a right-handed spiral toward the peripheral airways.
Conversely, a nucleus with a negative angle was positioned in a
left-handed spiral.
). Specimen was aligned with long axis of (ASM)
airway vertical, and was measured relative to transverse axis.
Microscopy. All measurements were
carried out by using a conventional light microscope (Leitz, NJ) at
×250 magnification. The microscope was equipped with a cross hair
in the eyepiece that was used as a marker to define the orientation of
the airway. The slide was placed on a microscope stage, and the cross
hair was aligned with the longitudinal axis of the tissue section. The
microscope was equipped with a drawing tube attachment that was used to
observe the tracer from the digitizing tablet (Jandel Scientific, Corte
Madera, CA), which was superimposed on the microscope image. A computer
software package (Sigma-Scan, Jandel Scientific) was used to measure
from the projected images.
RESULTS
Figure 2 shows photomicrographs of airway smooth muscle cut in longitudinal section at ×100 magnification; the principal axis of the bronchus runs vertically. Each panel represents one individual airway generation. Smooth muscle fibers lie approximately parallel to each other and are organized into bundles separated from one another by spaces filled with connective tissue. There was a tendency for the density of the bundles to diminish as one moved to the peripheral airways. The numerous elastic fibers stained yellow and were easily seen to run discontinuously between smooth muscle sheets.
The average number of nuclei measured per generation, ranging from 65 to 79, was similar among cats (Table 1). The number appeared to vary with airway generation; the smaller number of smooth muscle bundles in the periphery made it impossible to reach the target of 100 nuclei per section in the smallest airways. The number of nuclei measured and the variability were similar among the four cats.
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Smooth muscle fibers were oriented with both negative and positive values, mostly varying between 20° and 20° (Fig.
3). The distribution of varied greatly
across generations, exhibiting asymmetrical peaks (Fig.
4). Each of the cat specimens
showed a tendency for the proximal airways to have a larger proportion of muscle fibers with a negative . In large airways, distributions were narrower than in medium and small airways. A flat distribution was
found in peripheral airways, implying that the smooth muscle follows an
increasingly crisscross arrangement with increasing airway generation.
as function of airway generation in
cat 1. Proportion, proportion of
nuclei. is distributed approximately symmetrically around 0°
with majority of nuclei falling between 20° and
20°.
as function of generation in 4 cats.
A: generation
4. B:
generation 8.
C: generation
12. D:
generation 16. It can be seen that
distributions of were similar among cats. Distributions tended to
broaden with increasing airway generation.
The distribution of was qualitatively similar in the human lung
studied (Table 2). The shape of the
distributions in the human lung was somewhat more consistent across
generations than in the cats and did not show any tendency to flatten
in the higher generations. The distributions were also asymmetrical in
the human lung but, in contrast to the cats, had a larger proportion of nuclei with a positive .
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From a mechanical point of view, it is the absolute value of of the
muscle that is most important. was therefore also analyzed
independent of the sign of the angle (Table
3). If only the magnitude of
was considered, the average ranged from 12 to 14° in the four
cats in multiple airway generations. The overall mean value of was
13.2°. The results for the human specimen were qualitatively
similar to the observations in the cats with a mean value of of
13.1°.
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Given that the potential for these measurements is operator dependent,
we assessed the reproducibility of the en-face technique between
observers as follows. Two observers independently measured in all
generations of cat 1. We then compared
the distributions of the measurements by using a quantile-quantile plot
(2) as shown in Fig. 5. It can be seen that
at values of >5°, the measurement was highly reproducible. At
values <5°, there was a tendency for the second observer to
systematically report lower values than did the principal observer (who
measured the remaining specimens). Although there was also some
disagreement between observers at >25°, the error was small
relative to the measured values.
. Ordered results for 2 observers are plotted against each other; regression coefficient is
measure of reproducibility. There was good reproducibility among
observers, particularly at >5°.
DISCUSSION
We measured airway smooth muscle orientation across the airway tree by using a method based on two-dimensional histological sections cut along the longitudinal axis of the bronchial wall (en-face dissection). Although the orientation of individual fibers within an airway generation was variable, the mean fiber orientation was consistently between 10 and 15° in all specimens studied. En-face dissection appears to be a direct reproducible method of measuring airway smooth muscle orientation across many generations of intraparenchymal airways.
Airway smooth muscle orientation has the potential to influence the
mechanics of airway narrowing by influencing the vector of forces
acting on the airway wall during bronchoconstriction. The theoretical
basis for this has been discussed by Bates and Martin (1), who
constructed a theoretical model of the influence of airway smooth
muscle orientation on the relationship between muscle shortening,
muscle tension, and airway narrowing. Briefly, depending on the
mechanical properties of the airway wall, a portion of the force
developed during airway smooth muscle shortening potentially could act
to shorten the length of the airway as well as to cause airway
narrowing. The greater the value, the more likely it is for a
change in airway length to occur.
In their analysis, Bates and Martin (1) considered three cases
according to the constitutive properties of the airway wall. In
case 1, the airway is longitudinally
stiff. Under these conditions, modeling demonstrates that the degree of
airway closure for a given amount of muscle shortening is critically
dependent on . For in the range measured in the present study,
airway smooth muscle is expected to shorten by ~40% to result in
airway closure under case 1 conditions, requiring development of relatively less tension than for
values of >30°. In case 2 in
their analysis, Bates and Martin considered the circumferentially stiff
airway. Under these arguably unrealistic conditions, values of <30° imply the need for development of relatively high levels of
muscle tension to result in increased airway resistance, albeit with minimal shortening. Bates and Martin also considered a
case 3, in which the airway was both
circumferentially and longitudinally stiff. For <45°, the
results of the modeling qualitatively resemble those found under
case 1 conditions, although the muscle
is expected to generate higher levels of tension to increase airway
resistance.
Current approaches to the modeling of airway narrowing assume that
smooth muscle fibers are arranged around the airway circumference perpendicular to the long axis of the airway (25). It is therefore important to consider how values of closer to 15° would alter interpretation of these models. Although insufficient information is
currently available regarding the stiffness of the airway wall to
determine which of the above cases is most pertinent, it seems reasonable to speculate that pure case
2 conditions (airways much stiffer circumferentially
than longitudinally) are unlikely. For airways that are much more
compressible circumferentially than longitudinally
(case 1), a value of near
15° is not very different mechanically from 0°. In that case,
predictions from models that assume airway smooth muscle is arranged
perpendicular to the airway long axis will not be affected. For airways
that are compressible both longitudinally and circumferentially, there
are quantitative differences between the modeling results at 0 and
15°, although qualitatively they are similar (1).
It is somewhat deceiving to discuss as a single number, since our
data demonstrate considerable variation in within each generation.
Values of vary between 40° and 40°, with the
majority of between 20° and 20°. Furthermore, the
distribution is often asymmetric, particularly in the more proximal
airways, so that airway smooth muscle orientation tends to favor one
direction of coiling over the other. Although this finding is
intriguing, there is no obvious explanation for it. Smooth muscle has
been described as being helically arranged in other tubular structures, including the gut (9, 15), the ureter (14), and the vasculature (12).
In these organs, the musclaris is far more complete than in the
airways, and muscle fibers are arranged in well-defined layers that may
run perpendicular to each other. Thus in these tissues smooth muscle
serves as a connective tissue support as well as an agent that effects
propulsion of luminal contents. In contrast, in most
species the airways have relatively little muscle and appear to depend
on cartilage, other connective tissue, and surrounding structures for
mechanical support, particularly in the large airways. Nevertheless,
the presence of fibers wound in both directions and varying in
orientation likely contributes to the structural stability of the
airways. Furthermore, the crisscross arrangement of fibers may help
prevent buckling in the airway during muscle shortening.
A potential source of error in measurements of fixed pulmonary tissue
is the influence of shrinkage after fixation, which largely results from tissue dehydration (21). For measurements of
smooth muscle nuclear orientation, it is the relative shrinkage of
length to width that is critical, since the ratio of these measurements
forms the basis of the calculation of . To place an upper limit on
the size of any error associated with shrinkage (23), we measured
shrinkage of both length and width in four fixed feline tracheae.
Shrinkage averaged 4.5% for length and 11.5% for width. The
relatively isotropic nature of the shrinkage in this tissue is expected
given structural dominance of horizontal cartilaginous plates in the
trachea and is expected to decrease as one moves to the
periphery. Even this degree of anisotropy would yield
only a small error in ; however, if we assume a true of 13°,
the measured would be 14°. Given the small magnitude of this
error, we did not correct our results for shrinkage.
There are at least two reasons to believe that our measurements may
represent an upper limit on smooth muscle orientation. First, our
measurements were made in lobes inflated to near total lung capacity
(transpulmonary pressure = 25 cmH2O) before fixation. Because this tends to stretch the airways lengthwise, it would maximize
relative to transverse axis of the airways. To the extent that the
airway tree passively shortens with decreasing lung volume,
measurements from lungs closer to functional residual capacity might be expected to yield even lower values. An additional technical factor was uncovered when we verified
the reproducibility of measurements between observers. To do this,
we constructed a quantile-quantile plot (2) by using independent
measurements of from two observers. We found that the en-face
technique were very reproducible both within and between observers for
values between 5 and 25° (Fig. 5). Some differences between
observers of >25° were present, although they were relatively
small (i.e., <5%). On the other hand, for <5°, i.e.,
for muscle fibers that were arranged nearly parallel to the transverse
axis of the airway, there was less reproducibility: one observer
reported much higher values than the other. Because the results
reported here are those of the observer with the higher values for ,
it is possible that our finding of a mean value near 13° is also an
overestimate.
Relatively little has been published regarding quantitation of airway
smooth muscle orientation. Ebina et al. (8) used three-dimensional
reconstruction to measure the quantity of airway smooth muscle in
peripheral airways (6) and looked for evidence of hyperplasia and
hypertrophy in airways of subjects with asthma and chronic obstructive
pulmonary disease (7). In the course of these studies, they noted that
airway smooth muscle was orientated obliquely and stated that the
average value ~30°. This result is considerably higher than
our own, and we cannot directly account for the difference. No detailed
information is given in their report regarding the inflation volume or
the exact technique used to measure orientation, nor do they report any
systematic study across airway generations (8). It is possible that,
because their study was not designed to specifically investigate airway smooth muscle orientation, their sampling technique was not optimal to
address this question. It is also of interest to compare our findings
with those of Opazo-Saez et al. (19), who recently reported that when
assessed with a mechanical technique in rabbit airways, airway smooth
muscle orientation had an average of ~13°. This finding,
remarkably similar to our own, provides independent corroboration for
our results. Very recently, Sparrow et al. (20) used confocal
microscopy to study the innervation of the distal airways of fetal
pigs. Although they did not quantitate airway smooth muscle orientation
per se, they did observe evidence of circumferential arrangement of
airway smooth muscle.
Although the findings presented here will be useful in modeling studies
of bronchoconstriction, it is important to note that we did not
directly measure asthmatic airway smooth muscle. It is possible that
hypertrophy and hyperplasia of airway smooth muscle might alter the
distribution of airway smooth muscle cell orientation in asthmatic
airways, particularly in severely asthmatic individuals with a great
deal of airway remodeling. Unfortunately, we were not able to obtain
asthmatic tissue for study. Nevertheless, our data as well as those of
other investigators (19, 20) suggest that at least in healthy lungs is not large.
In conclusion, in the intraparenchymal airways, airway smooth muscle appears to be oriented at a slight angle relative to the transverse axis of the airway. Despite some modest regional heterogeneity in the distribution of airway smooth muscle orientation, it is remarkably uniform across generations. Although final determination of the physiological importance of airway smooth muscle orientation awaits detailed study of the constitutive properties of the airway wall, the modest degree of obliquity we have found is not likely to greatly influence the mechanics of bronchoconstriction.
ACKNOWLEDGEMENTS
The authors are indebted to C. Dolman for excellent technical assistance.
FOOTNOTES
Address for reprint requests: D. H. Eidelman, Meakins-Christie Laboratories, McGill Univ., 3626 St. Urbain St., Montreal, Quebec, Canada H2X 2P2.
Received 8 April 1996; accepted in final form 21 August 1996.
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M.-U. T. Tran, A. J. Weir, M. V. Fanucchi, A. E. Murphy, L. S. Van Winkle, M. J. Evans, S. M. Smiley-Jewell, L. Miller, E. S. Schelegle, L. J. Gershwin, et al. Smooth muscle development during postnatal growth of distal bronchioles in infant rhesus monkeys J Appl Physiol, December 1, 2004; 97(6): 2364 - 2371. [Abstract] [Full Text] [PDF]
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S. M. Smiley-Jewell, M. U. Tran, A. J. Weir, Z. A. Johnson, L. S. Van Winkle, and C. G. Plopper Three-dimensional mapping of smooth muscle in the distal conducting airways of mouse, rabbit, and monkey J Appl Physiol, October 1, 2002; 93(4): 1506 - 1514. [Abstract] [Full Text] [PDF]
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E. H. Oldmixon, K. Carlsson, C. Kuhn III, J. P. Butler, and F. G. Hoppin Jr. {alpha}-Actin: disposition, quantities, and estimated effects on lung recoil and compliance J Appl Physiol, July 1, 2001; 91(1): 459 - 473. [Abstract] [Full Text] [PDF]
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F. R. Shardonofsky, T. M. Officer, A. M. Boriek, and J. R. Rodarte Effects of smooth muscle activation on axial mechanical properties of excised canine bronchi J Appl Physiol, April 1, 2001; 90(4): 1258 - 1266. [Abstract] [Full Text] [PDF]
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