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Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California, Davis, California 95616-8732
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway smooth muscle remodeling is implicated in a number of constrictive pulmonary diseases such as asthma and may include changes in smooth muscle orientation and abundance. Both factors were compared in the normal distal bronchioles of the mouse, rabbit, and rhesus monkey (respiratory bronchioles included). Airway smooth muscle was measured by using a three-dimensional approach employing confocal microscopy and whole-mount cytochemistry with fluorochrome-conjugated phalloidin, a probe for polymerized actin. Smooth muscle orientation had a wide range of angles along the airway, but the distribution was conserved among species and among distal airway generations. At the bifurcation of proximal bronchioles, smooth muscle was nearly parallel to the longitudinal axis of the airway. Smooth muscle abundance was significantly different between species (abundance was less in the monkey compared with the mouse and rabbit), and there was a trend for abundance to decrease with each more distal airway generation. This study defines the normal distribution of smooth muscle in three test species and provides a basis for future comparisons with the diseased state.
species comparison; bronchiole; actin; peripheral airways; lung
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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AIRWAY SMOOTH MUSCLE REMODELING is implicated in a number of pulmonary diseases, including chronic obstructive pulmonary disease (35), sudden infant death syndrome (9), and asthma (6, 11). In each of these diseases, airway smooth muscle has been found to be increased (6, 9, 11, 35). For example, the excessive airway narrowing that occurs in asthma has been speculated to be due, in part, to increased smooth muscle contracting around a thickened airway wall. To assess the degree of involvement of smooth muscle in asthma and other diseases, smooth muscle needs to be studied in the healthy state first. Important factors to define include the abundance of smooth muscle as well as its orientation because both can influence the degree of airway constriction.
Defining the normal range of smooth muscle bundle abundance within an airway is key to understanding the potential restrictive capacity of airways, especially in animals used as models to study these types of disease. Changes from this baseline reveal how smooth muscle is changing with disease, as occurs in asthma. Little is known about how disease affects smooth muscle orientation. Smooth muscle has been described as being increasingly oriented in a helical pattern in the central and distal airways (22, 37). A helical arrangement gives muscle bundles both a longitudinal, or shortening, force and a circumferential, or narrowing, force (10), which influences the amount of constriction possible. The few quantitative studies of smooth muscle orientation have varied in the species studied, airway generations measured, methodology, and results (8, 17, 25). Human smooth muscle bundles have been found at various angles ranging from 0 to 30° from the transverse axis of the airway (8, 17, 34). In the cat, Lei et al. (17) found the average angle of smooth muscle in the conducting airways to be 13.1°, and Opazo-Saez et al. (25) calculated the average angle in the lobar bronchi of the rabbit to be 12.4 ± 3.5°.
The purpose of this study was to compare smooth muscle orientation and abundance (number of bundles per airway length) in the distal bronchioles of three species used to study allergic airway disease: the mouse, the rabbit, and the rhesus monkey (1, 18, 32). These species were also chosen because they represent the spectrum of airway sizes, and the rabbit lung is frequently used to model peripheral airway compliance (23, 38). Furthermore, the rhesus monkey has respiratory bronchioles, as do humans. Mice and rabbits do not have respiratory bronchioles.
This study focuses on the peripheral airways (bronchioles) because there is evidence that they contribute to constrictive airway disease (4, 15). Compared with larger airways, the bronchioles have a larger proportion of the airway wall consisting of smooth muscle (8, 20). The bronchioles have little to no cartilage to resist deformation (10), so the same degree of muscle shortening has a greater effect on the caliber of the small airways compared with large airways (41). Macklem and Mead (19) first demonstrated that peripheral airway resistance cannot be detected above 80% vital capacity. However, at lower capacities, peripheral airway resistance comprises 15% of the total lung resistance. Studies of peripheral airway function have been few because of the difficulty in separating their contribution to pulmonary mechanics from the large contribution of the more proximal airways. Yet there is much morphological data showing that distal airways undergo significant airway remodeling in lung diseases such as asthma (7, 12). For example, smooth muscle thickness and inflammatory infiltrate are significantly increased in bronchioles of patients suffering sudden fatal asthma (30). The dynamic changes caused by inflammation during nocturnal asthma have been attributed to perturbation of peripheral airway function (14). The peripheral airways are thought to be the major site of airway obstruction in asthma (16), and this has been verified by direct measurements of intrabronchial pressure in living asthmatic patients (42). Furthermore, smooth muscle in peripheral airways has been found to have heightened contractility in patients with chronic obstructive pulmonary disease (24).
In this study, airway smooth muscle was mapped and measured by using a three-dimensional approach employing confocal microscopy and whole-mount cytochemistry with fluorochrome-conjugated phalloidin, a probe for polymerized actin. The three-dimensional approach allows expedient study of large areas of sample without having to do serial sections. Issues defined include 1) how smooth muscle orientation and abundance vary among distal airway generations and 2) how smooth muscle orientation and abundance vary among the three animal species studied.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals and Experimental Protocol
Three adult male CFW Swiss Webster mice were obtained from Charles River (Wilmington, MA). Three young adult male New Zealand White rabbits were obtained from Kralek Farms (Turlock, CA). One female and three male juvenile rhesus monkeys were obtained from University of California Regional Primate Research Center (Davis, CA). All animals were free of respiratory disease. Animals were anesthetized with an overdose of pentobarbital sodium and killed by exsanguination. Lungs were infused in situ with 1% paraformaldehyde (Electron Microscopy Sciences, Fort Washington, PA) in 0.1 M phosphate buffer via tracheal or lobar bronchus cannulation. All lungs were inflated at 30 cmH2O for 1 h to ensure uniform inflation for muscle orientation. The right cardiac lobe of the mouse, the left cranial lobe of the rabbit, and the caudal part of the left middle lobe of the monkey were removed. The lobes were glued to coverslips by their costal surfaces with the use of Nexaband S/C veterinary adhesive (Veterinary Products, Phoenix, AZ) for dissection and whole-mount viewing. Beginning at the lobar bronchus, the axial pathway and its distal side branches were exposed by microdissection (26, 27). Smooth muscle orientation and abundance were defined for the costal half of the airways. Dissected lobes were permeabilized with 0.3% Triton X-100, washed with PBS, incubated in 0.066 µM Alexa Fluor 568 phalloidin (Molecular Probes, Eugene, OR), which stains polymerized actin, for 20 min, and washed with PBS.Confocal Microscopy
Axial pathways were imaged by using laser scanning confocal microscopy (BioRad MRC 1024 ES mounted on an Olympus BX50WI microscope) as described previously (28, 36). Briefly, a ×10 long working distance water-immersion objective was used to see smooth muscle labeled with Alexa Fluor 568 phalloidin (EX 578; EM 600) in the conducting airways. Before imaging began, airway generation was determined by direct count of all branches, beginning at the lobar bronchus and continuing along the axial path to the most proximal respiratory bronchiole. One to three bronchiolar axial pathways per animal were evaluated. Airway sites imaged within a bronchiolar axial pathway (Fig. 1) included the terminal bronchiole (TB); the next two most proximal airway generations, proximal bronchiole generation 1 (PG1) and proximal bronchiole generation 2 (PG2); the bifurcation (BF) between PG1 and PG2; and, in the rhesus monkey, the first and second respiratory bronchioles distal to the terminal bronchiole (RB1 and RB2, respectively). Respiratory bronchioles were identified by the presence of alveolar outpocketing. The terminal bronchiole was defined as the airway generation proximal to RB1. A series of images was taken through each three-dimensional sample (airway generation) at focal planes that were 20-40 µm apart and that had a depth of focus of 20 µm. These images were stacked together to produce a three-dimensional composite of the distal airway tree (Fig. 1). Between 25 and 50 images were used for each composite. Final magnification used for measurements was ×170.
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Quantitation
Three-dimensional composites were used to measure the orientation and abundance of airway smooth muscle. The entire airway of each generation, between the proximal branch point and the distal branch point, was measured. Orientation was based on the transverse axis of the airway (17). Zero degrees was considered transverse to the long axis of the airway, and 90° was considered parallel (Fig. 2). Three longitudinal uniform random sampling intercepts were evenly placed on an airway composite. The intercepts conformed to the curvature of the airway. At interceptions with smooth muscle bundles, the angle of each smooth muscle bundle was measured, and the absolute value was taken. The number of angles per airway generation was recorded in increments of 5°, ranging from 0 to 90° from the transverse axis of the airway. Each increment of 5° represented angles that were ±2.5° from the increment value (for example, 5 ± 2.5°). Data are presented as percentage of bundles per 5° increment for each airway generation and represent the sum of all bronchiolar axial pathways per animal species. The average bundle angle and standard deviation per airway generation and animal species were calculated as well. Smooth muscle orientation for each generation was compared with adjacent generations within and among species by
2 analysis using a two-way contingency
table (SAS; SAS Institute, Cary, NC). Angles >30° were summed for
statistical testing. Statistical significance was P < 0.05. Smooth muscle abundance was calculated as the number of smooth
muscle bundles per 100 µm of airway length. Data are expressed as
means ± SD for each airway generation and animal species. Smooth
muscle abundance for each generation was compared with adjacent
generations within and among species by analysis of variance (SAS).
Statistical significance was P < 0.05. The
intraspecies coefficient of variance was calculated as well (SAS).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Three-Dimensional Composites
Initial observation of three-dimensional composites of bronchiolar smooth muscle revealed differences in smooth muscle orientation and abundance between airway generations and among species (Fig. 1). All airways and species had smooth muscle bundles that appeared to be oriented nearly parallel to the longitudinal axis of the airway at bifurcations. This orientation was especially prominent at the bifurcation of PG1 and PG2.Smooth Muscle Bundle Orientation
Mouse.
Smooth muscle was oriented over a wide range of angles (0-45°)
within each bronchiolar generation (Fig.
3). The percentage of smooth muscle
bundles at each angle changed between the airways. The distribution of
angles was significantly different between PG2 and the TB
(P < 0.035) and between the PB1 and the TB
(P < 0.039). The average angle of smooth muscle
changed for each airway generation; the average was 12.10 ± 8.96° in PG2, 11.05 ± 8.84° in PG1, and 13.77 ± 9.75°
in the TB. At the bifurcation of PG2 and PG1, the range of angles
shifted to greater values compared with the airway segments; the range
fell between 25 and 90° (Fig. 4). The
average angle of smooth muscle at the bifurcation of PG2 and PG1 was
66.25 ± 24.81°, 52° greater than the largest average angle in
the airways (TB = 13.77°).
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Rabbit.
Smooth muscle orientation was oriented over a wide range of angles (0 to 90°) within each bronchiolar generation (Fig.
5). The distribution of angles in the
terminal bronchiole was significantly different between the rabbit and
the mouse (P < 0.003). The wider range of angles is
reflected in greater average angles of smooth muscle compared with the
mouse. In the rabbit, the average was 15.80 ± 14.77° in PG2,
16.93 ± 17.00° in PG1, and 18.82 ± 19.30° in the TB. At
the bifurcation of PG1 and PG2, the greatest percentage of muscle
bundles was found at 90°, parallel to the long axis of the airway
(Fig. 4). The average angle of smooth muscle at the bifurcation was
73.90 ± 16.42°, the largest average bifurcation angle of the
three animal species.
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Rhesus monkey.
Smooth muscle orientation was similar among distal bronchioles (Fig.
6). The monkey had average angles of
smooth muscle that were greater than those of the mouse but smaller
than those of the rabbit for each corresponding airway generation;
monkey average values were 13.99 ± 13.03° in PG2, 14.34 ± 11.33° in PG1, and 16.59 ± 15.04° in TB. Compared with the
mouse, the distribution of angles in the TB of the monkey was
significantly different (P < 0.009). In the
respiratory bronchioles of the monkey, the average angle of smooth
muscle was 15.98 ± 11.93° in RB1 and 15.60 ± 11.45° in
RB2. At the bifurcation of PG1 and PG2, the average angle of smooth
muscle was 61.67 ± 30.05°, the smallest average angle of the
three animal species (Fig. 4).
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Smooth Muscle Bundle Abundance
Mouse.
The average value of smooth muscle abundance was greater in the
proximal bronchioles compared with the TB (Fig.
7). There was significantly more smooth
muscle abundance in PG1 compared with the TB (4.97 ± 1.02 bundles
per 100 µm of airway length vs. 2.73 ± 1.11 bundles,
respectively). PG2 had an average of 3.63 ± 1.11 bundles per 100 µm of airway length. The coefficient of variance ranged from a low of
20.5% in PG1 to a high of 40.6% in the TB.
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Rabbit. Average values of smooth muscle abundance in the rabbit were similar to those in the mouse (Fig. 7). PG2 and PG1 had significantly more smooth muscle abundance than the TB; PG2 and PG1 each had ~4.6 bundles per 100 µm of airway length vs. 3.33 ± 0.44 in the TB. The coefficient of variance ranged from a low of 13.2% in the TB to a high of 21% in PG1.
Rhesus monkey. Average values of smooth muscle bundle abundance in the monkey were approximately half of those in the mouse and rabbit (Fig. 7). When the same airways were compared among species, abundance in the monkey was significantly decreased in the following airways: PG1, compared with the mouse, and PG2, PG1, and TB, compared with the rabbit. Average smooth muscle abundance was 2.17 ± 0.46 bundles per 100 µm of airway length in PG2, 1.83 ± 0.47 in PG1, and 2.21 ± 0.41 in the TB. A comparison of airway generations within the monkey found that RB1 and RB2 had significantly less smooth muscle abundance than the TB; 1.57 ± 0.24 bundles per 100 µm of airway length in RB1 and 1.59 ± 0.32 bundles in RB2. The coefficient of variance ranged from a low of 15.3% in RB1 to a high of 25.7% in PG1.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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A major component of airway remodeling in chronic airway diseases displaying hyperreactive airways is smooth muscle hyperplasia and hypertrophy. However, smooth muscle bundle orientation and abundance are rarely addressed. This study was designed to establish a baseline of smooth muscle distribution in the healthy state. Our study addresses the question of whether the orientation and abundance of smooth muscle are similar among distal airway generations (bronchioles) because there is evidence that peripheral airways contribute to constrictive airway disease (4, 15, 16). To establish whether smooth muscle is organized similarly in distal bronchioles of different animal species used to study airway disease, the distribution of smooth muscle was compared in the same airway generations in the mouse, rabbit, and monkey.
The first issue addressed was smooth muscle orientation. Rather than being arranged circumferentially, bundles of smooth muscle were found at angles ranging from 0 to 90° from the transverse axis of the airway. Only the mouse was found to have significant differences in smooth muscle orientation between airway generations. Miller (22) and von Hayek (37) described a spiral pattern of airway smooth muscle years ago with the use of serial sections, and smooth muscle bundles of the respiratory bronchiole in humans have been observed to spiral into the framework of the central alveolar ducts (39). The three-dimensional approach used in this study verifies these earlier observations and emphasizes the complexity of bundle arrangement within the airway tree.
A spiral arrangement of smooth muscle has been found in other tubular structures of the body, such as the urinary tract (21) and wall of the systemic muscular arteries (3). This arrangement has been speculated to be a protective device; the longitudinal (shortening) force and the circumferential (contracting) force work in some aspects against each other to protect the lumen from completely shutting down (10). Angularity allows muscle to "reach its limiting stress at a greater luminal diameter" (16). The angular arrangement (based on average angle of smooth muscle per airway) tends to increase in degree with increasing distance down the airway tree. Distal airways have little to no cartilage, and the walls are thinner and more pliable. Thus a more extreme angular arrangement may protect the lumen from complete closure.
Smooth muscle orientation was remarkably similar among the mouse, rabbit, and monkey. When comparisons were done on an airway-by-airway level basis, only the mouse terminal bronchiole was significantly different from the other two species. The only previous study comparing smooth muscle orientation between species (cats and humans) found that the mean angle for the entire airway tree was identical in those species, ~13° from the transverse axis (17). In contrast, a study of normal human autopsy lung indicated that the majority of the smooth muscle in "membranous bronchioles" was oriented ~30° from the transverse axis (8). Comparison with the present study is somewhat difficult because this study focused on the most distal conducting airways and used the point of alveolarization as the boundary for defining the position of the airways, whereas the other studies did not precisely define airway position. When our data are summarized by averaging the mean angle of the TB and the two next proximal bronchiole generations (Figs. 3, 5, and 6), the resulting angle from the transverse axis is 12.3° in the mouse, 17.2° in the rabbit, and 15° in the monkey. These values are in the range for average angle previously reported for the distal airways of cats and humans. Perhaps there is a physiological optimum in having smooth muscle with a mean angle of <20° from the transverse axis, and this is an evolutionary conservation. This knowledge may help in the development of mathematical models of constrictive airway disease and in the application of previously developed models.
The orientation of smooth muscle at the bifurcation of PG1 and PG2 was markedly different from that of the airway generations measured. The range of smooth muscle bundles shifted to higher angles (25-90°), and more than one-half of the smooth muscle bundles were 65° or greater. Longitudinally oriented smooth muscle has been observed previously but has never been analyzed quantitatively. In 1937, Miller (22) described "a triangular arrangement at the place where branches are given off" and illustrated smooth muscle distribution in a reconstruction of distal bronchioles in dog lung. He proposed that this orientation had to do with the arrangement of elastic fibers, which also wrap around branch points in a triangular fashion. Our study showed a wider number of fibers with a longitudinal orientation than in Miller's diagram and a wider range of orientation angles at the branch point. Longitudinally oriented smooth muscle is found in the vascular system and has been proposed as a way of offsetting extreme circumferential stress (13).
We also addressed whether there was a difference in smooth muscle abundance based on the density of bundles (number per unit airway length). Abundance did change with airway level. In the mouse and rabbit, smooth muscle abundance decreased in a proximal to distal direction. In the monkey, smooth muscle abundance was significantly less in RB than in the TB. Furthermore, the monkey had approximately one-half the bundle density of the mouse and rabbit in PG2, PG1, and the TB.
The three-dimensional approach used here is similar to what has been used to map the development of nerves and smooth muscle in the airway tree of the pig and human (34, 40). The advantages of using a three-dimensional approach using laser scanning confocal microscopy are that it allows rapid study of large surface areas without the need for serial sections, and the large surface area gives rare phenomena a greater chance to be observed than in traditional cross sections (36). In the pig and human studies, smooth muscle was reported to lie perfectly transverse to the long axis of the airway. Differences between the pig and human studies and ours may be due to methodology. The pig and human lungs were not fixed via inflation-perfusion, which could cause the geometric arrangement of smooth muscle around the airway to be misrepresented.
The three-dimensional approach allows for highly reproducible analysis of changes in quantity of smooth muscle. One of the key features of smooth muscle organization that may alter airway hyperreactivity and contractility, bundle abundance, may be masked by these two-dimensional approaches. The rationale for measuring density of smooth muscle rather than cross-sectional area is that this approach allows comparison of smooth muscle bundle abundance in relation to airway size (length). Cross-sectional area does not allow for this comparison. Although cross-sectional area can give an estimate of smooth muscle bundle mass, it does not indicate bundle density, which is also important if bundles do not increase in size but rather increase in number. In addition, because area is not normally adjusted for airway size or other static paramenters (such as basement membrane) in sections, it is much more susceptible to sampling bias and may be skewed by airway size. These issues are not a concern for our approach because we have sampled the entire airway. Estimates of smooth muscle abundance based on morphometric analysis on the volume per unit surface area, or the percentage of the airway wall mass, occupied by smooth muscle cannot distinguish among changes in bundle angle, increases in number of cells per bundle (smooth muscle hyperplasia), or individual increases in smooth muscle cells (smooth muscle cell hypertrophy).
Presumably, muscle mass is proportional to the strength of the muscle and hence its capacity to produce hyperresponsiveness. Total smooth muscle mass is the product of both the cross-sectional area of each bundle and the number of bundles. Current direct in vitro measurements of smooth muscle constriction are of two types: 1) those that measure decreases in the airway lumen of cross-sectional pieces (5, 33) and 2) those that measure force transduction directly in airway segments (29, 31). It is important to note that all of these preparations contain multiple bundles and that they generally measure muscle shortening in only one direction. Increased force may be due either to more bundles or to larger individual bundles. This also assumes that mass of smooth muscle is the only determinant of airway constriction. However, orientation, innervation, prior stretch, and smooth muscle receptor expression as well as the inherent elasticity of the airway tissue as a whole are additional factors that also influence constriction.
The differences in abundance among the airway generations found in this study may be related to the pliability of the airway generation, with distal airways needing less smooth muscle abundance for constriction purposes. Numerous studies quantifying smooth muscle mass do not address the issue of bundle density (see Ref. 12 for recent review). Our study substantiates that bundle density differs among distal airway generations as well as between species.
One of the key questions related to smooth muscle orientation and abundance is how any differences in these parameters would impact airway constriction. This question was theoretically addressed by Bates and Martin (2) through the use of mathematical equations based on a spiral orientation of smooth muscle around the airway. They determined that airway resistance is very sensitive to the geometric orientation of smooth muscle. If the airway was considered longitudinally stiff but circumferentially compressible, smooth muscle oriented at larger angles (more parallel to the long axis of the airway) would need more force to produce equivalent changes in airway resistance compared with smooth muscle oriented at smaller angles (more perpendicular to the long axis of the airway). If the airway was considered to be compressible both longitudinally and circumferentially (probably most realistic), as the angle of smooth muscle became larger, more force was required to produce resistance. However, at a certain point a change occurred, and larger angles needed less force. The Bates and Martin model was based on smooth muscle being uniformly oriented at one angle. Our present study has shown that there is a wide range in the orientation of individual bundles in the airways. It is unknown how these individual differences impact an airway's ability to narrow.
In summary, we used a three-dimensional method to quantitatively map and compare smooth muscle orientation and bundle abundance in distal conducting airways of three species: rabbit, mouse, and monkey. Smooth muscle orientation is conserved among species and among distal airway generations. At the bifurcation of proximal bronchioles, smooth muscle is found nearly parallel to the long axis of the airways. Smooth muscle abundance is significantly different between species (abundance is less in the monkey compared with the mouse and rabbit), and there is a trend for abundance to decrease with each more distal airway generation. These data provide a healthy baseline for smooth orientation and abundance in the distal airways that can be used when studying smooth muscle distribution in the diseased state.
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ACKNOWLEDGEMENTS |
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The authors acknowledge Natasha Yin, who conducted some of the initial work on this project.
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FOOTNOTES |
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This work was supported by National Institute of Environmental Health Sciences Grants ES-04311, ES-04699, ES-06700, ES-05707, and ES-00628, and by California Tobacco Related Diseases Research Program Grant 6KI0306.
Address for reprint requests and other correspondence: S. M. Smiley-Jewell, Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, 1321 Haring Hall, Univ. of California, Davis, CA 95616-8732 (E-mail: smsmiley{at}ucdavis.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/japplphysiol.01109.2001
Received 5 November 2001; accepted in final form 19 June 2002.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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