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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tissue resistance increases after agonist challenge. Parenchymal contractile cells may be the responsible element. We investigated the viscoelastic properties of human parenchymal strips before and after challenge with acetylcholine (ACh) (10
3 M). Thirteen subpleural strips were oscillated in the organ bath, and measurements of resistance (R), elastance (E), and hysteresivity (
) were obtained.
After physiologic measurements, tissues were fixed for morphometric and immunohistochemical
analysis. We quantitated the volume proportion of alveolar, airway, and blood vessel wall in individual strips. Smooth-muscle-specific actin was identified using a monoclonal antibody and the volume
proportion of actin quantitated by point counting. After ACh, there was a significant increase in tension (2.6 ± 0.6%), R (11.0 ± 1.8%), E (4.3 ± 0.7%), and (8.2 ± 2.4%) (p < 0.002). Four strips contained no identifiable airways, yet in strips with and without airways there was no difference in the
magnitude of the mechanical response or in the volume proportion of smooth-muscle-specific actin
in the alveolar walls. We conclude that human lung parenchymal strips respond to ACh challenge
with changes in dynamic mechanical behavior. Furthermore, small airways are not required for such a
response to occur. This implicates a direct contractile response at the level of the alveolar wall and/or
the alveolar duct.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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It has been shown in different animal species that tissue resistance, the pressure drop in phase with flow between the alveolus and the pleura, increases during both exogenous and endogenous constriction (1). In humans, the role of the lung tissues in contributing to the contractile response is less clear. Kariya and colleagues (5) reported that the parenchymal tissues contribute minimally to methacholine-induced responses. More recently, Kaczka and colleagues (6) showed that tissue resistance, measured using the optimal ventilator waveform, increased in normal humans during induced constriction. Kraft and coworkers (7) showed a predominantly alveolar eosinophil infiltration in patients suffering from nocturnal asthma. These latter data suggest the possibility that tissue responses may also be important in contributing to the contractile response in humans.
The site of the contractile response at the alveolar level is controversial. Potential mechanisms that may contribute include constriction of myofibroblasts or contractile interstitial cells (8, 9), alterations in the air-liquid interface, constriction-induced alterations in the mechanics of the collagen-elastin-proteoglycan matrix, and/or constriction of smooth muscle in alveolar ducts, small airways, and small vessels present at the level of the lung periphery (10). We have utilized rat lung parenchymal strips to study contractile responses in the periphery as these strips are fluid-filled and, therefore, changes in the air-liquid interface do not contribute to the contractile response (11, 12). However, the rat subpleural parenchymal strip contains substantial amounts of small airway and vessel, which may contribute to the contractile response (13, 14).
Similarly, human parenchymal strips contain small airways
and vessels. Bertram and colleagues (15) have shown that the
amount of airway and vessel is important in determining
changes in isometric tension with contractile stimulation in
human parenchymal lung strips. Whether this observation
holds for changes in the dynamic mechanical behavior is not
known. Indeed, there has been no data published on whether
contractile stimulation results in changes in the dynamic measures of resistance (R), elastance (E), and hysteresivity () in
human parenchymal strips. We believe that the response in
the dynamic measures is most pertinent to the in vivo state as
energy losses during tidal breathing are reflected by changes
in R and . Furthermore, Gunst and colleagues (16, 17) have
shown that oscillation reduces the response of airway smooth
muscle to contractile stimulation both in vivo and in vitro.
In order to address the question of whether changes in dynamic mechanical behavior occur during induced constriction
in human parenchymal strips and whether the amount of airway versus alveolar wall is important in determining the response, we performed the following experiment. We obtained
subpleural parenchymal strips from lungs surgically resected
for tumor. R, E, and were measured during dynamic oscillations before and after acetylcholine-induced constriction.
Strips were then fixed for morphometric assessment; the volume proportion of airway, blood vessel, and alveolar wall was
determined by point-counting. In addition, the amount of
smooth-muscle-specific actin present in the parenchymal strip
was measured in order to assess whether changes in parenchymal mechanics were correlated with the actual amount of
smooth muscle present in the sample at either the alveolar or
the small airway level.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Tissue Preparation
Peripheral lung tissue was obtained from 13 patients undergoing therapeutic lung resections for central lung tumor. Strips were placed in iced Krebs solution (mM: NaCl, 118; KCl, 4.5; NaHCO3, 25.5; CaCl2, 2.5; MgSO4, 1.2; KH2PO4, 1.2; glucose, 10. [Sigma Chemical, St. Louis, MO]) continuously bubbled with 95% O2/5% CO2 at a pH of 7.40. Subpleural lung strips (2 × 2 × 10 mm) were cut, and the resting length (Lr) and wet weight (Wo) of each strip were recorded.
Experimental Apparatus
Metal clips were glued to either end of the tissue strip with cyanoacrylate. Steel music wires (diameter, 0.5 mm) were attached to the clips and the strip suspended vertically in an organ bath. A mercury bead was placed in the bottom of the organ bath, allowing the music wire to pass through the bath but preventing the Krebs solution from leaking out. The bath was filled with 15 ml Krebs solution, maintained at 37° C, and continuously bubbled with 95% O2/5% CO2. One end of the strip was attached to a force transducer (Model 400A; Cambridge Technologies, Watertown, MA), which had an operating range of ± 10 g, resolution of ± 200 µg, and compliance of 1 µm/g, and the other end was connected to a servo-controlled lever arm (Model 300B; Cambridge Technologies). The lever arm was capable of peak-to-peak length excursions of 8 mm and length resolution of 1 µm and was in turn connected to a function generator (Model 3030; BK Precision, Chicago, IL), which controlled the frequency, amplitude, and waveform of the oscillation. The resting tension (T) was set by movement of a screw thumb wheel system, which effected slow vertical displacements of the force transducer. Length and force signals were low-pass-filtered (8-pole Bessel 902LPF; Frequency Devices, Haverhill, MA) with a corner frequency of 30 Hz, and converted from analog to digital with an analog-to-digital converter (DT2801-A; Data Translation Inc., Marlborough, MA) and recorded on an A/T compatible computer.
The linearity and hysteresis of the system were tested by measuring the moduli of a steel spring of stiffness comparable with that of the tissue strip. The spring was suspended in the bath by music wire in the same manner as the strip. The frequency and amplitude-dependence of the system were assessed over a range of frequencies (0.1 to 10 Hz). The spring stiffness did not show any dependence upon oscillatory frequency below 5 Hz. The hysteresivity of the system was independent of frequency and had a value < 0.003.
Protocol
Strips were preconditioned by slowly cycling tension from 0 to 2 g three
times. On the third cycle strips were unloaded from a tension of 2 g to a
tension of 1 g, and sinusoidal length oscillations of 2.5% Lr at a frequency
of 0.25 Hz were applied. After 60 min of stress relaxation, the final resting tension was approximately 0.7 g. Baseline recordings were then obtained and ACh (103 M) (BDH, Inc., Toronto, Canada) was added to
the organ bath. Measurements of length and T were collected continuously for an additional 15 min. Subsequent to the initial preconditioning, strips were continuously oscillated throughout the entire protocol.
Measurement of Strip Mechanics
Elastance (E) and resistance (R) were estimated by applying the recursive least-squares algorithm to the equation of motion (18):
|
(1) |
where l = length, 
l/t is the length change per unit time, and K is a
constant reflecting resting tension. Results were standardized for strip
size. The unstressed cross-sectional area (Ao) of the strip was obtained from the formula:
|
(2) |
where 
is the mass density of the tissue taken as 1.06 g cm3, Wo is the
wet weight in grams, and Lr is the unloaded length in cm. Values of E
and R were multiplied by Lr/Ao. Hysteresivity, , a dimensionless
variable coupling the dissipative and elastic behavior, was calculated
by the equation:
|
(3) |
where f is frequency (19).
Morphometric Study
After physiologic study, strips were fixed with 4% paraformaldehyde and embedded in paraffin for morphometric and immunohistochemical study.
Immunohistochemical staining using the APAAP method was performed in slides 5 µm thick using a monoclonal antibody to 
-smooth muscle actin (Dako, Carpenteria, CA). Sections were deparaffinized, hydrated, and incubated in 2% normal human serum (NHS) for 1 h at
room temperature. Sections were then rinsed with TBS (0.5 M TRIS;
pH, 7.6; 1.5 M NaCl) and incubated with antiactin (1:400 in TBS)
overnight at 4° C. After washing with TBS, the tissue was incubated
with an unconjugated rabbit antibody against mouse immunoglobulin
(Dako) (1:30 in 20% NHS) for 30 min, washed again, and incubated
with APAAP (soluable complexes of calf alkaline phosphatase and
murine monoclonal antibody to alkaline phosphatase) (Dako) (1:30 in
20% NHS) for 30 min. After further washing, sections were developed with Fast Red salt (Sigma) (1 mg/ml in alkaline phosphatase
substrate) for 10 min at room temperature. Sections were counterstained with Harris Hematoxylin for 1 min. Negative controls were
made by exclusion of the primary antibody.
A semiquantitative analysis was performed on the slides stained for actin by applying point-counting. Using a 121-point grid, we calculated the volume proportion of actin in airways, vessels, and parenchyma as the relation between the number of points falling on actin-stained and nonstained tissue. Measurements were performed in 20 fields per slide, using a magnification ×200. Using the same method, we also measured the fractional area of tissue constituents. Fractional areas were measured for bronchial wall (BW), blood vessel wall (BVW), and alveolar wall (AW). BW and BVW were counted when the point fell on the smooth muscle, the epithelial layer, the endothelial layer, or its associated connective tissue. Points falling on airway lumen and blood vessel lumen were excluded.
Data Analysis
A paired two-tailed t test was used to compare the different mechanical parameters in strips before and after challenge. An unpaired two-taled t test was used to compare the % increase in T, E, R, and and
the volume proportion of actin in the parenchyma in the two groups
of strips (those with and without airways). Results were considered
statistically significant at a probability level of 5%. Values are reported as means ± standard error.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The mean area fraction of alveolar (AW), blood vessel
(BVW), and bronchial (BW) walls for the 13 parenchymal
strips studied are shown in Table 1. AW represented 68 ± 3%,
BVW 26 ± 2%, and BW 6 ± 2% of the volume proportion of
the tissue. We defined two subpopulations of parenchymal
strips
one in which small airways were present (n = 9) and
one in which, despite repeated sectioning of the tissue blocks,
no airways were identifiable (n = 4).
|
Baseline values of R, E, and are shown in Table 2. There
were no differences in the baseline values of T, R, and E between the subgroups of strips with and without airways. There
was, however, a difference in the baseline values of between
the two groups (p < 0.05). ACh caused a significant increase
in the values of T, R, E, and in the 13 parenchymal strips
studies (2.6 ± 0.6%, 11.0 ± 1.8%, 4.3 ± 0.7%, and 8.2 ± 2.4%,
respectively, p < 0.002). The percent increase in T, R, E, and
was compared between strips with and without airways.
There was no significant difference in the response (Figure 1).
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Photomicrographs showing actin staining in strips with and without airways are shown in Figure 2. Note the presence of actin positivity in small airways, alveolar ducts, and alveolar walls. The volume proportion of actin staining is presented in Table 3 for all strips and for the two subpopulations, i.e., strips with and without airways. There was no significant difference in the volume proportion of actin in the parenchyma between the airway and the no airway groups. Finally, we tested to see whether there was a correlation between the amount of actin in a given strip and the magnitude of the contractile response. No significant correlation was determined (data not shown).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In the current study, human lung parenchymal strips responded to contractile stimulation with increases in the dynamic mechanical parameters, elastance, resistance, and hysteresivity. Equivalent increases were found regardless of whether strips contained or were devoid of small airways. These data argue that contractile responses occur at the parenchymal level.
A number of studies in which tissue resistance has been directly measured with alveolar capsules have shown that tissue resistance increases with both endogenous and exogenous contractile stimulation (1). The site of that response has been controversial. Potential mechanisms include smooth muscle cells at the level of the alveolar duct; pericytes, filament-containing cells that lie alongside capillaries; and contractile interstitial cells or myofibroblasts (20, 21). These last cells have been documented to respond to stimuli such as hypoxia and smooth muscle agonists (8, 9).
The lung parenchymal strip has been used as a model for the study of the mechanical and pharmacologic properties of the lung periphery (11, 12, 15). We and others (13, 14, 22) have published data showing changes in oscillatory mechanics after exposure to a range of contractile agonists in guinea pig and rat parenchymal strips. Human lung parenchymal strip studies have focused on investigating the isometric and isotonic behavior of the tissue before and after agonist challenge (15). Bertram and colleagues (15) measured isometric responses to 5-hydroxytryptamine and norepinephrine in human parenchymal strips. Stereologic examination showed that the lung strips contained 16.8% blood vessels, 4.8% airway walls, and 78.4% alveolar parenchyma, results similar to those of the current experiment. These investigators showed a significant correlation between the magnitude and type of response (contraction versus relaxation) and the ratio of blood vessel to airway volume. There was no correlation between the response and the proportion of alveolar tissue.
There have been no data published on whether contractile
stimulation results in changes in the dynamic measures of R,
E, and in human parenchymal strips. We believe that the response in the dynamic measures is most pertinent to the in
vivo state as energy losses during tidal breathing are reflected
by changes in R and . Moreover, Gunst and colleagues (16,
17) have shown that oscillation in and of itself can affect the
contractile response in isolated smooth muscle preparations.
In the current experiment, we observed a significant increase
in all dynamic mechanical parameters after ACh treatment.
The question arises as to what components within the strip account for the response. Contraction of small peripheral airways could be one important mechanism. Salerno and colleagues (13) assessed the relationship between dynamic oscillatory behavior and the fractional proportion of the different anatomic constituents in subpleural parenchymal lung strips of Sprague-Dawley rats. They observed a significant correlation between increases in the mechanical parameters and the amount of small airways and vessels when more proximal strips containing greater amounts of blood vessel and bronchial wall were examined, suggesting a major contribution of these structures to the response. In more peripheral strips, which contained lesser amounts of blood vessel and bronchial wall, no correlation was seen.
In the present study, the morphologic evaluation showed that, despite repeated sectioning of the tissue blocks, in some of the strips no airways could be identified. These strips devoid of airways showed a contractile response of the same magnitude as those strips containing small airways. Small vessels are unlikely to be the source of the contractile response, as in a previous experiment from this laboratory, vessels of the size present in the parenchymal strip (< 0.2 mm) did not react to ACh (14). This observation leads us to suggest a significant role for contractile cells at the extreme lung periphery in the response to ACh.
Data from other species corroborate these results. Drazen and Schneider (23) showed that ultrathin guinea-pig lung strips, which contained no conducting airways or blood vessels, contracted after histamine or carbachol challenge. These investigators concluded that alveolar interstitial cells and/or alveolar duct smooth muscle were responsible for the response. Evans and Adler (24) observed increases in isometric tension in rabbit parenchymal strips exposed to histamine, acetylcholine, and epinephrine. While they did not detect interstitial smooth muscle cells or significant amounts of alveolar duct smooth muscle when the strips were stained with Masson trichrome, indirect immunofluorescence showed positivity for actin in the interstitium. Electron microscopy confirmed the presence of filaments composed of actin in interstitial cells. These investigators concluded that the response of parenchymal strips could not be attributed solely to airway smooth muscle contraction.
In our study, immunohistochemical staining for actin was
most prominent in alveolar ducts, with relatively little actin
staining in alveolar walls. Actin-positive cells corresponded to
4.3% of the parenchymal tissue. We did not find a correlation
between the volume proportion of actin in parenchyma or airways and the magnitude of the response. It is possible that
changes in the alveolar geometry secondary to smooth muscle
contraction are more important in determining the magnitude
of response than the absolute actin content. Alternately, the
small splay in both the magnitude of the response and the actual actin content may have made a correlation difficult to
find. Finally, the specific antibody used, that against -smooth
muscle actin, may be more effective at identifying smooth muscle in alveolar ducts and in pericytes and less specific for myofibroblasts, at least in "normal" lungs (20, 25). It is possible we would have obtained a positive correlation had we used
an antibody which sampled all the contractile elements in the
lung periphery.
The data of the current experiment have potential implications for human asthmatic disease. Recently, there have been provocative reports implicating the lung periphery in the human asthmatic response. Kaminsky and colleagues (26) have published data examining the effects of hyperpnea in asthmatics and showed a predominantly peripheral response. Kraft and colleagues (7) have demonstrated in transbronchial biopsy specimens from nocturnal asthmatics that there is a primarily alveolar inflammatory infiltration. These data, coupled with our findings regarding the ability of human peripheral tissue to respond directly to contractile stimulation, suggest the possibility that the lung parenchyma plays a more prominent role in asthmatic disease than has previously been appreciated.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. M. S. Ludwig, McGill University, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, PQ, H2X 2P2 Canada.
(Received in original form January 20, 1998 and in revised form April 16, 1998).
Dr. Dolhnikoff is the recipient of a Fellowship from CNPq and FAPESP Brazil.Dr. Ludwig is a research scholar of the Fonds de la Recherche en Santé du Québec.
Acknowledgments: Supported by the J. T. Costello Memorial Research Fund and MRC Canada.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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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M. KRAFT, J. PAK, R. J. MARTIN, D. KAMINSKY, and C. G. IRVIN Distal Lung Dysfunction at Night in Nocturnal Asthma Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1551 - 1556. [Abstract] [Full Text] [PDF]
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J. J. FREDBERG Airway Smooth Muscle in Asthma . Perturbed Equilibria of Myosin Binding Am. J. Respir. Crit. Care Med., March 1, 2000; 161(3): S158 - 160. [Full Text] [PDF]
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T. Nagase, H. Kurihara, Y. Kurihara, T. Aoki-Nagase, R. Nagai, and Y. Ouchi Disruption of ET-1 gene enhances pulmonary responses to methacholine via functional mechanism in knockout mice J Appl Physiol, December 1, 1999; 87(6): 2020 - 2024. [Abstract] [Full Text] [PDF]
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