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Meakins-Christie Laboratories, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada H2X 2P2
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The object of this study was to investigate
how changes in the contractile state of smooth muscle would modify
oscillatory mechanics of tracheal muscle and lung parenchyma during
agonist challenge. Guinea pig tracheal and parenchymal lung strips were suspended in an organ bath. Measurements of length
(L) and tension (T) were recorded
during sinusoidal oscillations under baseline conditions and after
challenge with 1 mM ACh. Measurements were also obtained in strips
pretreated with the calmodulin inhibitor calmidazolium (Cmz) or
staurosporine (Stauro), a protein kinase C inhibitor. Elastance (E) and
resistance (R) were calculated by fitting changes in T,
L, and
L/t
to the equation of motion. Hysteresivity (
) was obtained from the
following equation: = (R/E)2
f,
where f is frequency. Finally, maximal
unloaded shortening velocity during electrical field stimulation was
measured in Cmz-pretreated and control tracheal strips. In tracheal
strips, pretreatment with Cmz caused a significant decrease in the response to ACh challenge and in maximal unloaded shortening velocity
measured during electrical field stimulation; Stauro decreased the T,
E, and R response to ACh. In parenchymal strips, Cmz decreased the response, whereas Stauro had no effect. These results suggest that
modifications in the contractile state of the smooth muscle are
reflected in changes in the hysteretic behavior and that T and may
be controlled independently. Second, inasmuch as changes in were
similar in parenchymal and tracheal strips, the contractile element is
implicated as the structure responsible for constriction-induced changes in the mechanical behavior of the lung periphery.
calmodulin; protein kinase C; smooth muscle contraction; elastance; resistance
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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HYPERRESPONSIVE AIRWAYS are characterized by excessive airway narrowing during in vivo challenge with smooth muscle agonists. However, studies in vitro have been largely unsuccessful at defining differences in the contractile response between asthmatic airway smooth muscle (ASM) and normal control ASM (4, 5). Solway and Fredberg (27) hypothesized that the lack of a difference in the contractile behavior of asthmatic ASM relates to the measures of contractility that have been employed to characterize smooth muscle response. For the most part, isometric force generation, which reflects the tonic component of smooth muscle contraction, has been measured, and little difference has been found between the asthmatic and the normal ASM. However, a few investigators (1, 7, 13, 18) have instead focused on measures of maximal shortening velocity (V0), which reflects the rate of cycling of actin-myosin cross bridges and myosin phosphorylation (14). With this approach, provocative data have been obtained demonstrating differences between hyperresponsive and/or sensitized and normal control ASM. Whereas V0 is altered in sensitized muscle, force generation is not. This implies that the difference in hyperresponsive airways may lie in events occurring earlier in the contractile process.
Measurement of V0
is technically difficult. Fredberg and co-workers (9) recently
published data showing that measurement of mechanical friction in ASM
(hysteresivity, ) gives information equivalent to that provided by
measurement of
V0; they propose that both reflect the rate of cross-bridge cycling. Measurement of offers certain advantages, in that mechanical friction or cross-bridge
cycling rate can be continuously obtained without unloading the in
vitro preparation and perhaps, more importantly, measurements can be
obtained in vivo.
We reasoned that if mechanical friction and force generation could be dissociated in sensitized ASM, as suggested by the above studies, then it could also be dissociated by biochemical modulation of the proteins that regulate contraction. Specifically, we examined how calmidazolium (Cmz) affected mechanical friction during ACh-induced contraction in guinea pig tracheal rings. Cmz antagonizes calmodulin, which is involved in the cascade leading to myosin light chain phosphorylation and cross-bridge activation (11). We also assessed how Cmz affected V0 during electrical field stimulation (EFS). In addition, we incubated tissues with staurosporine (Stauro), an inhibitor of protein kinase C (PKC), which is thought to be involved in the sustained, tonic component of smooth muscle contraction (31).
As a secondary objective, we made similar measurements in lung
parenchymal strips. Lung parenchymal strips are considered a good proxy
of the peripheral lung tissue and are a commonly used model for the
study of the mechanical and pharmacological properties of the lung
periphery (12, 17). However, parenchymal strips represent a complex
system of alveolar walls, small airways, and small vessels. When lung
parenchymal strips are challenged with a smooth muscle agonist,
hysteretic properties change (8, 24). However, the extent to which
changes in the parenchymal strip reflect changes in the hysteretic
behavior of the smooth muscle present in this preparation as opposed to
modification of the other elements that comprise the lung strip, e.g.,
the collagen-elastin-proteoglycan matrix, is not known. We hypothesized that if changes in reflect the behavior of the smooth muscle present in this preparation, then altering the activity of proteins involved in contractile regulation should result in changes in the
hysteretic behavior of these strips.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Strip Preparation
Male guinea pigs weighing ~400 g were obtained from Charles River (St. Constant, PQ, Canada) and housed in a regular animal facility. Each animal was anesthetized with pentobarbital sodium (30 mg/kg ip). To degas the lung, the guinea pig was tracheotomized and a tracheal cannula was inserted; a small animal respirator (model 683, Harvard Apparatus, S. Natick, MA) was used to mechanically ventilate the animal with 100% O2. The thorax was opened, and after 10 min the trachea was clamped and the O2 remaining in the lungs was absorbed into the bloodstream. The animal was then exsanguinated, and the heart, lungs, and trachea were carefully resected en bloc. The lungs were filled to total lung capacity with a modified Krebs solution (mM: 118 NaCl, 4.5 KCl, 25.5 NaHCO3, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 10 glucose; Sigma Chemical, St. Louis, MO) at pH 7.40 and 6°C. Tracheal strips (2 rings wide) were obtained by cutting sagittally the ventral portion of midtracheal rings. Lung parenchymal strips (1.5 × 1.5 × 10 mm) were cut, and after the pleura was dissected, resting length (Lr) and wet weight (W0) of each strip were recorded. The strips were kept in a recirculating bath of iced solution, which was continuously bubbled with 95% O2-5% CO2.Apparatus
Metal clips were glued to either end of tracheal and parenchymal strips with cyanoacrylate. In the case of the tracheal strip the clips were glued to the tracheal cartilage adjacent to the ASM. Steel music wires (0.5 mm diameter) were attached to the clips, and the strip was suspended vertically in an organ bath. A mercury bead was placed in the bottom of the organ bath, allowing the wire to pass through the bath but preventing the Krebs solution from leaking out. The bath was filled with 15 ml of 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) that had an operating range of ±10 g, resolution of ±200 µg, and compliance of 1 µm/g; 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, B & K Precision, Dynascan, 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 converted from analog to digital with a converter (model DT2801-A, Data Translation, 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 to 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 (0.1-10 Hz). The
spring stiffness did not show any dependence on oscillatory frequency
<5 Hz. The of the system was independent of frequency and had a
value <0.003.
To measure V0, EFS was delivered from a stimulator (model S44, Grass Instrument, W. Warwick, RI) via platinum electrodes present in the organ bath.
Drugs
ACh was purchased from BDH. Cmz and Stauro were obtained from Sigma Chemical; they were dissolved in DMSO and stored in aliquots. On the day of the experiment the aliquots were diluted in Krebs solution and added to the bath. The final concentration of DMSO in the organ bath was 1 mM.Protocol
Oscillatory mechanics: tracheal strips.
Tracheal strips were preconditioned by slow cycling of T from 0 to 2 g
three times. On the third cycle the strip was loaded to 2 g and
sinusoidal length oscillation of 1% of
Lr was applied at
a frequency of 1 Hz. The sample underwent 25 min of stress adaptation
with one change of bath solution. After stress adaptation the resting T
was reset at 2 g, and a baseline recording was obtained for 5 min. ACh
was then added to the bath, and data were collected for an additional
10 min. Strips were challenged with 1 mM ACh (n = 16), 1 mM ACh after 20 min of
preincubation with 10 µM Cmz (n = 8), or 1 mM ACh after 20 min of preincubation with 1 µM Stauro (n = 8). Tracheal strips were
preincubated with Cmz and Stauro during the 25 min of stress
relaxation. Direct effects of Cmz and Stauro were assessed by recording
oscillations during the preincubation period. The tracheal strips
included cartilage and connective tissue. Under baseline conditions the
mechanical behavior of this preparation includes contributions from the
contractile and passive elements of the structure. However, after
induced constriction, because of the relative stiffness of these
elements, changes in should be determined primarily by behavior of
the contractile component (9).
Measurement of V0. Tracheal strips (n = 9) were mounted in the organ bath as described above. Indomethacin (1 µM) was added to minimize spontaneous contractions. The tissue was allowed to equilibrate for 45 min, during which time the bath solution was changed once. Optimal length and the appropriate EFS parameters (60 Hz, 20-40 V, 2-ms pulse duration) to obtain a maximal response were established. V0 was calculated during quick release to a minimal afterload (~300 mg contributed by the weight of the lower music wire) 2 s after the onset of EFS (19). Measurements were obtained under baseline conditions and after 20 min of preincubation with 10 µM Cmz.
Oscillatory mechanics: parenchymal strips. Each parenchymal strip was preconditioned by slow cycling of T from 0 to 2 g three times. On the third cycle the strip was unloaded to a T of ~1.1 g, and a sinusoidal length oscillation of 1% of Lr was applied at a frequency of 1 Hz. The sample underwent 60 min of stress relaxation with one change of bath solution, then data were collected continuously for 15 min. After 5 min of recording, the strips were challenged and recording continued for an additional 10 min. Parenchymal strips were challenged with the same agonists at the same concentrations as the tracheal strips. Strips were challenged with 1 mM ACh (n = 15), 1 mM ACh after 20 min of preincubation with 10 µM Cmz (n = 8), or 1 mM ACh after 20 min of preincubation with 1 µM Stauro (n = 8). The direct effect of Cmz and Stauro on the preparation was assessed by recording oscillations during the preincubation period.
In both sets of experiments, for each parameter, the average of the 10 s before the drug challenge was used as baseline. The peak value of T, elastance (E), resistance (R), and was taken regardless of whether
the peak was reached at the same time point. In some tracheal
preparations, T and E had not peaked 10 min after challenge. In these
cases, we took the final value as the maximum response.
Measurement of Strip Mechanics
E and R were estimated by applying the recursive least-squares algorithm to the equation of motion (16)
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(1) |
l/t
is the length change per unit time, and
K is a constant term reflecting the
baseline T. Baseline results were standardized for strip size by
multiplying the values of E and R by
Lr / A0,
where A0 is the
unstressed cross-sectional area of the lung parenchymal strip obtained
from the following formula
![<IT>A</IT><SUB>0</SUB>(cm<SUP>2</SUP>) = W<SUB>0</SUB> /[&rgr;<IT>xL</IT><SUB>r</SUB>]](/content/vol85/issue1/fulltext/91/img002.gif)
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(2) |
is the density of the tissue taken as 1.06 g/cm3 and
W0 is the strip weight. Values of
E and R were multiplied by Lr /A0;
A0 varied between
0.018 and 0.038 cm2. The ,
defined by Fredberg and Stamenovic (10) as a dimensionless variable
coupling the dissipative and elastic behavior, was calculated by using
the following equation
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(3) |
V0 was calculated as the change in length over time between 100 and 200 ms after the unloading of the tracheal strip.
Data Analysis
Unpaired t-tests were used to determine whether a response different from baseline was obtained and whether preincubation with Cmz or Stauro affected the contractile response. Paired one-tailed t-test was used to compare V0 before and after Cmz preincubation. The Dunnett multiple comparison procedure, after Bonferroni correction for the number of time points studied, was used to compare the groups preincubated with Cmz or Stauro with the ACh control group. Results were considered statistically significant at a probability level of 5%. Values are means ± SE.| |
RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Tracheal Strip Responses
There were no significant differences in baseline mechanics between groups. Representative responses in a typical tracheal strip after ACh challenge are shown in Fig. 1. The response in peaks before that of T, E, and R. The peak values of the
different mechanical parameters after ACh alone, ACh after
preincubation with Cmz, and ACh after preincubation with Stauro are
presented in Table 1. In all groups, for
all parameters, ACh induced increases that were statistically different
from baseline. Cmz preincubation significantly decreased the peak response, whereas T, E, and R were not significantly affected. Stauro
significantly decreased the peak response of T, E, and R to ACh.
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The mean responses 30, 60, 180, 300, and 600 s after ACh challenge in
tracheal strips challenged with ACh alone and those preincubated with
Cmz and Stauro are shown in Fig. 2. At 180, 480, and 600 s there was a significant difference in response between Cmz-pretreated strips and strips treated with ACh alone. The
other parameters were not statistically different between the two
groups. In the Stauro-preincubated tracheal strips, responses in T, E,
and R were significantly smaller 60, 180, 300, and 600 s after ACh
challenge than after ACh alone.
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A typical tracing of changes in T and length with unloading of the tracheal strip during EFS is shown in Fig. 3. The V0 was significantly lower in the group preincubated with Cmz than in control strips (Fig. 4; P < 0.05). Maximal shortening, on the other hand, was comparable: 0.85 ± 0.08 and 0.88 ± 0.10 mm for control and Cmz-preincubated strips, respectively.
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Parenchymal Strip Responses
There were no significant differences in the baseline mechanics between groups. A representative tracing of the parenchymal strip response to ACh is shown in Fig. 5. The response in again peaks before that of T, E, and R. The peak values
of the different mechanical parameters after ACh alone, ACh after
preincubation with Cmz, and ACh after preincubation with Stauro are
presented in Table 2. In all groups, for
all parameters, ACh induced increases that were statistically different
from baseline. Cmz preincubation significantly decreased the peak
response in to ACh, whereas T, E, and R were not significantly
affected. Stauro, on the other hand, did not significantly affect peak
responses to ACh.
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Figure 6 shows the mean responses at 30, 60, 180, 300, and 600 s after ACh challenge in parenchymal strips
challenged with ACh alone, preincubated with Cmz, and preincubated with
Stauro. At 180 and 480 s the response in in the Cmz-pretreated
group was significantly different from that in the group treated with ACh alone. The other parameters, T, E, and R, were not statistically different between the two groups. There were no differences between Stauro-preincubated strips and those treated with ACh alone.
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Challenge with Cmz and Stauro alone did not significantly modify the
different mechanical parameters in the lung parenchymal strip. Cmz
pretreatment caused a mild increase in the measured mechanical
parameters in the tracheal preparation (3.3 ± 0.9, 4.4 ± 1.2, 7.5 ± 2.1, and 2.9 ± 1.7% for T, E, R, and , respectively).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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In this study we have shown that modulation of the activity of the proteins that regulate ASM contraction differentially affects hysteresis and force generation in isolated tracheal rings and lung parenchymal strips.
Numerous investigators have attempted to define differences in the smooth muscle contractility between asthmatic and normal control airways (4, 5). Generally, studies have focused on isometric force generation, and little difference has been found in the responsiveness of smooth muscle between these two groups. Stephens and colleagues (1, 7, 13), on the other hand, looked at the velocity of tracheal smooth muscle shortening (V0). V0 has been shown to be an index of cross-bridge cycling rate and myosin phosphorylation (14). Stephens and colleagues (1, 13) showed that V0 is altered in the tracheal smooth muscle of sensitized dogs, while isometric force generation is unchanged. Similarly, Mitchell et al. (20) showed that V0 measured during EFS was increased in human bronchial smooth muscle passively sensitized with atopic serum. Most recently, Fan et al. (7) showed in sensitized mice that V0 and maximal shortening capacity of tracheal smooth muscle are increased compared with other mouse strains, whereas isometric force generation was similar in all strains studied.
Cross-bridge cycling rate and V0 may be important factors in determining the magnitude of smooth muscle shortening and airway hyperresponsiveness. As pointed out by Solway and Fredberg (27), when bronchoconstriction occurs in vivo, the muscle is constantly oscillated; i.e, tidal breathing is ongoing. During ASM length oscillations, velocity of contraction would be especially critical; the amount of airway narrowing achieved between stretches could be a function of the velocity of shortening.
Fredberg and co-workers (8) suggested that the dissipative processes
responsible for the changes in hysteretic behavior of the smooth muscle
during constriction are largely accounted for by the mechanical
friction between myosin heads and actin filaments as cross bridges
rupture during cycling. More recent evidence in canine tracheal smooth
muscle from this same group showed striking correlations between and two established measures of cross-bridge cycling rate: actomyosin
ATP utilization and shortening velocity (9).
It has been observed that the viscoelastic behavior of ASM is modified
during contraction (9, 25). Sasaki and Hoppin (25) and Fredberg et al.
(9) showed that ASM demonstrates hysteretic behavior and that is
increased after agonist challenge. In addition, a particular timing in
the contractile process has been demonstrated, with the hysteretic
behavior being affected primarily in the early phase of activation and
the elastic behavior affected later (8, 9, 24), a pattern observed in
the current experiment. These data are consistent with the changes in
cross-bridge cycling rate described for smooth muscle activation (21,
29).
We postulated that manipulating the biochemical pathways involved in cross-bridge cycling rate should result in alterations in the hysteretic properties. In smooth muscle the contractile response to different agonists shows an initial phase, where myosin phosphorylation and isometric tension increase, and a steady-state phase, where the isometric tension is maintained with a decrease in the phosphorylation rate (21). The latter condition characterized by low levels of phosphorylation and a reduced rate of cross-bridge cycling is sometimes referred to as the latch state (21). Calmodulin is involved in the regulation of smooth muscle contraction through a number of potential mechanisms (22, 30). The principal mechanism involves activation of myosin light chain kinase, phosphorylation of the myosin light chain, and stimulation of the cyclic interaction of the myosin and actin filaments. Increased myosin light chain phosphorylation is believed to increase the actin-myosin cross-bridge cycling rate (14, 22). In addition, calmodulin is thought to modulate the thin filament-associated proteins caldesmon and calponin (30). Finally, calmodulin may affect movement of Ca2+ across the sarcolemmal and sarcoplasmic reticulum membranes (30).
Cmz has been shown to be a potent and relatively specific calmodulin
inhibitor that is thought to affect the activity of
calmodulin-dependent enzymes (11). In isometric studies on tracheal
preparations, calmodulin inhibitors have been shown to affect early
force development (2). We reasoned, therefore, that preincubation with
Cmz would affect the initial phase of ACh-induced smooth muscle
contraction and thereby the rate of cross-bridge cycling. In the
current experiment, when tracheal strips were preincubated with Cmz,
the response to ACh was altered; the peak response was decreased.
However, maximal force generation was unaffected. In addition,
V0 was lower in
Cmz-pretreated tracheal strips than in controls. Hence, there was a
dissociation between changes in cycling rate and maximal force
generation.
Stauro is a potent inhibitor of PKC (26, 28). It has been suggested
that PKC plays a role in the sustained, tonic component of smooth
muscle contraction (31). This hypothesis is based on the observation
that phorbol esters induce contractions that are not necessarily
associated with changes in intracellular
Ca2+ or myosin phosphorylation
(31). The mechanism of PKC action is thought to be via myosin-activated
protein kinase-induced phosphorylation of thin filament-associated
proteins such as caldesmon and calponin. Phosphorylation of these
proteins alleviates inhibition of actin-activated myosin Mg-ATPase.
Stauro is known to act at the catalytic site of PKC (26) and has been
shown to inhibit phorbol 12-myristate 13-acetate-induced changes in
guinea pig tracheal smooth muscle tension (28). However, there is
evidence to suggest that Stauro may not be completely specific for PKC.
Stauro may also affect tyrosine-specific kinases as well as other
serine- and threonine-specific kinases (26). Moreover, as stated above,
calmodulin may also be involved in the regulation of thin
filament-associated proteins. This makes interpretation of data
somewhat more difficult. Nonetheless, preincubation with Stauro
resulted in a pattern of alteration in the contractile response of the
tracheal strip different from that after preincubation with Cmz; the
increases in T, E, and R were modified, whereas the response was
unaffected. Again, there was a dissociation between changes in and
maximal force generation.
In the parenchymal strip, results obtained after pretreatment with Cmz
were similar to those in the tracheal strip. Cmz caused a decrease in
the peak response, whereas peak T was unaffected. Conversely,
Stauro had no effect on the response to ACh in the parenchymal strips.
The difference in the effect of Stauro between tracheal and parenchymal
strips may reflect the smaller amount of smooth muscle in the
parenchymal preparation. The similarity of the response to Cmz
incubation in the tracheal and parenchymal strip suggests that changes
in of the smooth muscle were responsible for changes in of lung
parenchyma during contraction. We and others have shown in previous
experiments that viscoelastic or hysteretic properties of parenchymal
strips change after challenge with smooth muscle agonists (8, 24).
Modification of the hysteretic behavior of the lung parenchyma during
agonist challenge could be the result of changes in the viscoelastic
properties of the smooth muscle or modification of the structures in
series with the contractile elements, i.e., alterations in parenchymal geometry (23) or modifications in the mechanical behavior of surfactant
or in the viscoelastic characteristics of the extracellular matrix
(18). Small airways, vessels, alveolar ducts, and alveolar walls have
contractile properties (3, 6, 15), and all could contribute to changes
in viscoelastic behavior during agonist challenge (3, 24). Our data
showing a similar pattern in tracheal muscle and parenchymal strips
implicates peripheral smooth muscle as the element responsible for
changes in .
In conclusion, our findings on the different effects of Cmz and Stauro
on the mechanical properties of tracheal strips during contraction
demonstrate that, under certain circumstances, , V0, and maximal
force generation may be subject to separate controls. These findings
support the contention of Stephens and others (1, 7, 13, 18) that
measuring only maximal force generation in asthmatic or sensitized
smooth muscle is insufficient. Inasmuch as the cross-bridge cycling
rate may be important in determining the ultimate degree of ASM
shortening, dissociation among ,
V0, and force
generation represents a potentially important mechanism to explain
differences in airway responsiveness between asthmatic patients and
control subjects.
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ACKNOWLEDGEMENTS |
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This study was supported by the J. T. Costello Memorial Research Fund, the Respiratory Health Network of the Centres of Excellence, and the Medical Research Council of Canada. M. S. Ludwig is a research scholar of the Fonds de la Recherche en Sante du Quebec. F. G. Salerno was supported by a research fellowship from the Montreal Chest Hospital Research Institute and Telethon Italia.
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FOOTNOTES |
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Address for reprint requests: M. S. Ludwig, Meakins-Christie Laboratories, 3626 St. Urbain St., Montreal, PQ, Canada H2X 2P2.
Received 10 April 1997; accepted in final form 27 February 1998.
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REFERENCES |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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