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1 Department of Chemical and Bio-Resource Engineering, University of British Columbia, Vancouver V6T 1Z4; 2 Pulmonary Research Laboratory, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V6Z 1Y6; and 3 Pediatric Pulmonology, James Witcomb Riley Hospital for Children, Indianapolis, Indiana 46223
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway responsiveness is exaggerated in infancy and declines with maturation. These age-related differences (R.S. Tepper, T. Du, A. Styhler, M. Ludwig, and J.G. Martin. Am. J. Respir. Crit. Care Med. 151: 836-840, 1995; R.S. Tepper, S.J. Gunst, C.M. Doerschuk, Y. Shen, and W. Bray. J. Appl. Physiol. 78: 505-512, 1995; R.S. Tepper, J. Stevens, and H. Eigen. Am. J. Respir. Crit. Care Med. 149: 678-681, 1994) could be due to changes in the smooth muscle, the lung, and/or the airway wall. Folding of the mucosal membrane can provide an elastic load (R.K. Lambert, J. Appl. Physiol. 71: 666-673, 1991), which impedes smooth muscle shortening. We hypothesized that increased stiffness of the mucosal membrane occurs during aging, causing an increased mechanical load on airway smooth muscle and a decrease in airway responsiveness. Forty female New Zealand White rabbits between 0.75 and 35 mo of age were studied. Rectangular mucosal membrane strips oriented both longitudinally and circumferentially to the long axis of the trachea were dissected, and the stress-strain relationships of each strip were tested. The results showed that the membrane was stiffer in the longitudinal than in the circumferential direction of the airway. However, there was no significant change with age in either orientation. We conclude that the mechanical properties of the airway mucosal membrane did not change during maturation and were not likely to influence age-related changes in airway responsiveness.
asthma; airway; bronchial constriction
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EXAGGERATED AIRWAY NARROWING in response to pharmacological agonists is a characteristic feature of patients who have asthma. Because the narrowing of the airway in response to pharmacological stimuli is predominantly related to airway smooth muscle (ASM) contraction (10), the factors that relate ASM stimulation and airway narrowing, such as the elastic loads that ASM has to overcome during contraction, are of considerable interest. It has been speculated (10) that the load on ASM must limit its shortening because in vitro the muscle is capable of shortening more than 70% (14), a degree of shortening that could completely occlude all airways if it occurred in vivo.
When bronchial smooth muscle contracts and the diameter of the bronchus is reduced, the airway mucosal membrane develops folds to accommodate the reduction in diameter (6, 23). It has been suggested that this folding provides a load to the ASM. In a recent morphometric study of airway narrowing in canine lung (11), it was found that the degree of ASM shortening was inversely related to the relative mucosal area in individual airways. Theoretically, the bending stiffness of the mucosal membrane will vary as the third power of its thickness. If the stiffness of the mucosal membrane is significant, this result supports the potential role of mucosal folding as an impediment to airway narrowing. The results of a number of recent studies have shown that airway responsiveness declines with maturation (15-17). These age-related differences could be due to changes in ASM function and/or to changes in the mechanical properties of the lung parenchyma or airway wall. Progressive loss in compliance or increase in stiffness with age has been observed throughout the body (2, 18), e.g., the heart, arteries, lungs, and skin. This widespread increasing rigidity of tissues very likely plays an important role in the generalized physiological decline that characterizes the aging syndrome. If airway mucosal membrane folding represents a significant impediment to ASM shortening, a change in its thickness or mechanical properties could contribute to the decrease in airway responsiveness that occurs with increasing age. To test this hypothesis, we have measured the tensile stiffness of the tracheal mucosal membrane in rabbits between the ages of 0.75 and 35 mo. Two experimental techniques were employed. One is the static tensile testing technique, which measures tissue response to step input. This is particularly useful in terms of matching a mechanical model to the tissue's viscoelastic properties. The other technique, the so-called single-pulse testing, was used at each of the three levels of static extension before the next step change. This technique is efficient in terms of revealing the time-dependent mechanical properties of the tissue samples.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Material and preliminary tests. A custom-designed stress-strain tester (19) was used in these experiments. The apparatus was equipped with a transducer that was able to measure force to 10 mg (Kulite transducer, BG series, Leonia, NJ) and a motor arm that moved in steps as small as 0.25 µm. By using the apparatus, changes in sample length over a wide range could be applied in either static or dynamic patterns. Both dynamic and static responses of the equipment were checked by testing a standard spring. It was shown that the equipment displayed its own dynamic response only at frequencies >100 Hz. The apparatus was coupled to a computer, which was used both to control and to record the length and tension signals. Both signals were calibrated before each tissue sample was mounted for testing. The classical Krebs solution was altered to eliminate Ca2+, which may facilitate the denaturation of collagen in the tissue (9) and thus could have altered the mechanical properties of the samples. The ingredients of the altered Krebs solution are (in g/l) 6.90 NaCl, 0.35 KCl, 0.29 MgSO4 · 7H2O, 0.16 KH2PO4, 2.10 NaHCO3, and 2.00 glucose. The solution was stored in a reservoir, which fed a 17-ml tissue bath. The reservoir was bubbled with 95% oxygen-5% carbon dioxide. The tissue bath was heated to maintain the Krebs at 37°C in the bath. By continuously circulating fresh solution to the tissue bath at a predetermined flow rate (27 drops/min), the pH was maintained at 7.4-7.5.
Tracheal mucosal membrane obtained from New Zealand White female rabbits was used in this study. The animals were killed with an intravenous overdose of ketamine hydrochloride. A few preliminary tests were performed to measure the strain imposed on the membrane in situ, the elastic limit of the membrane, and the strain distribution in a tissue sample along the direction in which elongation was applied. Five animals were used to measure the strain of the mucosal membrane while the trachea was still intact (in situ). The trachea was removed from the animal's chest without being opened. Pairs of micromarkers (dots of carbon powder) were inserted on the inner surface of the tracheal tube on the tracheal wall opposite to the posterior membranous portion by looking down from one end. One pair of the markers was in the circumferential and the other in the longitudinal direction. The micromarkers were very stable; they can remain in place on the tissue for several hours. The distance between the two markers in each pair was measured to obtain the length in situ. The trachea was then cut open from the posterior membranous portion, the region where the smooth muscle resides, to eliminate the smooth muscle from the membrane samples. The trachea was fixed on a dissection surface with the cartilaginous portion of the trachea facing a magnifying glass (Fig. 1). The tissue samples between the markers were dissected. It was observed that the membrane did not wrinkle up (or buckle) after resection, but instead a simple decrease of strain was seen. To measure the length in vitro, the dissected membrane was allowed to rest on a flat surface. The strain was calculated as (length in situ
length in vitro)/(length in
vitro). Results were all positive, suggesting that the tracheal mucosal
membrane is stretched in situ (see Table
1).
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Experimental procedure. Forty animals were used for the experiments. All of the tests were performed and completed within 6-8 h (5) of the death of the animals. One of the two samples (circumferential or longitudinal) from each animal was tested first in each experiment, and the order was randomized so that the freshness of the samples was about equal.
The trachea was removed and opened as described above. Two rectangular mucosal membrane strips (6 × 3 × 1 mm) were dissected from the cartilaginous portion of the trachea (free of smooth muscle) with the use of a razor blade. In one strip, the longest dimension was in the longitudinal direction of the trachea and in the other the longest dimension was circumferential to the tracheal long axis. Care was taken that the cartilage under the mucosal membrane was not included in the tissue samples. Both strips of tissue were tested individually; the strips were dissected immediately before mounting. Both ends of a tissue sample were held by small aluminum clips with cyanoacrylate glue. The specimen was mounted vertically between the two clip holders in the apparatus. The upper and lower holders were set at the appropriate angles to avoid twisting of the sample during elongation. One of the holders was attached to the force transducer, which remained in a fixed position; the other holder was attached to the motor arm that was moved along the long axis of the specimen by the stepper motor (Fig. 2). The motor arm was used to apply uniaxial deformation. The tension in the specimen was continuously monitored.
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Data analysis and modeling. Representative tracings of the motor arm position and tension signals are illustrated in Figs. 3 and 4. As shown in Fig. 3, the tension first increased to a certain level and then decreased with time until it approached a plateau. This phenomenon is called stress relaxation and is characteristic of a viscoelastic material (2, 18).
To be consistent with the literature and to derive meaningful parameters to characterize the mechanical properties of the tissue samples, the tension data were converted to engineering stress and the position data were converted to engineering strain imposed on the tissue samples. By definition (4, 18), engineering stress (
) and
strain (
) are expressed as
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(1) |
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(2) |
Analysis of static data.
Ten to fifteen minutes after each extension in the static tensile test,
the tension approached a plateau (Fig. 3). The tension at the plateau
yielded the stress at steady state. In Fig.
5, the steady-state stress measured in
repeated tests from the same sample was plotted against strain to show
reproducibility. A linear relationship was fitted between the mean
value of the stress and the strain over the entire range. The
correlation coefficients were found to be >0.99. In this example, the
longitudinal sample had a slope of 2,744 and the error of the slope was
153; for the circumferential sample, the slope was 509 and error of the
slope was 22. The lines have been forced through the origin. A possible systematic error could have occurred in the experiments. Due to the
effect of gravity, because the samples were mounted vertically, a state
at which both the stress and strain were at zero was difficult to find.
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Analysis of pulse data.
The stress-strain data from the pulse tests were converted into
frequency domain, and a transfer function was obtained from each pulse
test. The algorithm for calculating the transfer function of the
experimental data was (13, 20)
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(3) |
, 
= frequency (rad/s), and
t was the sampling interval (s).
Equation 3 was solved by using Euler's formula
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(4) |
hj) to give a single complex number (a + bj).
Finally, the amplitude ratio or absolute gain (G) was given
by
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(5) |
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(6) |
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested the repeatability of the results using the youngest group of animals (between 0.75 and 1 mo old). The experimental error was within 8%.
Static experiments.
Table 2 shows the steady-state stiffness
results (means ± SD). Five age groups are shown in Fig.
6: the youngest group and four groups of
mature rabbits (16). There was not a statistically significant
relationship between stiffness and age (P 
0.3). ANOVA tests
showed that there was no significant difference in the mean
stiffness between the immature and the mature rabbits and that there
was no difference among the mature ones. A t-test showed
(P = 0.018) that the mean stiffness of the longitudinal samples
was significantly larger than that of the circumferential samples.
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Dynamic experiments (pulse tests). Unlike the results from the static experiments, the steady-state stiffness was calculated at each strain. It was obtained from a different experimental technique and analysis method. The steady-state stiffness was extrapolated from the absolute gain, which approaches a constant as the frequency approaches zero. Results (means ± SD) of the stiffness are presented in Table 2. The longitudinal samples were stiffer than the circumferential ones. There was a statistically significant increase in stiffness with strain. Also, similar to that found in the static experiments, the relationship between the steady-state stiffness and the age of the animals between 0.75 and 35 mo in both longitudinal and circumferential directions was not significant.
The stiffness at 1 Hz, which is close to breathing frequency, was calculated from the pulse test data. The mean stiffness is presented in Table 3. The longitudinal samples were still stiffer than the circumferential ones. Unlike that found at steady state, the tissue was significantly stiffer at 1 Hz, and the strain had no effect on the stiffness.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The results of the study showed that the rabbit airway mucosal membrane displayed viscoelastic properties, suggesting that the membrane is capable of providing elastic and viscous loads to the ASM during contraction. The membrane was stiffer in the longitudinal than in the circumferential direction of the airway. The magnitude of the steady-state stiffness measured using a static tensile test agreed with that derived from a dynamic pulse test. The dynamic pulse tests revealed that, under a steady-state condition (0 Hz), the stiffness increased with strain. However, under physiological conditions, the tissue is not likely to be at zero strain or at steady state. As shown by our data, the tissue samples were stretched to a strain ~20-30% before being removed from the trachea. At breathing frequency close to 1 Hz, the stiffness was significantly greater than that at steady state at all three strain levels. The effect of strain on the stiffness at 1 Hz was not significant, whereas the viscous component as measured by the magnitude of the phase angle changed inversely with strain and was greater in the circumferential than the longitudinal samples. There was no age effect on the stiffness. The stiffness at all ages was variable. This variation is partly due to the quantity and partly due to the orientation of the elastic fibers in each sample, which is described in the accompanying study (20a).
It is generally accepted that the ASM contracts against loads provided by the surrounding tissues such as the lung parenchyma. Okazawa et al. (11, 12) measured ASM shortening in canine lung lobes stimulated with maximal concentrations of carbachol. The degree of shortening of the ASM was significantly less than predicted on the basis of maximal unloaded shortening in the canine trachealis. To explain the limitation of shortening, they calculated the load that the lung parenchyma applied to the ASM. They found that the load related to the parenchymal distortion was insufficient to explain the limitation of ASM shortening in situ, and they suggested that additional loads may be provided by airway wall structures.
Mechanically, the mucosal membrane can be viewed as a thin-walled elastic tube, which collapses under the influence of a pressure difference across the wall. Lambert (7) suggested a model to describe the behavior of the bronchial basement membrane during airway collapse. The hypothesis, based on mathematical and physical considerations, was that this thin-walled elastic tube is capable of supporting some of the pressure imposed by the contracting ASM. This ability increases with the number and depth of folds into which the tube collapses. It is possible that the folding of the mucosal membrane accounts for the discrepancy between the observed and the predicted ASM shortening. Wiggs et al. (22) suggested a new airway mucosal folding model in which the membrane was viewed as two concentric layers of tissue having homogeneous but different Young's moduli. By varying the relative thickness and the mechanical properties of these two layers, the number of folds as well as the force necessary to generate the folds can be simulated (10, 11, 23).
Both of these models predict that the folding of the mucosal membrane may constitute a significant load influencing the ASM shortening, but knowledge of the mechanical properties of the mucosal tissue is required to quantify this effect. Ideally, it would be desirable to measure the stiffness of the mucosal membrane in the intraparenchymal airways, which are the sites of predominant airway narrowing. However, in this study, the tracheal mucosal membrane was chosen because it is more easily removed and separated from the ASM.
Numerous studies have been conducted to measure the elastic constant, or Young's modulus of soft biological tissues, although little has been reported on the incremental stiffness. As pointed out by Fung (2), the incremental modulus (equivalent to the stiffness measured at different strains) has a different physical meaning from the slope of the stress-strain relationship obtained from a static tensile test. In this study, the static tensile tests provided the conventional elastic constant, whereas the pulse tests gave incremental moduli. Table 2 compares the static results with the pulse results at all three strain values. Table 3 gives the incremental modulus at 1 Hz. We found that the incremental modulus was a function of frequency and only under steady-state conditions a function of strain. At steady state, the difference between the stiffness and the incremental modulus was small. For example, the magnitude of the stiffness measured from the pulse tests at 20% strain roughly represents a mean value of results at all three strains, and these results agree well with those measured using static tensile tests. This agreement supports the use of a static tensile test for the estimation of the steady-state stiffness of the airway mucosal membrane. Under physiological conditions that are not at steady-state, the incremental stiffness became significantly greater than that at steady state. This was not found using the static method.
When the two experimental methods are compared, the static tensile test is good for measuring the steady-state stiffness of tissues, and the static tracing can be used to suggest a mechanical model. On the other hand, the pulse test is a quick and efficient means by which to reveal important dynamic mechanical parameters such as the stiffness at various frequencies, the viscosity, and the time constants. These parameters characterize the viscoelastic properties of the tissue.
The tracing of the tension decay seen in a static tensile test can be used to obtain dynamic information. We have fitted a few static tracings and verified that the parameters obtained from the pulse analysis were reasonable. However, analyzing the static decay has been proved to be disadvantageous. First of all, as we have also shown in our study, the stiffness changes with frequency, which is not apparent from the static tests. Second, there was a large amount of noise in the static tracing, and it was sometimes difficult to find a true plateau of the tension signal. Third, if there was a response originated from the testing apparatus that had to be separated out from the collected data, the pulse test is certainly more convenient.
Young's modulus of ovine tracheal wall in the circumferential direction was reported by Codd et al. (1) to be ~20 kPa. In the case of ovine airways, there has not been a report on age-related changes either in the mechanical properties or in the airway responsiveness as has been reported for rabbits. The magnitude of the steady-state stiffness of the rabbit airway mucosal membrane in tension found in this study suggests that the mucosal membrane is capable of providing a significant load counterbalancing the stress generated by the ASM. A fold can be viewed as two compartments separated by an imaginary neutral plane in the center (7). If a fold is formed, the outer compartment is under tension, whereas the inner one is under compression. To describe fully the mechanical loads involved with folding, both an accurate measurement of the thickness of the membrane and the knowledge of the compressive properties of the tissue are still required (22). Furthermore, a model that predicts the interrelationship between the two compartments must be developed. Our study presented here only provides measurements of the mechanical properties in tension. It cannot be directly related to the buckling phenomenon.
Because there was no significant effect of age on the mechanical properties of the mucosal membrane, there must be another explanation for the age-related changes in airway responsiveness.
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ACKNOWLEDGEMENTS |
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Financial support for this research was supplied by the Medical Research Council of Canada and the Natural Science and Engineering Research Council of Canada.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: P. D. Paré, Pulmonary Research Lab., Univ. of British Columbia, St. Paul's Hospital, McDonald Research Wing, 1081 Burrard St., Vancouver BC, Canada V6Z 1Y6 (E-mail: ppare{at}mrl.ubc.ca).
Received 4 November 1998; accepted in final form 6 November 1999.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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,
Longitudinal sample; 
, circumferential sample.