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Departments of Pediatrics and Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, Indiana 46223; and School of Electrical and Computer Engineering, Purdue University, West Lafayette, Indiana 47907
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
FOOTNOTES
REFERENCES
ABSTRACT 
Shen, X., V. Bhargava, G. R. Wodicka, C. M. Doerschuk, S. J. Gunst, and R. S. Tepper. Greater airway narrowing in immature than
in mature rabbits during methacholine challenge. J. Appl. Physiol. 81(6): 2637-2643, 1996.
It has
been demonstrated that methacholine (MCh) challenge produces a greater
increase in lung resistance in immature than in mature rabbits (R. S. Tepper, X. Shen, E. Bakan, and S. J. Gunst.
J. Appl. Physiol. 79: 1190-1198, 1995). To determine whether this maturational difference in the response to MCh was primarily related to changes in airway resistance (Raw) or changes in tissue resistance, we assessed airway narrowing in
1-, 2-, and 6-mo-old rabbits during intravenous MCh challenge (0.01-5.0 mg/kg). Airway narrowing was determined from
measurements of Raw in vivo and from morphometric measurements on lung
sections obtained after rapidly freezing the lung after the MCh
challenge. The fold increase in Raw was significantly greater for 1- and 2-mo-old animals than for 6-mo-old animals. Similarly, the degree of airway narrowing assessed morphometrically was significantly greater
for 1- and 2-mo-old animals than for 6-mo-old animals. The fold
increase in Raw was highly correlated with the degree of airway
narrowing assessed morphometrically
(r2 = 0.82, P < 0.001). We conclude that the
maturational difference in the effect of MCh on lung resistance is
primarily caused by greater airway narrowing in the immature rabbits.
airway reactivity; maturation; airway morphometry
INTRODUCTION BRONCHOCONSTRICTION with methacholine (MCh) produces a
significantly greater increase in the lung resistance
(RL) of immature rabbits than
that of mature rabbits (24, 27). This maturational difference in the
pulmonary response to MCh suggests that maximal airway narrowing is
greater in immature lungs than in mature lungs. However, studies in
mature animals have demonstrated that under nonconstricted conditions,
the viscoelastic properties of the lung parenchyma can be a significant
component of the energy dissipation that occurs during tidal
ventilation (4, 8, 10, 15, 18, 21). Energy dissipation from the lung
parenchyma that is in phase with flow in the airways has been called
tissue resistance (Rti) and can account for 50% of
RL in the nonconstricted lung (8, 10, 15, 18, 21). In addition, during bronchoconstriction Rti may
increase even more than airway resistance (Raw) (8, 10, 15, 18, 21),
and in puppies Rti has been reported to increase before an increase in
Raw (22). Therefore, the greater increase in
RL of immature than of mature
rabbits during MCh challenge may not result from a greater increase in
Raw but rather from a greater increase in Rti.
The increase in Rti during bronchoconstriction has been attributed to a
direct effect of agonists on the lung parenchyma (14, 15, 18, 20, 21).
Recent studies, however, suggest that the apparent increase in Rti may
be related to airway narrowing and to ventilation inhomogeneity within
the lung during bronchoconstriction (3, 16). We have previously
demonstrated in isolated rabbit lungs that airway closure occurs more
frequently and at higher transpulmonary pressures in immature lungs
than in mature lungs during maximal MCh stimulation (25). Therefore, we
hypothesized that the greater increase in
RL in immature than in mature
rabbits during MCh challenge was related to greater airway narrowing in the immature lung. In this study, we assessed airway narrowing by using
both physiological and morphometric measurements. To assess airway
narrowing physiologically, we partitioned
RL into the airway and the
tissue components by superimposing volume oscillations at different
frequencies. At the completion of the MCh challenge, rabbit lungs were
rapidly frozen with liquid nitrogen for morphometric analysis of airway
caliber.
METHODS Animal Preparation
Tracheal pressure was measured with a piezo-resistive pressure transducer (model 8507C0-2, Endevco), and tracheal flow was measured with a screen pneumotachometer (model 8410A, Hans Rudolph) and a differential pressure transducer (±2.25 cmH2O; model MP45, Validyne). Analog signals of flow and pressure were filtered above 50 Hz, amplified, and digitized at 100 samples/s (model DT2801-A, Data Translation). Digital signals were stored in an IBM-compatible personal computer (model 486, Zeos International) by using data-acquisition software (RHT Infodat).
Measurements of RL
The frequency dependence of RL was assessed by small- volume (1-2 ml/kg) forced oscillations in flow that were generated with a small piston attached to a linear motor as previously described (26). The motor was controlled by the microcomputer via a digital-to-analog converter. The digital signal was composed of 14 frequencies (0.146, 0.342, 0.537, 0.830, 1.123, 1.416, 1.807, 2.002, 2.294, 2.588, 2.979, 3.467, 3.857, 4.053 Hz). The frequencies were chosen as a nonsum nondifference sequence so as to minimize harmonic overlapping (23). The signal was 23 s in length.Experimental Protocol
Oscillatory measurements were obtained under baseline nonconstricted conditions (pre-MCh) as follows. Mechanical ventilation was stopped at end expiration (PEEP = 5 cmH2O), and the animal was apneic. The forced oscillatory signal was then applied, after which mechanical ventilation was resumed. The same sequence was followed after challenge with intravenous doses of MCh (0.01, 0.05, 0.5, 1.0, and 5.0 mg/kg). Measurements were begun when the MCh dose produced a maximal increase in tracheal pressure, which occurred ~30-60 s after MCh administration. After completion of the forced oscillation measurements for the last MCh dose administered, the lungs were rapidly removed from the chest cavity and frozen with liquid nitrogen (18). While the lung was being frozen, a PEEP of 5 cmH2O was maintained with a bias flow of air connected to the tracheotomy tube.Analysis
Resistance. Lung impedance at the different frequencies were estimated from the Fourier transforms of flow and pressure as previously described (26). RL was the real part of lung impedance, and RL values at the different frequencies were fit to the following equation by using least squares regression
|
(1) |
Morphometry. The frozen rabbit lungs
were fixed in Carnoy's solution (60% ethyl alcohol, 30% chloroform,
10% acetic acid) at 
70°C for 18 h. Progressive
concentrations of ethanol at 20°C were then substituted for
the Carnoy's solution until 100% alcohol was reached, and then the
lungs were maintained at 4°C overnight. Before sectioning, the
lungs were placed at room temperature for 
2 h. The left lower lobe
was divided into four equally spaced blocks of tissue that were
embedded in paraffin. With a microtome, 5-µm sections were cut and
then stained with Masson's trichrome method. A light microscope with a
camera lucida was used to project the image onto a digitizing board
(Jandel Scientific), and the following morphometric measurements
were obtained: 1) the length of the
epithelial basement membrane
(LBM) and the
area it circumscribed (ABM),
2) the area circumscribed by the
internal surface of the epithelium in the airway lumen
(Al), and
3) the area circumscribed by the
external border of the airway wall. An ideal relaxed airway area
(Ar) was
calculated as
|
(2) |
Statistical analysis. Physiological measurements among the different age groups were compared with analysis of variance. For morphometric measurements, the airways of the animals within each age group were pooled and the airways among the different age groups were compared by analysis of variance. P < 0.05 was considered statistically significant.
RESULTS
Physiological Measurements
RL in the nonconstricted state. RL vs. frequency for a representative rabbit in each age group is illustrated in Fig. 1. The RL values at the discrete frequencies of volume oscillations are indicated by individual symbols, and the solid lines are the fitted Eq. 1. For all animals, the correlation coefficients for the fitted equations were >0.95. RL was greatest at the lowest frequency, and with increasing frequency RL rapidly decreased and approached a relatively constant value. The values of Raw and B, which were calculated from the fitted equations, decreased significantly with increasing age (Table 1).
), 2 (*), and 6 (
) mo]. Symbols
represent individual RL values
measured at indicated frequencies; lines represent equations fitted to
individual values by using hyperbolic function
[RL = Raw + B/(9.2 · f), where Raw is constant that approximates airway resistance,
B is constant that characterizes
frequency dependence of RL, and
f is frequency] and least squares regression analysis (see
text).
|
||||||||||||||||||||||||
), 0.05 (
), 0.50 (
), 1.00 (), and 5.00 (
) mg/kg]
for single 1-mo-old rabbit. Symbols represent RL values measured at single MCh
dose; lines represent hyperbolic equation fitted to individual values
[RL = Raw + B/(9.2 · f)].
Greater increases in Raw for immature animals. The increases in Raw from baseline with increasing doses of MCh are illustrated for the three different age groups in Fig. 3. MCh increased Raw in all animals in all groups. At all MCh doses >0.01 mg/kg, the 1- and 2-mo-old rabbits had significantly greater increases in Raw compared with the 6-mo-old animals. At the highest MCh dose that all animals received (1.0 mg/kg), the fold increase in Raw was significantly greater for 1- and 2-mo-old animals compared with 6-mo-old animals [49 ± 20 (SE), 27 ± 2, 4 ± 1; P < 0.05]. The 2-mo-old rabbits had smaller increases in Raw compared with 1-mo-old animals; however, the difference was statistically significant only at the MCh dose of 0.05 mg/kg.
), 2 (
), and 6 ()
mo]. Values are means ± SE. Significantly different at
P < 0.05 compared with values of:
* 1- and 2-mo-old animals; ** 2-mo-old animals.
Greater increases in frequency dependence of RL in immature animals. B increased with increasing doses of MCh (Fig. 4). The 6-mo-old rabbits had a smaller increase in B than the 1- and 2-mo-old animals; however, the difference between different age groups was statistically significant only at a MCh dose of 1.0 mg/kg.
), 2- (), and 6-mo-old animals
(). Values are mean ± SE. B
increases with increase in frequency dependence of
RL. * Significantly
different compared with values of 1- and 2-mo-old animals,
P < 0.05.
Morphometric Measurements
The average number of airways examined per animal was not significantly different for the three age groups (Table 2). There were relatively few cartilaginous airways per animal examined in each group, and there were no differences in the number of cartilaginous airways examined per animal among the groups. The average airway size assessed by LBM was significantly greater for the 6-mo-old rabbits compared with either the 1- or 2-mo-old animals.
|
||||||||||||||||||||||||||||||||||||
The degree of airway narrowing was assessed as the relative airway caliber, ABM of the constricted airway divided by the calculated ideal Ar (ABM/Ar). A smaller relative airway caliber (ABM/Ar) indicates greater airway narrowing. The 1-mo-old rabbits had the smallest relative airway caliber and thus the greatest degree of airway narrowing (Table 3). The 2-mo-old animals had a greater relative airway caliber and thus less airway narrowing than the 1-mo-old animals, and the 6-mo-old rabbits had the greatest relative airway caliber and thus less airway narrowing than both the 1- and 2-mo-old animals. There was a large variability in the relative airway caliber within each age group. The coefficient of variation for ABM/Ar was greatest in the least mature rabbits and smallest in the most mature rabbits. When the relative airway caliber was assessed from the area within the airway lumen divided by the idealized airway area (Al/Ar), there were similar maturational differences among the age groups. The 1-mo-old animals had the smallest relative airway caliber and thus the greatest degree of luminal narrowing; 6-mo-old animals had the greatest relative airway caliber and thus the smallest degree of luminal narrowing. The normalized values for Aw (Aw/Ar) and Ae (Ae/Ar) were also significantly greater in 1- and 2-mo-old rabbits compared with 6-mo-old animals.
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Because we were not able to match airway generations among the
different-aged rabbits, we examined the degree of airway narrowing after MCh relative to relaxed airway size, as assessed by
LBM. The airways
were grouped into those with
LBM <750 µm
and those with
LBM >750 µm.
In Fig. 5, airway caliber after MCh for the 1-, 2-, and 6-mo-old animals is plotted for the two different-sized groups of airways. The relative airway caliber after MCh was greater in
the larger sized airways than in the smaller-sized airways for both 1- and 2-mo-old rabbits, indicating that less narrowing occurred in these
airways after MCh. This relationship was not observed in the airways of
the 6-mo-old animals, where the relative airway caliber was similar for
all airways. For the larger sized airways
(LBM >750
µm), there were significant differences in the relative airway
caliber among the three age groups. The 1-mo-old rabbits had the
smallest relative airway caliber, indicating the most airway narrowing;
2-mo-old animals had a larger relative airway caliber than the 1-mo-old
animals; and 6-mo-old animals had the largest relative airway caliber
and thus the least degree of airway narrowing. For airways with
LBM <750 µm,
the 6-mo-old animals had the greatest relative airway caliber,
indicating the least airway narrowing; however, there was not a
significant difference between the airway narrowing for the 1- and
2-mo-old animals. Similar results were obtained if airways were divided
into small and large by using an
LBM of 1,000 µm.
Correlation between physiological and morphometric
measurements. The increase in Raw produced by the last
dose of MCh was highly correlated with the relative airway caliber
measured morphometrically (ABM/Ar)
(Fig. 6). Those animals with a greater
increase in Raw had airways that narrowed to a smaller fraction of
their ideal airway caliber. This relationship was present with all of
the rabbits combined as well as within each group of rabbits.
, 1-mo-old animals; 
,
2-mo-old animals; , 6-mo-old animals.
DISCUSSION
In the present study, we demonstrated that the greater pulmonary response to MCh in the immature than in the mature rabbits is related to greater airway narrowing in the immature animals. The greater airway narrowing in the immature rabbits was demonstrated both physiologically and morphologically, and we found that these two measurements were highly correlated. Although we previously reported that MCh challenge produced a greater increase in the RL of immature rabbits compared with mature rabbits (24, 27), this greater increase could have been produced by increases in Raw and/or increases in Rti. The present study, therefore, extends our previous results by demonstrating that the maturational differences in airway responsiveness can be accounted for by greater airway narrowing in the immature than in the mature rabbit.
Greater Airway Narrowing Induced by MCh in Immature Animals
In this study we assessed airway narrowing by measuring the frequency dependence of RL and fitting the values to a hyperbolic equation in which Raw was the asymptote. The hyperbolic function provided an excellent fit to RL data for all age groups (Figs. 1, 2), and changes in the values for Raw paralleled the changes in airway caliber during bronchoconstriction (Fig. 6). It has previously been demonstrated that in rabbits, as in several other species, Rti is greatest at very low frequencies and becomes negligible between 2 and 4 Hz as RL approximates Raw (4, 10, 11, 23, 26).In this study, the increase in Raw produced by MCh was 10 times greater in the immature compared with in the mature rabbits. It has been demonstrated that RL measured at 1 Hz increases 5-10 times more in response to MCh in the immature than in the mature rabbit (24, 27). The similarity of the magnitudes of these responses suggests that the changes in RL can be attributed primarily to changes in airway narrowing. Consistent with this conclusion is a previous study of Tepper et al. (25), which reports that airway closure occurs more frequently in isolated immature rabbit lungs compared with isolated mature rabbit lungs during maximal MCh stimulation. Greater airway narrowing in the immature rabbit lung could also account for the observation that pulmonary hyperinflation occurred in the immature but not in the mature rabbits during MCh challenge in vivo (27).
Morphometric analysis also indicated greater airway narrowing in the immature rabbit lungs than in the mature rabbit lungs after constriction with MCh. As expected, the larger more mature animals had a larger mean airway size (LBM); however, we obtained a similar number of airways per animal for analysis from each group of lungs and most of the airways examined in all groups were noncartilaginous airways (Table 2). Although we are not able to compare specific airway generations among different age groups, we observed maturational differences in the degree of airway narrowing over the entire range of airways examined (Fig. 5). By using similar sectioning techniques for all of the rabbit lungs, we assumed that we obtained similar generations of airways from the different age groups of animals. Thus the maturational difference in airway narrowing that we observed are not likely to be due to differences in the airway generations sampled.
We also found a high correlation between the morphometric assessment of airway caliber and the independent measurement of Raw (Fig. 6), strongly suggesting that we were examining the physiologically important airways in the three different age groups. If we assume laminar flow within the airways, then Raw should increase in a manner that is inversely proportional to the square of the decrease in airway caliber. Our results indicate an even greater fold increase in Raw relative to the degree of airway narrowing; this suggests that in addition to airway smooth muscle (ASM) shortening, luminal secretions within the airway may have also contributed to the observed increase in Raw.
Greater Heterogeneity of Airway Response to MCh in Immature Animals
Frequency dependence of RL can result from the viscoelastic properties of the lung parenchyma and from ventilation inhomogeneity within the lung (3, 9, 19). In the nonconstricted lung, the frequency dependence of RL is attributed to the viscoelastic properties of the lung parenchyma because ventilation throughout the lung is relatively homogenous (2, 10). However, it is unclear whether the increased frequency dependence of RL during bronchoconstriction is due primarily to alterations in the viscoelastic properties of the lung parenchyma or to ventilation inhomogeneity that develops within the lung. Studies of mature animals from several different species have used morphometric, physiological, and radiographic approaches to demonstrate that within the lung there is a marked heterogeneity in the degree of airway narrowing after bronchoconstriction (5-7, 9, 13). There is also recent evidence that heterogeneity of airway narrowing and not changes in lung parenchymal tissue properties can account for the increased frequency dependence of RL after bronchoconstriction and the apparent increase in Rti. Bates and Peslin (3) have demonstrated that marked ventilation inhomogeneity and not increases in static lung elastance best account for increases in RL and dynamic elastance during bronchoconstriction in mature dogs. In addition, Lutchen et al. (16) have recently demonstrated in rats that increases in Raw during bronchoconstriction can account for changes in lung mechanics previously attributed to changes in the viscoelastic properties of the parenchymal tissue.In our study, the coefficient of variation for the distribution of airway narrowing as assessed by morphometric analysis was significantly greater in the immature than in the mature rabbit lungs (Table 3). This finding is consistent with a greater ventilation inhomogeneity in the immature lung after bronchoconstriction in vivo, as also suggested by our observation of a greater increase in the frequency dependence of RL in the immature than in the mature rabbit (Fig. 4). The increase in the frequency dependence of RL paralleled the increase in Raw in all age groups (Figs. 3, 4), suggesting that both phenomena result from a common mechanism. The results of a previous study in which we used alveolar capsules in rabbits during bronchoconstriction in vivo also suggest that immature rabbits have greater ventilation inhomogeneity than mature rabbits (27). In that study, we calculated negative values of Rti in the immature rabbits after bronchoconstriction, whereas values of Rti remained positive in the mature rabbits. Negative values for Rti can occur when flow measured at the trachea is not in phase with local alveolar flow due to ventilation inhomogeneity (13). In sum, both our morphometric and physiological data are consistent with a greater heterogeneity of the airway response to MCh in immature than in mature rabbit lungs.
Mechanisms for Greater Airway Narrowing
Greater airway narrowing may have occurred in the immature rabbit lungs for any or all of the following reasons: 1) greater force generation by ASM; 2) smaller forces limiting ASM shortening; and 3) thicker airway walls. The results of Tepper et al. (25) suggest that differences in ASM contractility or quantity are unlikely to account for the large differences in airway narrowing in immature and mature rabbit lungs. This previous study also suggested that differences in the forces of interdependence between the airways and the lung parenchyma in immature and mature rabbits may be significant determinants of maturational differences in airway narrowing during bronchoconstriction. Airway closure occurs at higher transpulmonary pressures in immature compared with mature isolated rabbit lungs. In addition, there is a marked difference in the effect of transpulmonary pressure on the response of RL to MCh challenge in immature and mature rabbits (28). These findings are consistent with the hypothesis that in the immature rabbit lung there is less interdependence between the airways and the lung parenchyma and that this allows greater airway narrowing.Airway wall geometry can also be a significant determinant of airway narrowing. For the same degree of ASM shortening, airways with thicker walls have greater luminal narrowing (17, 29). In the present study, both the normalized Aw and Ae were greater in the immature animals (Table 3). The airways in our study were frozen and fixed after MCh challenge, and, therefore, it is unclear whether the greater thickness of the airway wall and epithelium was present in the nonconstricted state. Our data do not address potential mechanisms for the greater normalized airway wall thickness, which could include increased collagen matrix, increased edema formation, and/or more mucosal and submucosal folding. In humans, preliminary data in nonconstricted airways have suggested that infants have greater airway wall thickness relative to airway size compared with adults (12). In addition, in hamsters, bronchoconstriction produces greater airway wall edema in immature than in mature animals (1). Thus a greater normalized airway wall thickness might also contribute to the maturational differences in airway narrowing during bronchoconstriction observed in our study.
Conclusions
In the present study, MCh challenge resulted in a greater increase in Raw and a greater degree of airway narrowing in immature rabbit lungs than in mature rabbit lungs. There was an excellent correlation between two independent measurements of airway narrowing, Raw and the morphometric assessment of airway caliber. We also observed that the frequency dependence of RL increased more in immature than in mature rabbit lungs. The data suggest that the greater frequency dependence of RL in the immature rabbit lung during MCh challenge may be caused by greater airway narrowing and ventilation inhomogeneity. Our results also indicate that maturational differences in RL response to MCh challenge can be accounted for by differences in airway narrowing. Maturational differences in airway narrowing and airway closure may result from less interdependence between the airways and the lung parenchyma.FOOTNOTES
Address for reprint requests: R. S. Tepper, James Whitcomb Riley Hospital for Children, Dept. of Pediatrics, Pulmonary Section, 702 Barnhill Dr., Indianapolis, IN 46223.
Received 17 April 1996; accepted in final form 6 August 1996.
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R. K. Lambert, R. Ramchandani, X. Shen, S. J. Gunst, and R. S. Tepper Computational model of airway narrowing: mature vs. immature rabbit J Appl Physiol, August 1, 2002; 93(2): 611 - 619. [Abstract] [Full Text] [PDF]
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J. Kovar, P. D. Sly, and K. E. Willet Postnatal alveolar development of the rabbit J Appl Physiol, August 1, 2002; 93(2): 629 - 635. [Abstract] [Full Text] [PDF]
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K. S. Kott, K. E. Pinkerton, J. M. Bric, C. G. Plopper, K. P. Avadhanam, and J. P. Joad Methacholine responsiveness of proximal and distal airways of monkeys and rats using videomicrometry J Appl Physiol, March 1, 2002; 92(3): 989 - 996. [Abstract] [Full Text] [PDF]
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S. J. Gunst, X. Shen, R. Ramchandani, and R. S. Tepper Bronchoprotective and bronchodilatory effects of deep inspiration in rabbits subjected to bronchial challenge J Appl Physiol, December 1, 2001; 91(6): 2511 - 2516. [Abstract] [Full Text] [PDF]
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 A. DUGUET, C.-G. WANG, R. GOMES, H. GHEZZO, D. H. EIDELMAN, and R. S. TEPPER Greater Velocity and Magnitude of Airway Narrowing in Immature Than in Mature Rabbit Lung Explants Am. J. Respir. Crit. Care Med., November 1, 2001; 164(9): 1728 - 1733. [Abstract] [Full Text] [PDF]
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R. F. M. Gomes, F. Shardonofsky, D. H. Eidelman, and J. H. T. Bates Respiratory mechanics and lung development in the rat from early age to adulthood J Appl Physiol, May 1, 2001; 90(5): 1631 - 1638. [Abstract] [Full Text] [PDF]
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R. Ramchandani, X. Shen, C. L. Elmsley, W. T. Ambrosius, S. J. Gunst, and R. S. Tepper Differences in airway structure in immature and mature rabbits J Appl Physiol, October 1, 2000; 89(4): 1310 - 1316. [Abstract] [Full Text] [PDF]
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X. Shen, R. Ramchandani, B. Dunn, R. Lambert, S. J. Gunst, and R. S. Tepper Effect of transpulmonary pressure on airway diameter and responsiveness of immature and mature rabbits J Appl Physiol, October 1, 2000; 89(4): 1584 - 1590. [Abstract] [Full Text] [PDF]
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H. TIDDENS, M. SILVERMAN, and A. BUSH The Role of Inflammation in Airway Disease . Remodeling Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): S7 - 10. [Full Text] [PDF]
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P. Chitano, J. Wang, C. M. Cox, N. L. Stephens, and T. M. Murphy Different ontogeny of rate of force generation and shortening velocity in guinea pig trachealis J Appl Physiol, April 1, 2000; 88(4): 1338 - 1345. [Abstract] [Full Text] [PDF]
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R. S. Tepper, B. Wiggs, S. J. Gunst, and P. D. Pare Comparison of the shear modulus of mature and immature rabbit lungs J Appl Physiol, August 1, 1999; 87(2): 711 - 714. [Abstract] [Full Text] [PDF]
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X. Shen, S. J. Gunst, and R. S. Tepper Effect of tidal volume and frequency on airway responsiveness in mechanically ventilated rabbits J Appl Physiol, October 1, 1997; 83(4): 1202 - 1208. [Abstract] [Full Text] [PDF]
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P. Chitano, C. M. Cox, and T. M. Murphy Relaxation of guinea pig trachealis during electrical field stimulation increases with age J Appl Physiol, May 1, 2002; 92(5): 1835 - 1842. [Abstract] [Full Text] [PDF]
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