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1 Departments of Pediatrics, and Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, Indiana 46202; and 2 Institute of Fundamental Sciences-Physics, Massey University, Palmerston North, New Zealand 5331
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We previously demonstrated that airway responsiveness is greater in immature than in mature rabbits; however, it is not known whether there are maturational differences in the effect of transpulmonary pressure (Ptp) on airway size and airway responsiveness. The relationship between Ptp and airway diameter was assessed in excised lungs insufflated with tantalum powder. Diameters of comparable intraparenchymal airway segments were measured from radiographs obtained at Ptp between 0 and 20 cmH2O. At Ptp > 8 cmH2O, the diameters were near maximal in both groups. With diameter normalized to its maximal value, changing Ptp between 8 and 0 cmH2O resulted in a greater decline of airway caliber in immature than mature airways. The increases in lung resistance (RL) in vivo at Ptp of 8, 5, and 2 cmH2O were measured during challenge with intravenous methacholine (MCh: 0.001-0.5 mg/kg). At Ptp of 8 cmH2O, both groups had very small responses to MCh and the maximal fold increases in RL did not differ (1.93 ± 0.29 vs. 2.23 ± 0.19). At Ptp of 5 and 2 cmH2O, the fold increases in RL were greater for immature than mature animals (13.19 ± 1.81 vs. 3.89 ± 0.37) and (17.74 ± 2.15 vs. 4.6 ± 0.52), respectively. We conclude that immature rabbits have greater airway distensibility and this difference may contribute to greater airway narrowing in immature compared with mature rabbits.
maturation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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WE HAVE PREVIOUSLY DEMONSTRATED that maximal methacholine (MCh) challenge in vivo produces greater increases in lung and airway resistances and greater airway narrowing in immature than in mature rabbits (23, 26, 28). In addition, airway closure occurs at higher transpulmonary pressure (Ptp) during maximal MCh stimulation in isolated lungs from immature rabbits than in isolated lungs from mature rabbits (27). At a Ptp of 4 cmH2O, airway closure was present in most immature rabbit lungs; in contrast, airway closure was infrequent in mature rabbit lungs. These findings suggest that in rabbits, as in humans, there are maturational differences in maximal airway narrowing during bronchoconstriction (17, 29).
The elastic load that airway smooth muscle (ASM) must shorten against is a significant determinant of airway narrowing during bronchoconstriction. With a high elastic load, there is minimal ASM shortening and minimal airway narrowing. Decreasing the elastic load produces greater airway narrowing and could potentially lead to airway closure. The elastic loads that the ASM must shorten against include the airway wall and its attachment to the surrounding lung parenchyma. The elastic load from the airway wall is determined by its structural components, and the elastic load of the lung parenchyma includes the static elastic recoil pressure and the additional pressure required to distort the lung parenchyma surrounding the airway as it narrows.
In mature animals, airway compliance increases from central to peripheral airways, and the lower elastic load of the more compliant peripheral airways contributes to greater airway narrowing in the peripheral than the central airways. In rabbits and other species, tracheal compliance decreases during gestation and early in life (1, 4). However, we are unaware of published data assessing maturational differences in the distensibility of intraparenchymal airways.
We hypothesized that the greater airway narrowing in immature than mature rabbits in situ is related to more compliant airways in immature animals. In immature animals of most species, intraparenchymal airways are very small and fragile and therefore technically very difficult to isolate from the surrounding lung parenchyma to evaluate the elastic properties in a leak-free system. We assessed maturational differences in the airways in situ by comparing the relationship between Ptp and airway diameter measured from tantalum bronchograms in isolated rabbit lungs. In addition, we evaluated whether there were corresponding maturational differences in the relationship between Ptp and airway responsiveness in vivo.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Ptp vs. Lung Volume and Airway Diameter in Excised Lungs
Animal preparation. Immature (3-4 wk; 0.4-0.6 kg; n = 4) and mature (6 mo; 2.5-3.0 kg; n = 4) New Zealand White rabbits were anesthetized with intravenous pentobarbital sodium (50 mg/kg) and mechanically ventilated. After thoracotomy, intravenous atropine (0.4 mg/kg) and epinephrine (0.2 mg/kg) were administered before the animals were killed by exsanguination. The lungs were removed.
Static deflation pressure volume curves of the excised lungs were obtained between 20 and 0 cmH2O. After several inflation-deflation maneuvers to establish a volume history, the lung was inflated to 20 cmH2O. Volume was withdrawn with a syringe in a stepwise manner, and tracheal pressure (Ptr) was recorded at each volume after an allowance of several seconds for equilibration of pressure. Tantalum powder was then insufflated into the lungs via a catheter placed in the central airways. The excised lung was inflated several times and initially set at a Ptp of 20 cmH2O by use of a bias flow of air attached to an underwater seal. Radiographs of the lung were obtained with a 50-kV energy source at a distance of 50 cm with the lung inflated at Ptp of 20, 12, 8, 5, 2, and 0 cmH2O.Analysis.
Lung volume was normalized to the lung volume at a Ptp of 20 cmH2O. The data of normalized lung volume vs. Ptp were
fitted to an exponential equation using least square analysis
(3)
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(1) |
Ptp vs. RL Response to MCh In Vivo
Animal preparation. Immature (3-4 wk; 0.4-0.5 kg) and mature (6 mo; 2.5-3.0 kg) New Zealand White rabbits were anesthetized with intravenous pentobarbital sodium (50 mg/kg). An appropriately sized tracheotomy tube was inserted and securely tied in place to prevent air leaks. Animals were mechanically ventilated (Harvard no. 628) with a tidal volume of 5 ml/kg at a frequency of 60 breaths/min. The expiratory port of the ventilator was connected to a water column, which was used to adjust Ptr. A jugular venous catheter was inserted to administer normal saline, MCh, and additional anesthetic. The abdominal and thoracic cavities were widely opened, and a warming pad was used to prevent cooling of the animal.
Ptr was measured with a piezoresistive pressure transducer (Endevco no. 8507C0-2, San Juan Capistrano, CA). Because the animals were open chested, Ptr was also the Ptp. Tracheal airflow (
) was measured
with a screen pneumotachometer (Hans Rudolph no. 8410A, Kansas City,
MO) and a differential pressure transducer (Validyne MP45; ±2.25
cmH2O, Northridge, CA). Analog signals of flow and
pressure were filtered above 50 Hz, amplified, sampled, and
digitized at 100 Hz (Data Translation no. DT2801-A, Marlborough, MA).
Digital signals were stored in an IBM-compatible personal computer
(Zeos 486, St. Paul, MN) using data acquisition software (RHT Infodat,
Montreal, PQ, Canada).
Protocol.
A total of 17 mature and 16 immature rabbits underwent bronchial
challenge with intravenous MCh. Each animal was challenged at a single
Ptp: 2, 5, or 8 cmH2O. Baseline values of
and Ptr were recorded for 30 s during mechanical ventilation;
measurements were repeated after administration of intravenous saline.
After each dose of intravenous MCh (0.001, 0.01, 0.05, 0.1, 0.5 mg/kg), and Ptr were recorded for 5 min. The maximal increase in Ptr occurred within 1 min and then gradually declined. Each subsequent MCh
dose was administered after Ptr returned to baseline.
Analysis.
Lung resistance (RL) and elastance (EL) during
mechanical ventilation were calculated by using least squares linear
regression analysis to fit Ptr, , and digitally
integrated volume (V) signals to the following equation of motion
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(2) |
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Ptp vs. Airway Diameter in Excised Lungs
Mean airway diameters (mm) vs. Ptp (cmH2O) for airway segments 1-9 from the excised immature and mature rabbit lungs are illustrated in Fig. 1. For both groups, the diameters of all of the airway segments increased with increasing Ptp. The greatest increase in airway diameter occurred between 0 and 8 cmH2O, and the diameter remained relatively constant between 8 and 20 cmH2O. This can be more clearly seen when the airway diameter of each airway segment is normalized to the diameter measured at Ptp of 20 cmH2O (Fig. 2). Airway distensibility was calculated as the change in normalized diameter between 0 and 8 cmH2O. In general, airway distensibility increased from the central to the peripheral airways in both mature and immature lungs. The airways were grouped as extraparenchymal airways (segments 1-3), proximal intraparenchymal airways (segments 4-6), and distal intraparenchymal airways (segments 7-9). Airway distensibility was greater in immature than mature rabbit lungs in all three airway groups, and distensibility was greatest in the distal intraparenchymal airways for both mature and immature rabbit lungs when analyzed by ANOVA (Fig. 3).
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From the data of Ptp vs. normalized airway diameter, we also calculated
normalized airway area (
), assuming the airway was circular. For
each generation the group mean data were fit to the following equation
(13)
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(3) |
0 is the normalized area at pressure (P) = 0, S is the slope, and P
is the asymptotic pressure.
The values for 0 and S at zero Ptp for
each generation are illustrated in Fig. 4
for the immature and mature airways. 0 decreased from
central to peripheral airways, and the immature airways had lower
values than the mature airways when compared by nonparametric analysis (P < 0.01). Slope at zero Ptp increased with
increasing generation for the first five generations and then remained
relatively constant for the more peripheral generations. The slope was
higher for the immature than the mature airways when compared by
nonparametric analysis (P < 0.01).
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Ptp vs. Lung Volume in Excised Lungs
The data for each individual animal were fit to an exponential curve (Eq. 1), and there were no significant differences between mature and immature lungs for the exponential constant k (Table 1). The volume constants Vmax and A were significantly greater for the mature than for the immature rabbits, reflecting the larger lungs of the mature animals. Lung volume normalized to maximal volume vs. Ptp for all of the immature and the mature rabbit lungs is illustrated in Fig. 5. There is no difference in the fitted exponential equations for the mature and the immature animals.
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Ptp vs. RL Response vs. MCh In Vivo
In Fig. 6, the fold increases in RL over baseline with increasing MCh are compared for immature and for mature animals at Ptp of 2, 5, and 8 cmH2O. At the highest Ptp, 8 cmH2O, there were no differences in the fold increases in RL at the two highest doses of MCh, although the increases in RL were statistically slightly greater for the mature animals at lower MCh doses. At Ptp of 5 and 2 cmH2O, the fold increases in RL were significantly greater for immature than for mature animals at all MCh doses greater than 0.01 mg/kg.
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The MCh dose required to increase RL to 1.5 times the
baseline value was calculated as an index of airway sensitivity from the dose response curves of each individual animal. A MCh concentration to double RL could not be used because RL did
not double for either mature or immature animals at Ptp of 8 cmH2O. The effect of Ptp on airway sensitivity to MCh is
illustrated in Table 2. In both groups,
MCh sensitivity increased as Ptp decreased from 8 to 5 to 2 cmH2O. There was no significant difference in MCh
sensitivity between the mature and the immature animals at Ptp of 5 and
2 cmH2O; however, at Ptp of 8 cmH2O, the mature
animals were more sensitive to MCh than the immature animals.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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In the present study, we found that the distensibility of the airways within isolated rabbit lungs was greater in immature than mature animals; however, we did not find a maturational difference in the distensibility of the lung parenchyma when assessed by pressure-volume curves. In addition, at Ptp of 8 cmH2O, airway diameter was near maximal, and this elastic load almost completely inhibited the in vivo airway response to MCh in both mature and immature animals. At Ptp of 5 and 2 cmH2O, immature animals had greater maximal airway narrowing but no difference in MCh sensitivity. Our present findings are consistent with the hypothesis that maturational differences in the elastic load, either the airway wall or the interdependence between the wall and the lung parenchyma, may contribute to greater airway narrowing in immature animals.
Our finding of greater distensibility of immature than mature airways is consistent with other evidence that maturation does affect airway wall compliance. In rabbits and other species, tracheal compliance decreases during gestation and early in life (1, 4). However, we believe that our data are the first to indicate that there are maturational differences in the distensibility of the intraparenchymal airways. Our finding that airway diameter remained relatively constant above a Ptp of 8 cmH2O is consistent with previous reports in other larger mature species assessed by tantalum bronchograms or computed tomography scan (2, 8, 9, 19, 31). We also found that airway distensibility between 8 and 0 cmH2O was greater in the more distal than the more central airways, a finding also consistent with previous reports in other mature species.
The difference in the relationship between airway caliber and Ptp for mature and immature rabbit lungs may be related to maturational differences in the structure and function of the airway wall and/or maturational differences in the forces of interdependence between the airway and the surrounding lung parenchyma. A more distensible airway wall in the immature animal could decrease the load that ASM must shorten against and thus increase the degree of airway narrowing. In addition, in the unconstricted state, more compliant immature airways may be subject to collapse. Greater airway wall distensibility of the immature airway could result from maturational differences in the relative composition of the airway wall components (cartilage, muscle, collagen, and elastin), maturational differences in the mechanical properties of the individual components, and/or the mechanical linkage of the components within the airway wall. If there was any residual ASM tone in our isolated lung preparations, then maturational differences in residual tone could contribute to differences in airway distensibility. However, in rabbits, cutting, cooling, or stimulating vagal nerves has been reported to have only slight effect on ASM tone (10), and vagotomy or atropine had no significant effect on the baseline resistance (6). In addition, our measurements were obtained initially at high Ptp after several deep inflations, maneuvers that should also minimize any residual airway tone. Therefore, we do not believe that ASM tone accounted for the maturational difference in airway distensibility.
Airway wall compliance not only affects the elastic load that the ASM must shorten against but also affects the geometric factors that influence airway narrowing. As airway caliber decreases from its maximum to minimum value, the ratio of wall thickness to airway lumen increases. For the same degree of ASM shortening, airways with a greater ratio of wall thickness internal to the ASM relative to the airway lumen diameter will have a greater narrowing of the airway lumen secondary to encroachment of the airway wall into the lumen (18). At low Ptp, the airways of immature animals are at a lower fraction of their maximal diameter compared with the airways of mature animals. Therefore, immature airways should have a greater ratio of wall thickness to airway lumen, and this geometric factor would be magnified if at maximal diameter the ratio of wall thickness to airway diameter were greater in the immature animal.
In the present study, we measured Ptp and not transmural pressure. Because of tissue fragility and small size, it was technically not feasible to obtain isolated leak-free airways from the rabbit lungs, particularly the immature animals. In an intact lung, the peribronchial pressure is determined by the relationship between the elastic properties of the airways and the distortability of the lung parenchyma surrounding the airway, which can be characterized by the shear modulus. The analysis of Lai-Fook and co-workers (11) indicates that lungs with a higher shear modulus should have a more negative peribronchial pressure. A lower shear modulus for the immature than the mature rabbit lung would result in a higher peribronchial pressure and a lower transmural pressure for the immature airways. For the same Ptp, there would be a lower transmural pressure for the immature than the mature airway and thus a smaller normalized diameter for the immature airways at pressures less than maximal diameter. In our laboratory's recent study of isolated rabbit lungs, we found a lower shear modulus in immature compared with mature rabbit lungs (30). Thus this lower shear modulus could contribute to the relatively smaller normalized airway diameter and the greater distensibility of the immature airways that we observed in the present study of isolated rabbit lungs (30). At the present time, we are not able to separate the relative contributions of the elastic properties of the airway wall from the forces of interdependence between the airway wall and the surrounding lung parenchyma.
In this study, we measured the increase in RL during MCh challenge. Both airway resistance and tissue resistance are components of RL, and each resistive component may increase during bronchial challenge (14, 20-22). However, we have previously demonstrated that the greater MCh-induced pulmonary response of immature than mature rabbits at a Ptp of 5 cmH2O can be accounted for by greater increases in airway resistance, which correlated with greater airway narrowing in immature than in mature animals (23). In addition, studies in rats as well as computational models of airway narrowing have indicated that measured increases in tissue resistance during moderate to severe airway narrowing may be attributed primarily to ventilation inhomogeneity within the lung, rather than changes in the viscoelastic properties of the lung parenchyma (15, 16). Therefore, we do not believe that the maturational differences we observed in the effect of Ptp on the RL response to MCh are likely to be due to differences in lung parenchymal responses to MCh challenge but rather to differences in the airway response.
Maturational differences in the contractile properties of the ASM could also account for greater maximal airway narrowing in the immature rabbit. However, we previously reported that maximal active stress was significantly greater in trachealis muscle from mature compared with immature rabbits (27). In addition, using isolated bronchial strips from rabbits, Tanaka and Grunstein (25) reported that there was no maturational difference in the maximal isometric tension of trachealis muscle in response to MCh. No current data suggest that the immature rabbit ASM generates greater maximal stress than mature rabbit ASM, and therefore maximal stress is not likely to account for the greater maximal airway response in the immature rabbit unless the immature airway has proportionately more ASM.
In the present study, at Ptp of 8 cmH2O, both immature and mature rabbits had a very small airway response to MCh, indicating that, near maximal airway caliber, the forces that limit ASM shortening can greatly limit the degree of airway narrowing in both age groups of rabbits. This finding is consistent with previous reports that high stress on the airways limits ASM shortening and thus the degree of airway narrowing during bronchoconstriction (5, 7, 12, 24, 32). At both lower Ptp, the maximal responses were greater in the immature than the mature rabbits, although there were no differences in airway sensitivity to MCh. If the elastic load progressively decreased from Ptp of 5 to 2 cmH2O, we would expect that the maximal airway response of immature compared with mature lungs would be greater at Ptp of 2 than 5 cmH2O. However, we did not find a statistically greater difference between the responses of the immature than the mature lungs at 5 cmH2O than at 2 cmH2O. The absence of a difference may have resulted secondary to the large interanimal variability in responsiveness, because responses were assessed in different groups of animals and not within the same animal. Alternatively, the immature animals may have attained their maximal response at 5 cmH2O with significant airway closure, and therefore the immature animals may not able to obtain a greater response at the lower Ptp.
In summary, the distensibility of the airways within the lung parenchyma was greater in immature than in mature rabbit lungs, and the distal airways were more distensible than the proximal airways for both mature and immature animals. At Ptp of 8 cmH2O, the airways were near maximal size and the airway response to MCh was almost completely inhibited. At lower Ptp, airway narrowing was greater in immature than in mature animals. We conclude that a lower elastic load in the immature lung, either greater airway wall compliance or a lower shear modulus for the immature lung parenchyma, may be factors contributing to the greater airway narrowing of immature airways during bronchoconstriction.
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ACKNOWLEDGEMENTS |
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This research was supported by National Heart, Lung, and Blood Institute Grants HL-48522 and HL-29289; a James Whitcomb Riley Memorial Association Research Grant; and an American Lung Association of Indiana Career Development Research Grant.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. S. Tepper, James Whitcomb Riley Hospital for Children, Section of Pediatric Pulmonology, Rm. 2750, 702 Barnhill Dr., Indianapolis, IN 46202 (E-mail: rtepper{at}iupui.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 13 October 1999; accepted in final form 17 May 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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R. Ramchandani, X. Shen, S. J. Gunst, and R. S. Tepper Comparison of elastic properties and contractile responses of isolated airway segments from mature and immature rabbits J Appl Physiol, July 1, 2003; 95(1): 265 - 271. [Abstract] [Full Text] [PDF]
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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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 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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Distal
intraparenchymal airways had higher values than proximal
intraparenchymal airways and extraparenchymal airways for both immature
and mature animals, P < 0.05.
) vs. mature (
) rabbits at Ptp of 2, 5, and 8 cmH2O; * Statistically significant differences
in RL response of immature and mature animals
(P < 0.05).