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1Center for Life Science and Technology, School of Fundamental Science and Technology, and 7Department of System Design Engineering, Keio University, Yokohama 223-8522; 4Advanced Computing Center and 5Integrated V-CAD System Research Program, Institute of Physical and Chemical Research (RIKEN), Wako, Saitama 351-0198; and 2Life and Environmental Science Division, Japan Synchrotron Radiation Institute (SPring-8), Hyogo 679-5198, Japan; 3Biomedical Engineering Department, The University of Michigan, Ann Arbor, Michigan 48109-2099; and 6Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom
Submitted 17 June 2003 ; accepted in final form 18 December 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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150 µm ID) and then evaluated the localized compliance as a function of airway generation (Z). For smaller (<300-µm-diameter) airways, diameter was 36% larger at end-tidal inspiration and 89% larger at total lung capacity; length was 18% larger at end-tidal inspiration and 43% larger at total lung capacity than at functional residual capacity. Diameter, especially at smaller airways, did not behave linearly with V1/3 (where V is volume). With increasing lung pressure, diameter changed dramatically at a particular pressure and length changed approximately linearly during inflation and deflation. Percentage of airway volume for smaller airways did not behave linearly with that of lung volume. Smaller airways were generally more compliant than larger airways with increasing Z and exhibited hysteresis in their diameter behavior. Airways at higher Z deformed at a lower pressure than those at lower Z. These results indicated that smaller airways did not behave homogeneously. soft tissue; morphometry change; tissue elasticity; surface tension
V/P, where V is volume and P is pressure) of the P-V curve, based on the relation between lung pressure and lung volume, but also the more localized compliance, based on microscopic regions of parenchyma and airways, needs to be determined. The overall P-V curve of the lung describes bulk compliance and hysteresis, which are dominated by tissue elasticity and surface tension. Respiratory diseases, however, occur most frequently at small airways (26), and the condition of small airways has important physiological and clinical implications. In many respiratory diseases, significant compliance abnormalities mainly occur in localized regions of bronchi and bronchioles, and thus, in addition to the overall compliance, the localized, or the microscopic, compliance of parenchyma and small bronchi or bronchioles based on small-scale observations must be identified. Many studies have dealt with airway dynamics (7), surfactant transport (1, 31), and particle deposition (2) that occur in small airways. The concept of analyzing the microscopic compliance was introduced in the 1970s by Hughes et al. (8), Menkes et al. (15), and Sittipong and Hyatt (23). They insufflated tantalum powder into a lung as a contrast agent and then used bronchograms to analyze regional volume changes and changes in diameter and length of individual bronchial segments at various transmural pressures. However, those measurements were limited to large (>0.5-mm-diameter) bronchi.
Two principles have been used to analyze the mechanical properties of small airways. One approach is to visualize dehydrated and fixed preparations by using optical microscopy (10, 18). However, the preparation procedure significantly deforms the sample tissue, and it is extremely difficult to observe the morphometric changes of the same airways at various lung volumes. The other approach is to measure the mechanical properties of excised small airway segments in vitro (27). However, in situ, the intrapulmonary airways are surrounded by lung parenchyma, and the effective microscopic airway compliance is influenced by the surrounding support (Fig. 1). The larger intrapulmonary bronchi are surrounded by the peribronchial sheath (an invagination of the visceral pleura), which in turn is connected to the alveolar parenchyma. At some anatomically unspecified distance along the peripheral bronchial tree, the bronchi penetrate the peribronchial sheath and become directly connected to the parenchyma. As a consequence, the surface pressure acting on the larger bronchi is the pressure within the peribronchial space, which may be lower (more negative) than the effective pressure exerted by the parenchyma directly, as is the case for the smallest airways; this difference in pressure, however, may not be large unless inhomogeneous conditions, such as forced expiration, are undertaken. Hyatt and Flath (9) and Takishima et al. (25) measured diameter and length behavior of large (>1-mm-diameter) airways and reported that intact airways are stiffer than excised airways. No accurate measurements have been reported for small intact airways.
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In this study, we hypothesize that small airways were also stiffened in parenchyma, and their diameter-volume relation will not follow that of the surrounding parenchyma. The length-volume relation would be expected to follow the conventional proportionality to V1/3 to reflect the overall need to maintain connectivity and be space filling.
We determined diameters, lengths, and "localized compliance" of small airways to establish their mechanical properties. This localized compliance reflects the compliance of restricted regions under "near"-physiological conditions, in which small airways are embedded in lung parenchyma without dehydration and fixation. The measurements can be used potentially as a physiological and a clinical index.
We previously developed the staining-and-CT (SCT) imaging method to visualize small airways in detail by staining the lung tissue with a radiopaque solution and then visualizing the tissue by using a cone-beam microfocal X-ray CT system (21). In the present study, we visualized the three-dimensional structure of small airways of an excised rat lung by using the SCT method, analyzed the diameter and length of the same small airways at various lung volumes by using a three-dimensional thinning (skeletonization) algorithm, and then evaluated the localized compliance in the airway generation (Z) from 8 to 16, where Z is the number of bifurcations from the trachea to the airway of interest as proposed by Weibel (30).
Our results show that not all airway generations deform in the same manner. During earlier and later steps of static P-V curves, small airways behaved similarly to large airways. However, the diameter of small airways did not behave linearly with V1/3, and the percentage of airway volume for the small airways was not similar to that of lung volume. The diameter of the small airways changed dramatically at a specific lung pressure with increasing lung pressure, although the length changed linearly. The smaller airways exhibit hysteresis, especially in their diameter, and the localized compliance increases with Z. These results indicated that the small airways did not behave homogeneously.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Measurements. The bulk static P-V curves of the lungs were determined by stepwise inflation of the lungs in 1-ml increments to total lung capacity (TLC) and deflation in 1-ml decrements to FRC. The pressure and volume of the stained excised lungs in the cylinder could be externally regulated. Pressure was measured by using a pressure transducer (model EPI-541-0.35B, Entran) that had been calibrated using a manometer. In this study, we injected radiopaque solution into the pulmonary arteries via the IVC to stain the lung tissue, while the chest was opened and the lungs were kept inflated at FRC. As a result of this procedure, we could not measure the volume at FRC accurately. However, in previous studies using body plethysmography, saline displacement, and a neon dilution method, rat FRC was 2.5-3.7 ml (11, 12, 24). Therefore, in this present study, we arbitrarily, but reasonably, defined the volume at FRC as 3 ml. The volume (TV) was defined as FRC + 2 ml, which approximated the anticipated tidal volume (7 ml/kg). TLC was defined as FRC + 8 ml, and pressure at TLC was 26.52 ± 2.25 cmH2O. The lungs were inflated and deflated to various volumes using a 1-ml glass syringe at an accuracy of 0.02 ml, and micro-CT images (see Imaging) were obtained.
Imaging. The small airways were imaged using a microfocal X-ray CT system (model MCT-CB100MF, Hitachi Medical, Japan, Tokyo; Fig. 2). To reconstruct the CT images, a summed projection was acquired at 625 rotational positions. The resolution was 480 x 480 pixels, and 200 slice images per rotation were obtained. To visualize small airway networks, 1 cubic voxel was 16 µm, which meant that 1 square pixel was 16 x 16 µm and the space between each image was also 16 µm. All images of the excised rat lung over a 360° rotation were obtained in 2.5 min. Before taking CT images, we confirmed that the lung pressure was stable for 1 min at each lung volume. If there were air leaks during a sample rotation, the reconstructed CT images had some artifacts due to the high-resolution CT systems. To determine the diameter (D) and length (L) of an airway, the same branching networks were visualized for a volume between FRC and TLC during a stepwise inflation process in 2-ml increments and the deflation process in 2-ml decrements. The experimental time from the initial to the final measurement (including image reconstructions) was <2 h.
Analysis. To determine the morphometry of the small airways, we identified the cross sections of the small airways by using the threshold method (21) and then analyzed these cross sections by using the three-dimensional thinning algorithm of Toriwaki and Mori (28). This algorithm involves the Euclidean distance transformation and repeatedly checks the deletability of points in a sequence in which the Euclidean distance value is small and, finally, finds the skeletonized lines and the branching points of the airway network without changing the topology of the airways. However, this algorithm left "false" spurs, which we removed "manually" until the middle lines agreed with the input images.
The L and D of the airways were determined by approximating the airway as a cylinder network (21). The fractional increases in L and D (
L and D, respectively), normalized by L and D at FRC (LFRC and DFRC, respectively), were calculated as follows
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where L' and D' are expressed as L and D at each lung volume.
In this study, the localized compliances CTV and CTLC of the airways were evaluated at volumes defined by the volume infused (based on the volume infused by the syringe) to inflate the airways from FRC to TV and from FRC to TLC as follows
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To determine Z, we macroscopically imaged the entire lung by using micro-CT (1 cubic voxel of 43 x 43 x 43 µm) and identified the generation of the airways manually.
Statistical analysis. The size changes and the localized compliance are presented as means ± SE as a function of Z (n = 7-17 per Z) and lung condition (volume and pressure; n = 18-45 per lung condition). The lungs used during the inflation measurement process were different from those used during the deflation process. Differences between inflation and deflation groups and between each lung condition were tested for significance by analysis of variance followed by Tukey-Kramer multiple comparisons. Differences in D, L, CTV, and CTLC as a function of Z were also assessed for significance by analysis of variance followed by Steel-Dwass multiple comparisons. P < 0.05 was considered to be statistically significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The three-dimensional structure of the same branching networks at FRC and TLC was reconstructed on the basis of the tomographic images using an isosurface approach in the Visualization Toolkit, which is an open-source, object-oriented software system for three-dimensional computer graphics and imaging processing used by many researchers (Kitware, http://www.kitware.com/). Figure 4 shows the reconstructed three-dimensional structure. The branching networks expanded dramatically in three dimensions from FRC to TLC. D and L of each airway segment were increased at TLC compared with D and L at FRC, although D was larger than L.
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Bronchial hysteresis. Figure 5 shows the overall P-V relation for whole lungs with the representative bronchial hysteresis illustrated at a given lung pressure (10 cmH2O), and Fig. 6 shows the same at a given lung volume (TV); the P-V curves and CT images in Figs. 5 and 6 were obtained from the same lung. A 1-ml glass syringe was used to inject air in 2-ml increments into the lungs from FRC to TLC. When pressure was stabilized, it was measured, and further increments of air were injected. The entire stained excised rat lung exhibited lung hysteresis in the overall P-V curve (Figs. 5 and 6, top), and the bronchial D (arrows in Figs. 5 and 6, bottom) was larger during deflation than during inflation at the same pressure and the same volume. At 10 cmH2O pressure, D was 1.28-1.44 times larger during deflation (Fig. 5D) than during inflation (Fig. 5B), and at TV D was 1.21-1.35 times larger during deflation (Fig. 6D) than during inflation (Fig. 6B). These results indicated hysteresis of localized alveolar regions in the vicinity of the small airways.
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Bronchial diameter. Figure 7 shows the average D at TV and TLC during inflation as a function of Z. D increased with Z, and D of TV and D of TLC were statistically larger at Z = 16 than at Z = 8 (P < 0.01), and D of TLC was significantly larger than D of TV at Z = 11-16 (P < 0.05). These results are consistent with those reported previously (23).
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Figure 8 shows representative changes in the cross section of a small airway during inflation and deflation. During inflation, D remained relatively constant between FRC and FRC + 4 ml and started to increase between FRC + 4 ml and FRC + 6 ml. In contrast, during deflation, D remained approximately constant between TLC and TLC - 6 ml and started to decrease at TLC - 6 ml, indicating that the local cross-sectional change shows typical hysteresis in the overall lung P-V curve.
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Figure 9 shows the percentage of average D for the larger (>300-µm-diameter) and smaller (<300-µm-diameter) airways as a function of the percentage of V1/3. During the inflation process, the percentage of D for smaller airways was significantly larger at (TV + 4 ml)1/3 than at (TV + 2 ml)1/3 (P < 0.001). Also, the percentage of D for smaller airways at TV1/3 and (TV + 2 ml)1/3 was significantly larger during deflation than during inflation (P < 0.001). The percentage of D changed more linearly with the percentage of V1/3 for large airways than for smaller airways, and the differences between inflation and deflation were not statistically significant. For smaller airways, the percentage of D changed dramatically at specific V1/3, and the percentage of D also changed linearly with that of V1/3. These results indicate that all airways behaved very similarly and isotropically, except at specific lung volumes.
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Figure 10 shows the progressive average D in larger (>300-µm-diameter) airways compared with smaller (<300-µm-diameter) airways during inflation and deflation as a function of pressure. The localized pressure-D curves differed between the smaller and larger airways; for smaller airways, D increased 36% at TV and 89% at TLC, whereas for larger airways, D increased 18% at TV and 47% at TLC. The hysteresis for larger airways was fairly moderate, whereas that for smaller airways was more pronounced. For 12 and 16 cmH2O pressure, D values for smaller airways were significantly larger during deflation than during inflation (P < 0.001), whereas D for larger airways was statistically not so. During inflation, small airway D increased dramatically at a specific pressure; during inflation, D for smaller airways was signifi-cantly larger at 20 than at 16 cmH2O pressure (P < 0.001). This tendency is similar to that previously reported by Naureckas et al. (17). With further increase in pressure, D in small airways remained relatively constant. During deflation, D in small airways gradually decreased as pressure fell from 20 to 12 cmH2O and then decreased dramatically when pressure reached 12 cmH2O.
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Bronchial length. Figure 11 shows the average L at TV and TLC during inflation as a function of Z. Although L increased at lower Z as Z increased (Z = 8-11), it remained relatively constant at higher Z (Z = 12-16) at TV and TLC. L was statistically larger at TLC than at TV at Z = 11-16 (P < 0.05). This difference was similar to that of D shown in Fig. 7, although L was smaller than D in smaller airways (cf. Figs. 7 and 11).
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Figure 12 shows the average length behavior for smaller (<300-µm-diameter) airways during inflation and deflation: the percentage of the average L as a function of the percentage of V1/3 and the progressive average L as a function of pressure. The percentage of L changed linearly with the percentage of V1/3, and the differences between inflation and deflation were not statistically significant. These results indicate that L changed isotropically. L increased by 18% at TV and by 43% at TLC. L was not statistically larger during deflation than during inflation, and it changed linearly with pressure during inflation and deflation, resulting in the absence of hysteresis.
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Bronchial volume. Figure 13 shows the average airway volume (Vaw) for smaller (<300-µm-diameter) and larger (>300-µm-diameter) airways during inflation and deflation as a function of lung volume. The airway volume was calculated as follows: Vaw = D2 * L * 
/4. The values of airway and lung volume are presented as a percentage of the values at TLC. We found that the airway volume behaved more linearly with lung volume for larger airways than for smaller airways and that differences between inflation and deflation were not statistically significant. For the smaller airways, at lower and intermediate lung volume, airway volume was significantly larger during deflation than during inflation (P < 0.001). During inflation, airway volume was smaller at lower lung volume and larger at high lung volume. During deflation, airway volume was larger at high and intermediate lung volume and smaller at lower lung volume. Similar to the behavior of D as a function of V1/3 (Fig. 9), airway volume behaved linearly with lung volume, except a specific lung volume.
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Localized compliance. The localized compliances (CTV and CTLC) of individual airway segments were determined by using Eq. 1. Figure 14 shows the average CTV and CTLC as a function of Z. CTV and CTLC gradually increased with increasing Z, and CTLC was significantly larger than CTV at Z = 12-15 (P < 0.05). We calculated the average overall CTV (
) and CTLC (
) as follows
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was 0.06 ± 0.004 and was 0.10 ± 0.01, and CTV and CTLC above Z = 9 were significantly larger than and (Fig. 14; P < 0.05).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The localized mechanical properties of small airways are highly affected by surrounding lung parenchyma (Fig. 1). In our study, the localized airway compliance was defined as the compliance normalized by the airway segment volume at FRC and was similar to normalized lung macroscopic compliance by lung volume at FRC [specific compliance defined as V/(P * FRC)]. Tiddens et al. (27) calculated the specific compliance of isolated human small (1.3 ± 0.39 mm average diameter) airway segments on the basis of the volume of the segments inflated from 0 to 15 cmH2O in Krebs buffer and reported that the average specific compliance was 0.053. Our results show a smaller compliance: CTV at Z = 8 was 0.043 for D 430 µm (21). This difference in compliance indicates that the localized compliance is indeed influenced by the surrounding lung parenchyma and surface tension and that isolated airways are more compliant than intact airways (8, 9, 25). Although compliance is partially influenced by surface tension, in the experiments by Tiddens et al. (27) the isolated airway segments were placed in an organ bath and filled with buffer, and thus the effects of surface tension were eliminated. It is well known that a saline-filled lung, which does not exhibit air-surfactant interface or surface tension, is more compliant than a normal lung. Furthermore, small airways in lung parenchyma are surrounded by many alveoli (Fig. 1). The alveolar wall acts as a spring, and the localized compliance is determined not only by airway pressure but also by interdependence between the airway and the alveoli (3, 15), and therefore isolated airways are more compliant.
The small airways in our study exhibited hysteresis; D was larger during deflation than during inflation at 12 and 16 cmH2O pressure (P < 0.001; Fig. 10), although L remained relatively constant (Fig. 12). Because the larger airways are inherently stiffer than smaller airways, diameter of the smaller airways is more affected by changes in lung volume of the tissue surrounding them, whereas larger airways are relatively unaffected. Smooth muscle tone and surface tension are important factors in hysteresis (19). Using a tantalum bronchogram technique, Hughes et al. (8) analyzed the change in bronchial L and D of excised dog lungs during inflation and deflation. They reported that the bronchial segments did not exhibit hysteresis in L or D and explained that the reason was that the surfactant did not completely cover the entire surface of the large bronchi (D = 0.1-1.17 cm). The airway behavior in large airways is hardly affected by airway surfactant and, so, exhibits less hysteresis. A saline-filled lung without lung surfactant does not exhibit hysteresis in its P-V curve. Tiddens et al. (27) reported that isolated human small airways (D = 1.3 ± 0.39 mm) exhibited hysteresis in the P-V curve. In their experiments, the airway segments were placed in an organ bath and filled with buffer, and the observed hysteresis in the P-V curve was caused by the behavior of D. Shardonofsky et al. (22) lengthened and shortened dog bronchial segments (Z = 4 or 5) in the axial direction in Krebs solution and reported no significant differences in axial strain between the lengthened and shortened airways and reported no hysteresis. Our results are consistent with all these previous results. However, although Tiddens et al. reported that D gradually increased as pressure increased, we found that D changed dramatically at a specific pressure (Fig. 10).
This dramatic change in D at a specific pressure can be explained as follows. As shown in Fig. 10, D sharply changed at 16 cmH2O pressure during inflation and at 12 cmH2O pressure during deflation. This variation in D could be closely associated with the airway opening-and-closing process. Using a model, Gaver et al. (4) studied the airway opening process in experiments and reported that pressure at which D sharply increased depended on D and surface tension. Using the tantalum bronchograms obtained by microfocal X-ray imaging, Naureckas et al. (17) analyzed D of excised rat lungs during inflation and reported that D increased from 400 to 700 µm when the lung pressure was increased slowly from 0 to 25 cmH2O. Our results showed similar trends (Fig. 10), in that D gradually increased when pressure was increased from 0 to 12 cmH2O, and then the airways appeared to "pop" open when pressure was further increased. The opening process of small airways during inflation is determined by tissue elasticity and surface tension. At low pressure before the airways suddenly opened, a balance among tissue elasticity, surface tension, and transmural pressure was maintained, and thus D was relatively constant (Fig. 10). At a specific pressure, the balance was not maintained, and thus D dramatically increased (Fig. 10).
All airways did not deform in the same way: the smaller airways expanded and contracted more at lower pressure than did the larger airways. In our study, early in the inflation, the air space increased, but D of small airways remained relatively constant, whereas late in the inflation, the air space increased only slightly but D dramatically increased (Fig. 8A). A key result in our study is that small airways were more compliant at higher Z (Fig. 14). Martin and Proctor (14) measured the P-V curve of dog bronchi and reported that peripheral airways were more compliant than central airways. Naureckas et al. (17) reported that the specific pressure at which D dramatically increased depended on D and that pressure was lower in smaller airways. Mercer et al. (16) analyzed alveolar diameter of fixed rat lungs at various lung pressures and reported that the diameter increased remarkably between 0 and 10 cmH2O (between 43.3 ± 2.3 and 100.3 ± 3.3 µm) and was approximately constant at >10 cmH2O. Their results indicate that the smaller airways opened at lower pressure during inflation than did larger airways. In addition, dCTV/dZ increased and dCTLC/dZ decreased with increasing Z at higher Z (Fig. 14).
Interestingly, D, especially of smaller (<300-µm-diameter) airways, did not change linearly with V1/3, although as would be expected, L did (Figs. 9 and 12A). Our results differ from those of Hughes et al. (8), who reported that there were no differences in D and L between large and small bronchi and that D and L changed linearly as V1/3. Furthermore, the airway volume of smaller airways (unlike the larger airways) did not behave linearly with lung volume (Fig. 13). Previous studies suggested that airway properties were homogeneous. However, the airway wall structure varies along the path. Ma et al. (13) analyzed the mechanical properties of muscle strips of canine airways of different generations (Z) and demonstrated the heterogeneity of airway smooth muscle, thus indicating that small and larger airways may not expand similarly.
We do not consider that the difference in larger and smaller airway behavior is due to the effects of the peribronchial sheath, present around the larger bronchi. Inasmuch as the ventilation-distension process is essentially static, the pressure within the sheath would be expected to reflect closely the surrounding alveoli.
In summary, the SCT method allowed successful visualization of small airways under near-physiological conditions: the airways were embedded in lung parenchyma without dehydration or fixation. Our study is the first to evaluate localized airway compliance by using this method, which may have physiological and clinical applications in animal experiments. Compared with the values of D and L at FRC, D was 36% higher at TV and 89% at TLC and L was 18% higher at TV and 43% at TLC. All airways did not deform in the same manner. Large airways demonstrated similar inflation and deflation diameter change patterns; however, with increasing Z, local compliance of the small airways exhibited clear hysteresis. During the earlier steps of inflation, small airways inflated similarly to the larger airways, following a path very dissimilar from their deflation path, but at above 16 cmH2O, the small airways experienced a rapid increase in diameter and thereafter followed a path very close to the deflation path at high lung volume.
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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. Section 1734 solely to indicate this fact.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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rotation stage, an image intensifier, and a 12-bit charge coupled device (CCD) camera. Excised rat lung in the Plexiglas cylinder was mounted on the rotation stage.
, vessels. Scale bar, 500 µm.
