Airway Distensibility in Adults with Asthma and Healthy Adults, Measured by Forced Oscillation Technique

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1 Airway Distensibility in Adults with Asthma and Healthy Adults, Measured by Forced Oscillation Technique Nathan J. Brown 1,2,3, Cheryl M. Salome 1,2,3, Norbert Berend 1,2,3,4, C. William Thorpe 3,5, and Gregory G. King 1,2,3,4 1 Woolcock Institute of Medical Research, Camperdown, Australia; 2 Department of Medicine, University of Sydney, Sydney, Australia; 3 Cooperative Research Centre for Asthma, Sydney, Australia; 4 Department of Respiratory Medicine, Royal North Shore Hospital, St. Leonards, Australia; and 5 Bioengineering Institute, University of Auckland, Auckland, New Zealand Rationale: Reduced airway distensibility in subjects with asthma compared with control subjects may be related to differences in lung elastic recoil and bronchomotor tone. Objectives: To examine the contribution of lung elastic recoil and bronchomotor tone to airway distensibility. Methods: We compared airway distensibility in 18 subjects with asthma with 19 control subjects before and after bronchodilator administration and, in a subgroup of 7 subjects with asthma and 8 control subjects, correlated distensibility with pressure volume parameters. Measurements and Main Results: Distensibility was measured, using the forced oscillation technique, as the linear slope of conductance versus volume between total lung capacity (TLC) and 75% TLC and between 75% TLC and FRC. Transpulmonary pressure was recorded concurrently with distensibility, using an esophageal balloon. Pressure conductance data were described using linear regressions and pressure volume data were described using exponential equations. Subjects with asthma had lower baseline FEV 1 (p ) and conductance (p 0.002) than did control subjects. Distensibility above 75% TLC was less in subjects with asthma than in control subjects (p ), but there was no difference below 75% TLC. Bronchodilator administration did not alter distensibility despite increases in FEV 1 (p ) and conductance (p ) in subjects with asthma, and conductance (p ) in control subjects. After bronchodilator administration, subjects with asthma had reduced lung elastic recoil compared with control subjects (p 0.03) and a reduced pressure conductance slope (p 0.01), but there were no correlations between pressure volume characteristics and airway distensibility. Conclusions: Airway distensibility measured by forced oscillation technique is reduced in subjects with asthma compared with subjects without asthma, is not related to lung elastic recoil, and is unchanged by bronchodilator administration. Airway wall remodeling remains the most likely cause of reduced airway distensibility in asthma. Keywords: respiratory mechanics; oscillometry; bronchi Previous studies showing reduced airway distensibility in subjects with asthma compared with healthy control subjects (1 5) and reduced airway compliance during forced expirations in subjects with asthma (6) imply that airways of subjects with asthma are stiffer than those of individuals without asthma. It (Received in original form September 14, 2006; accepted in final form April 26, 2007 ) Supported by the Cooperative Research Centre for Asthma and by a University of Sydney Bridging Grant. Correspondence and requests for reprints should be addressed to Nathan Brown, Woolcock Institute of Medical Research, P.O. Box M77, Missenden Road, Camperdown, NSW, 2050 Australia. njb@woolcock.org.au This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 176. pp , 2007 Originally Published in Press as DOI: /rccm OC on April 26, 2007 Internet address: AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Airway distensibility is reduced in subjects with asthma compared to control subjects but it is not known if this is due to differences in either lung elastic recoil or bronchomotor tone. What This Study Adds to the Field Bronchomotor tone has little effect on airway distensibility measured by forced oscillation technique, and airway distensibility does not correlate with pulmonary pressure volume characteristics. has been suggested that this increased airway stiffness is due to airway remodeling (1, 5, 6). Ward and coworkers reported a negative correlation between the thickness of the reticular basement membrane and airway distensibility in subjects with mild asthma (5), providing direct evidence that airway distensibility may be a marker of airway remodeling. A simple physiological marker of airway remodeling such as airway distensibility would be a valuable tool that could help improve the understanding and treatment of airway structural changes associated with asthma. To quantify airway distensibility, airway caliber must be measured at different lung volumes and thus different airway transmural pressures. In previous studies of distensibility airway caliber has been measured as anatomic dead space by N 2 (1) or CO 2 washouts (4, 5), as airway resistance (7), or as lung resistance (2, 3, 8). However, the clinical usefulness of these methods is uncertain because they are technically difficult and/or timeconsuming to perform. The forced oscillation technique (FOT) has been used to track airway caliber in real time during bronchoprovocation and bronchodilation (8 10). We have previously described a relatively simple method for measuring airway distensibility, using the FOT, as the linear slope of respiratory system conductance versus lung volume (11). In that study airway distensibility measured by the FOT correlated with distensibility measured on the basis of anatomic dead space (11). However, because of the small sample size, differences in distensibility, determined by this method, between subjects with asthma and healthy subjects were not reported. Lung elastic recoil pressure, which may be reduced in asthma (12, 13), and airway smooth muscle tone are both major determinants of airway caliber (2, 3, 14). Accordingly, reduced airway distensibility could be due to increased airway smooth muscle tone or to reduced lung elastic recoil pressure, as well as to remodeling. For airway distensibility to be a clinically useful marker of remodeling the effects of these possible confounders must be determined.

2 130 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL The aims of the current study were to measure airway distensibility by the FOT in subjects with asthma and healthy control subjects and to determine whether differences in distensibility between groups were due to basal airway smooth muscle tone or lung elastic recoil. Some preliminary results of these studies have been previously reported in the form of abstracts (15, 16). METHODS Subjects Subjects between 18 and 75 years of age were recruited via advertisements at the Woolcock Institute of Medical Research (Camperdown, Australia), the University of Sydney (Sydney, Australia), and in the local media. Healthy control subjects had no history of symptoms, diagnoses, or regular medication use for either respiratory or cardiac disease. Asthma was defined by National Asthma Education and Prevention Program guidelines (17, 18). All subjects gave written, informed consent. The study was approved by the Human Ethics Committee of the University of Sydney (protocol no. X ). Experimental Protocol Subjects attended two separate laboratory visits, having withheld shortand long-acting bronchodilator medications for at least 6 and 12 hours, respectively. At the first visit, subjects completed a respiratory health questionnaire and underwent skin-prick tests to a panel of 14 common aeroallergens, measurements of spirometry and lung volumes, respiratory system conductance (mean Grs), and airway distensibility by the FOT. In a subgroup, airway distensibility was also measured on the basis of single-breath nitrogen washouts (SBNWs). At the second visit, subjects had measures of spirometry, mean Grs, and airway distensibility by FOT before and after 200 g of salbutamol was administered via spacer. In addition, 8 of 19 healthy subjects and 7 of 18 subjects with asthma (lung elastic recoil pressure [Pel] subgroup) had transpulmonary pressure measured simultaneously during the distensibility measurements. Airway distensibility measurements from visit 1 and visit 2 were used to assess repeatability. Equipment and Measurements Lung volumes were measured with an Autobox 6200 DL plethysmograph (Sensormedics Corporation, Yorba Linda, CA) and spirometry was performed with a Vmax 20c spirometer (Sensormedics). The forced oscillation device, used to measure mean Grs and the index of airway distensibility at 6 Hz, has been previously described (10) and was modified in this study to enable simultaneous measurement of transpulmonary pressure (for details see the online supplement). Deflation pressure volume curves between total lung capacity (TLC) and functional residual capacity (FRC) were constructed for each subject and fitted with the exponential function V A Be KP (3), where V is lung volume, P is lung recoil pressure, A and B are constants, K represents the degree of curvature, and B/A% represents the position of the curve relative to the pressure axis. Airway distensibility was also measured by SBNW (1), using a bagin-box system that has been previously described (11), and Fowler s equal-area method for determining anatomic dead space at four different lung volumes: FRC, near TLC, and two intermediate volumes. SBNW distensibility (ml L 1 ) was calculated by least-squares regression as the linear slope of the relationship between anatomic dead space (ml) and lung volume (L). Predicted values of the European Coal and Steel Community (19), Crapo and coworkers (20), and Pasker and coworkers (21) were used for spirometry, lung volumes, and conductance, respectively. Index of Airway Distensibility by FOT Subjects followed the breathing protocol shown in Figure 1 adapted from Johns and coworkers (4). After 1 minute of stable tidal breathing (during which mean Grs was measured) subjects inhaled slowly to TLC and then resumed tidal breathing. Subjects then inhaled slowly to near TLC and breathed at approximately tidal volumes with progressively decreasing end-expiratory lung volumes until end expiration was near FRC, at which point normal tidal breathing was resumed. This deflation maneuver was performed twice and the breathing protocol was terminated with a final slow inhalation to TLC. If one of the deflation maneuvers consisted of four or fewer tidal excursions then the subject was asked to perform a third maneuver to ensure that a sufficient number of data points was obtained. This was most likely to occur if the subject had a small inspiratory capacity or large tidal volume. Absolute lung volumes were calculated by referencing the inhalations to TLC with plethysmographic TLC. The respiratory system resistance (Rrs) and volume recordings during the deflation maneuvers (Figure 1) were examined for potential outliers. Any values of Rrs exceeding mean end-expiratory Rrs immediately before each maneuver were considered to be due to closure of the glottis and were excluded. Other outlying, low Rrs values due to leakage at the mouth were excluded and high Rrs values due to excessive movement and closure of the glottis were also excluded. All remaining Rrs values were converted to Grs by taking the reciprocal (1/Rrs). In developing this method, deflation instead of inflation maneuvers were chosen because they proved easier for subjects to perform and resulted in fewer data points being excluded because of movement of the glottis. Using the deflation limb also minimized the effects of lung recruitment and other hysteretic effects. For the index of distensibility, only Grs and volume data at instances of zero flow (end inspiration and end expiration) were used (Figure 2A), thus avoiding the effects of flow on resistance (22). The data from all maneuvers were combined and Grs was plotted against volume (Figure 2B). The mean number of data points obtained between TLC and FRC at baseline was 25 (range, 15 40). This relationship was curvilinear between TLC and FRC and so the data were divided at 75% TLC, which allowed linear fitting. The index of distensibility was calculated as the linear least-squares slope of Grs/ volume between TLC and 75% TLC, and separately between 75% TLC and FRC. The intercepts were determined at 75% TLC and FRC, respectively. At 6 Hz, FOT provides a good estimate of airway conductance with little contribution from lung tissue (23) and minimal contribution from the chest wall, particularly as lung volume increases (9). Transpulmonary pressure measured at the zero flow points, measures lung elastic recoil pressure (Pel). The pressure Grs relationship was linear between TLC and FRC, and therefore the linear least-squares slope of Grs/ Pel was determined over this volume range. This index of airway distensibility differs slightly from that previously described using FOT (11), with the Grs and volume data being fitted with only a single linear function between TLC and FRC. Using two linear functions to describe the data enables a better representation of the curvilinear nature of the relationship. Statistical Analyses Data are shown as means with 95% confidence intervals unless otherwise specified. p Values less than 0.05 were considered to be statistically significant. Data were analyzed with the SAS system (SAS Institute, Inc., Cary, NC). Repeatability from visit 1 to visit 2 was assessed by calculating the intraclass correlation coefficient and the 95% limits of agreement (24). Differences between subjects with asthma and healthy subjects were examined using unpaired t tests. Bronchodilator effects were examined using paired t tests. Univariate correlations were determined using Pearson correlation analyses. RESULTS Eighteen subjects with asthma and 19 healthy subjects participated in the study. All subjects were free of symptoms of acute respiratory infection within the previous 6 weeks, were current nonsmokers, and each had less than 10 pack-years of past smoking. There were no differences in age, height, weight, TLC, or FRC between the groups (Table 1). Residual volume (RV) was higher in subjects with asthma compared with healthy subjects, as was RV/TLC (p 0.03 and p 0.02, respectively). Bronchodilator administration increased FEV 1 by more than 10% in 6 of 18 subjects with asthma and by more than 15% in 4 of 18 subjects with asthma (Table 2). Index of Airway Distensibility Examples of volume Grs, pressure volume, and pressure Grs relationships for nonasthmatic and asthmatic subjects of similar

3 Brown, Salome, Berend, et al.: Airway Distensibility in Asthma 131 Figure 1. Example of deflation maneuvers with corresponding resistance and transpulmonary pressure recordings. Rrs respiratory system resistance. age are shown in Figure 3 and clearly indicate the distinct curvilinearity of the volume Grs relationship. Mean values of the index of airway distensibility for subjects with asthma and healthy subjects are shown in Table 3 and plotted in Figure 4A. At high lung volumes, the ranges of values for the slope of Grs/ volume in subjects with asthma and healthy subjects were and L second 1 cm H 2 O 1 L lung volume 1, respectively. The slope of Grs/ volume between 75% TLC and FRC was not different between groups, but in the high-volume range it was lower in the subjects with asthma. Effect of Bronchodilator Administration Subjects with asthma had lower spirometry and Grs compared with healthy subjects (Table 2). Bronchodilator administration increased FEV 1 (p ), FEV 1 /FVC (p 0.001), and mean Figure 2. Example of identification of respiratory system conductance (Grs) and volume points at end inspiration and end expiration in a single deflation maneuver (A ). These data are plotted (B) with separate linear regressions fit to the data above and below 75% TLC. Dotted line in B represents a second-order polynomial fit to data across the full volume range.

4 132 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 1. ANTHROPOMETRIC CHARACTERISTICS AND LUNG VOLUMES: ALL SUBJECTS Subjects without Asthma Subjects with Asthma (n 19)* (n 18) Mean 95% CI Mean 95% CI Age, yr Height, cm Weight, kg TLC, % predicted (L) (6.54) (6.77) 5.6 FRC, % predicted (L) 99.9 (3.31) (3.33) 10.6 RV, % predicted (L) (1.73) (2.27) 17.9 RV/TLC, % FRC/TLC, % Atopic, n 7 14 ICS weekly, n 0 13 BD weekly, n 0 7 BD weekly, n 0 9 Ex-smokers, n (range, pack-years) 3 ( ) 3 ( ) Definition of abbreviations: BD bronchodilator; CI confidence interval; ICS inhaled corticosteroid; RV residual volume. * Of the 19 subjects, 12 were male. Of the 18 subjects, 11 were male. Width of 95% CI. ICS use in previous 12 months. BD ( 2 -agonist) use in previous 12 months. Grs (p ) in subjects with asthma and FEV 1 /FVC (p 0.009) and mean Grs (p 0.004) in healthy subjects (Table 2). The intercepts of Grs/ volume at both high- and low-volume ranges were lower in the subjects with asthma at baseline. The intercept of Grs/ volume above 75% TLC correlated with FEV 1 (r 0.68, p 0.002), FEV 1 /FVC (r 0.50, p 0.03), and Grs (r 0.67, p 0.002) only in subjects with asthma. After bronchodilator administration, the intercept of Grs/ volume correlated with FEV 1 (r 0.67, p 0.004), FEV 1 /FVC (r 0.60, p 0.01), and Grs (r 0.69, p 0.002) in subjects with asthma; and with FEV 1 (r 0.49, p 0.03) in healthy subjects. After bronchodilator administration, there were no changes in the slopes of Grs/ volume and the between-group difference for the high-volume range remained. The intercepts of Grs/ volume at FRC and at 75% TLC increased in both groups after bronchodilator administration and were no longer different between asthmatic and nonasthmatic subjects. Effect of Lung Elastic Recoil Pressure Characteristics of the seven subjects with asthma and eight healthy subjects (Pel subgroup), who had measurements of lung elastic recoil pressure, are summarized in the online supplement (see Table E1 of the online supplement). Anthropometric characteristics, lung volumes, lung function (see Table E1), and distensibility indices (Figure 4B; and see Table E2) of this subgroup were similar to those of the study group as a whole. In this subgroup only one subject with asthma and one healthy subject reported a past history of smoking (4.2 and 0.2 pack-years, respectively). The mean pressure volume curves for subjects with asthma and healthy subjects are shown in Figure 5A. At baseline, subjects with asthma had lung compliance similar to that of healthy subjects, but there was a leftward shift in the asthmatic pressure volume curve that indicated a loss of lung elastic recoil, although TABLE 2. LUNG FUNCTION BEFORE AND AFTER BRONCHODILATOR ADMINISTRATION: ALL SUBJECTS Significance of Subjects without Asthma Subjects with Asthma Difference Mean 95% CI* Mean 95% CI (p Value) FEV 1, % pred (L s 1 ) Before BD 99.7 (3.87) (2.97) After BD (3.93) (3.17) p Value (paired t test) FVC, % pred (L s 1 ) Before BD (4.71) (4.30) After BD 99.7 (4.66) (4.34) p (paired t test) FEV 1 /FVC, % Before BD After BD p Value (paired t test) Mean Grs at 6 Hz, % pred (L s 1 cmh 2 O 1 ) Before BD (0.47) (0.33) After BD (0.54) (0.42) p Value (paired t test) Definition of abbreviations: BD bronchodilator; CI confidence interval. * Width of 95% confidence interval.

5 Brown, Salome, Berend, et al.: Airway Distensibility in Asthma 133 Figure 3. (A F) Plots of Grs versus lung volume, volume versus lung elastic recoil pressure (Pel), and Grs versus Pel for a male without asthma and a male with asthma of similar age. this was not statistically significant (p 0.1 for the difference in B/A%). Although there were no statistically significant changes in pressure volume characteristics after bronchodilator administration, there was a difference in lung elastic recoil pressure between subjects with asthma and healthy subjects (p 0.03 for the difference in B/A%, p for the difference in maximal static elastic recoil pressure at TLC). See the online supplement for mean data and between-group comparisons. The mean slopes and intercepts at FRC of the pressure Grs relationships are plotted in Figure 5B (see also Table E2). Subjects with asthma had a reduced slope of Grs/ Pel compared with healthy subjects (p 0.08 at baseline, p 0.01 after bronchodilator administration). After bronchodilator administration there were no changes in the slopes of Grs/ Pel, but there was an increase in intercept (p 0.02 in subjects with asthma only). The slope of Grs/ Pel did not correlate with either lung function or pressure volume characteristics, suggesting that lung elastic recoil pressure is not a significant contributor to airway distensibility. Although the intercept of Grs/ volume above 75% TLC correlated with the position (B/A%) of the pressure volume curve in subjects with asthma (r 0.81, p 0.03 at baseline; r 0.74, p 0.06 after bronchodilator administration) there were no other correlations between the index of airway distensibility and pressure volume characteristics. The index of airway distensibility (slope of Grs/ volume above 75% TLC) correlated with distensibility measured as the slope of Grs/ Pel (r 0.71, p at baseline; r 0.64, p 0.01 after bronchodilator administration). Repeatability Subject characteristics for the 15 subjects with asthma and 18 healthy subjects, who had repeat measures of airway distensibility by FOT, are summarized in the online supplement (see Table

6 134 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL TABLE 3. INDEX OF AIRWAY DISTENSIBILITY BEFORE AND AFTER BRONCHODILATOR ADMINISTRATION: ALL SUBJECTS Subjects without Significance of Asthma Subjects with Asthma Difference Mean 95% CI* Mean 95% CI (p Value) Grs/ Volume at High Lung Volumes (TLC to 75% TLC) Slope before BD, L s 1 cmh 2 O 1 L lung volume Slope after BD, L s 1 cmh 2 O 1 L lung volume p (paired t test) Intercept before BD, L s 1 cmh 2 O Intercept after BD, L s 1 cmh 2 O p (paired t test) Grs/ Volume at Low Lung Volumes (75% TLC to FRC) Slope before BD, L s 1 cmh 2 O 1 L lung volume Slope after BD, L s 1 cmh 2 O 1 L lung volume p (paired t test) Intercept before BD, L s 1 cmh 2 O Intercept after BD, L s 1 cmh 2 O p (paired t test) Definition of abbreviations: BD bronchodilator; CI confidence interval. * Width of 95% confidence interval. E4). Repeatability of the index of airway distensibility (slope of Grs/ volume above 75% TLC) was consistent, with an intraclass correlation coefficient of 0.81 and 95% limits of agreement of Correlation between Airway Distensibility Measured by FOT and by SBNW A subgroup of 12 subjects (6 subjects with asthma) had airway distensibility measured by SBNW (see the online supplement for subject characteristics). Subjects with asthma had reduced SBNW distensibility ( ml L 1 ) compared with healthy subjects ( ml L 1,p 0.046). The slope of Grs/ volume above 75% TLC correlated with SBNW distensibility (r 0.73, p 0.007). DISCUSSION Results from previous studies, using alternative methods of measuring airway distensibility, suggest that subjects with asthma have less distensible airways than do nonasthmatic healthy control subjects (1, 4, 5, 8), and the present study confirms this finding on the basis of an index of airway distensibility measured by the forced oscillation technique. More importantly, we have shown that airway smooth muscle tone has little effect on the index of airway distensibility and that there is no correlation between lung elastic recoil and the index of airway distensibility. Airway distensibility is most appropriately measured as the relationship between airway caliber and airway-distending pressure; however, because this requires the use of an esophageal balloon it is impractical as a routine test. Using the forced oscillation technique to measure airway distensibility assumes that respiratory system conductance represents actual airway caliber and that lung volume represents airway-distending pressure. It is likely that respiratory system conductance, measured at 6 Hz and high lung volumes, is a good marker of airway caliber, although comparison with a direct measurement of airway caliber such as high-resolution computed tomography (25) would be valuable confirmation. At 6 Hz, the resistance of the respiratory system is due predominantly to airway properties with little contribution from the lung tissue (23) or chest wall. Resistance due to the chest wall is minimized at higher lung volumes, decreasing from about 0.5 to 1.0 cm H 2 O L 1 second during tidal breathing to nearly zero at TLC, an effect that is similar in normal and asthmatic subjects (9). The significant correlation between the slope of Grs/ Pel and the slope of Grs/ volume above 75% TLC suggests that lung volume is a good proxy for airway-distending pressure. It was important, in the present study, to determine whether reduced airway distensibility was simply a function of the reduced lung elastic recoil pressure that is well described in subjects with asthma (12, 13, 26 30). We used a technique similar to that of Jensen and coworkers (8) to measure lung elastic recoil pressure and conductance simultaneously and observed a linear relationship between pressure and conductance between TLC and FRC, which is consistent with previous studies (2, 7). The reduced slope of Grs/ Pel in subjects with asthma compared with healthy subjects implies reduced airway distensibility. However, although lung elastic recoil was lower in subjects with asthma than in healthy subjects there were no correlations between the slope of Grs/ Pel and either the position or shape of the pressure volume curve. Importantly, there were also no correlations between our index of airway distensibility and either the position or shape of the pressure volume curve. Although the subjects with asthma in this study had normal lung compliance, it is possible that in disease states such as emphysema the index of airway distensibility may be affected by abnormal lung compliance. Our observation that bronchodilator administration did not alter airway distensibility (slope of Grs/ volume) conflicts with the theory of Jensen and coworkers, who proposed that asthmatic airway smooth muscle is in a more latchlike state at FRC, making the muscle and therefore the airways stiffer, a conclusion reached after observing the effects of single deep inspirations on airway dilation (8). If reduced airway distensibility in subjects with asthma were due to increased bronchomotor tone (increased actin myosin cross-bridge activity) then bronchodilator administration should increase airway distensibility. We acknowledge that 200 g of salbutamol may be insufficient to completely eliminate bronchomotor tone (31), yet there was not even a small increase in airway distensibility that might be interpreted as dose related. Any effect of airway smooth muscle on airway distensibility is more likely due to remodeling of the muscle rather than to an increase in contractility. Modeling

7 Brown, Salome, Berend, et al.: Airway Distensibility in Asthma 135 Figure 4. Mean linear regressions of Grs against lung volume between TLC and 75% TLC and between 75% TLC and FRC. (A ) All subjects, n 37. (B) Pel subgroup, n 15. Regression lines are plotted between mean minimal and maximal lung volumes within each volume range. BD bronchodilator. studies have shown that increased thickness of airway smooth muscle (even with normal contractility) leads to excessive airway narrowing during bronchoconstriction (32). Thus the increased airway smooth muscle bulk in asthma (33, 34) could increase the load against which airway-distending forces must act, making the airway stiffer. Any increase in extracellular matrix within the smooth muscle layer (35) could amplify such effects but would not necessarily respond to bronchodilator administration. Other structural changes may also stiffen airways including wall thickening, stiffening of noncontractile elements such as collagen, and inflammation or remodeling of the adventitia, leading to reduced interdependence between lung tissue and airways (36). Some of these properties are difficult to measure and clarifying their precise effects, if any, on airway distensibility would require new measurement techniques. The volume conductance relationship has been previously studied using repeat measurements of airway conductance at different thoracic gas volumes (7, 37, 38). This is the first study Figure 5. Mean pressure volume curves (A ) between TLC and FRC. Curves are plotted between mean minimal and maximal lung volumes. Mean linear regressions of Grs on Pel (B) between TLC and FRC. Regression lines are plotted between minimal and maximal Pel from the pressure volume plots. BD bronchodilator. to use the forced oscillation technique, which offers the advantage of being able to measure conductance at many different lung volumes within a single test. We observed a curvilinear volume conductance relationship, which is consistent with previous studies (7, 38, 39). In view of the linear pressure conductance relationship and the curvilinear pressure volume relationship (see Figure 3) a curvilinear volume conductance relationship is not surprising. By dividing the volume conductance data at 75% TLC into a high- and low-volume range, this relationship could be described by two linear functions, and clearly showed that differences in the relationship between subjects with asthma and healthy subjects occurred at high lung volumes. Possible confounding factors such as airway surface tension, heterogeneous airway narrowing, airway closure/recruitment, changes in airway length, and effects of the chest wall may make betweengroup differences virtually undetectable at low lung volumes but have minimal effects at higher lung volumes as the mucosa unfolds and airway wall tissues stretch. Airway distensibility measured by FOT was compared with a previously published method, which involves measuring anatomic

8 136 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL dead space by SBNW at different lung volumes (1). The slope of anatomic dead space/ lung volume correlated with the index of airway distensibility (slope of Grs/ volume) above 75% TLC. Encouragingly, it has been shown, in a group of subjects with mild asthma, that anatomic dead space/ lung volume is negatively correlated with the thickness of the reticular basement membrane (5). The FOT index of airway distensibility will require its own validation against a well-recognized measure of airway remodeling, either from bronchial biopsies or high-resolution computed tomography. The functional consequences of the wide range of structural changes that constitute airway remodeling are poorly understood. It appears that thickening of the reticular basement membrane stiffens the airways, resulting in both reduced distensibility and a lower maximal airway caliber at TLC (5). Remodeling may also decrease airway collapsibility. Brackel and coworkers measured airway compliance ( airway cross-sectional area/ transpulmonary pressure) with a Pitot static probe and bronchoscope and observed that the central airways of subjects with stable asthma were less compressible (appeared stiffer) during forced expirations compared with healthy control subjects (6). They concluded that, during bronchoconstriction, increased airway stiffness may confer a protective effect by increasing the load on airway smooth muscle (6). So in relating structure to function it would appear that increased airway stiffness due to remodeling may result in a beneficial effect during bronchoconstriction but possibly a detrimental effect during lung inflation. In conclusion, we have shown that the index of airway distensibility measured by the forced oscillation technique is reduced in subjects with asthma compared with healthy subjects. The measurement is repeatable and correlates with distensibility measured by SBNW. We have also shown that the index of airway distensibility does not correlate with pressure volume characteristics of the lung and does not change after bronchodilator administration and suggest, as have other investigators (1, 5, 6), that reduced airway distensibility in subjects with asthma most likely represents the effects of airway structural changes or remodeling. The clinical importance of remodeling may be considerable particularly if, as Elias (40) suggested, remodeling is responsible for the well-recognized, rapid decline in FEV 1 seen in a significant proportion of subjects with asthma (41, 42). If it can be shown, in longitudinal studies, that inhaled corticosteroids increase airway distensibility over time, then the index of airway distensibility could play an essential role in improving current therapies and developing new treatments for asthma that specifically target airway remodeling. Conflict of Interest Statement : N.J.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.M.S. has received research grants up to a total of AUS $120,000 per annum from GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. The Woolcock Institute of Medical Research has received unrestricted grants from AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim/Pfizer, and maintains consultancy agreements with AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim/Pfizer on behalf of its employees. N.B. serves on advisory boards for GlaxoSmithKline, AstraZeneca, Pfizer, and Boehringer Ingelheim, is a coinvestigator on a grant of $50,000 from Boehringer Ingelheim, and has been sponsored to attend a number of meetings by GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim. C.W.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.G.K. has received travel sponsorship from GlaxoSmithKline to attend the ATS annual scientific meeting in 2003 (approximately AUS $9,000) and a GlaxoSmithKline meeting in 2003 (approximately AUS $10,000), travel sponsorship from AstraZeneca to attend the ATS annual scientific meeting in 2004 (approximately AUS $10,000) and two AstraZeneca scientific meetings (approximate combined value AUS $20,000), an honorarium paid to his research institute from GlaxoSmithKline to speak at a sponsored conference in Southeast Asia (AUS $3,000) in 2005, a travel grant from AstraZeneca to attend the ATS annual scientific meeting in 2005 (AUS $6,000), and a travel grant from GlaxoSmithKline to attend the ATS annual scientific meeting in 2006 (AUS $5,000). A proportion of the research work performed by G.G.K. is conducted at the Woolcock Institute of Medical Research, which receives unrestricted grants from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, and Vita Medical for such work. The Woolcock Institute of Medical Research also has a consultancy agreement with Pfizer, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline for which G.G.K. provides consultancy services related to asthma and COPD. His research group receives a proportion of the grants and monies that arise from those companies, as part of specific and general allocations of those funds for research purposes across all research groups of the Woolcock Institute of Medical Research. References 1. Wilson JW, Li X, Pain MC. The lack of distensibility of asthmatic airways. Am Rev Respir Dis 1993;148: Colebatch HJ, Finucane KE, Smith MM. Pulmonary conductance and elastic recoil relationships in asthma and emphysema. J Appl Physiol 1973;34: Colebatch HJH, Greaves IA, Ng CKY. Exponential analysis of elastic recoil and aging in healthy males and females. J Appl Physiol 1979;47: Johns DP, Wilson J, Harding R, Walters EH. Airway distensibility in healthy and asthmatic subjects: effect of lung volume history. 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Reduced airway distensibility in asthmatics measured by forced oscillatory conductance and lung elastic recoil [abstract]. Proc Am Thorac Soc 2005;2:A National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute. Expert panel report 2: guidelines for the diagnosis and management of asthma National Institutes of Health Publication No Available from: nih.gov/guidelines/asthma/asthgdln.htm (accessed May 2007). 18. National Asthma Education and Prevention Program, National Heart, Lung, and Blood Institute. Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics National Institutes of Health Publication No Available from: (accessed May 2007). 19. Quanjer PH, Tammeling GJ, Cotes JE, Pederson OF, Peslin R, Yernault J-C; European Coal and Steel Community. Lung volumes and forced ventilatory flows: report of the Working Party on Standardization of Lung Function Tests. 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