J Appl Physiol 97: 2083-2089, 2004.
First published August 6, 2004; doi:10.1152/japplphysiol.00588.2004
8750-7587/04 $5.00
Effect of small flow reversals on aerosol mixing in the alveolar region of the human lung
Chantal Darquenne and
G. Kim Prisk
Department of Medicine, University of California at San Diego, La Jolla, California 92093-0931
Submitted 9 June 2004
; accepted in final form 3 August 2004
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ABSTRACT
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It has been suggested that irreversibility of alveolar flow combined with a stretched and folded pattern of streamlines can lead to a sudden increase in mixing in the lung. To determine whether this phenomenon is operative in the human lung in vivo, we performed a series of bolus studies with a protocol designed to induce complex folding patterns. Boli of 0.5- and 1-µm-diameter particles were inhaled at penetration volumes (Vp) of 300 and 1,200 ml in eight subjects during short periods of microgravity aboard the National Aeronautics and Space Administration Microgravity Research Aircraft. Inspiration was from residual volume to 1 liter above 1 G functional residual capacity. This was followed by a 10-s breathhold, during which up to seven 100-ml flow reversals (FR) were imposed at Vp = 300 ml and up to four 500-ml FR at Vp = 1,200 ml, and by an expiration to residual volume. Bolus dispersion and deposition were calculated from aerosol concentration and flow rate continuously monitored at the mouth. There was no significant increase in dispersion and deposition with increasing FR except for dispersion between 0 and 7 FR at Vp = 300 ml with 0.5-µm-diameter particles, and this increase was small. This suggested that either the phenomenon of stretch and fold did not occur within the number of FR we performed or that it had already occurred during the one breathing cycle included in the basic maneuver. We speculate that the phenomenon occurred during the basic maneuver, which is consistent with the high degree of dispersion and deposition observed previously in microgravity.
stretch and fold; acinar mixing; aerosol bolus; microgravity
IN A PREVIOUS STUDY (5), our laboratory measured total deposition of 0.5- to 3-µm-diameter particles in normal gravity and also in microgravity and hypergravity utilizing the National Aeronautics and Space Administration (NASA) Microgravity Research Aircraft. Particle deposition is mainly attributed to three mechanisms: inertial impaction, gravitational sedimentation, and Brownian diffusion. Because sedimentation, a gravitationally dependent process, is the dominant deposition mechanism for this particle size range deep in the lung, deposition was expected to be increased in the hypergravity environment and decreased in the microgravity environment compared with deposition occurring in normal gravity. Those expectations were confirmed, but comparison of experimental data with numerical predictions showed significant and potentially important discrepancies. Specifically, in the microgravity environment, when deposition due to sedimentation was necessarily zero, total deposition of the smallest particles (0.5, 1, and 2 µm) was significantly greater than that predicted by a numerical model (3, 5). Measured deposition was found to be 50–100% higher than predicted values. Because impaction is negligible for these particles sizes, we concluded that the additional deposition must have occurred through some enhanced diffusion process.
Because gas flow in the acinar region of the lung occurs at a very low Reynolds number, it has long been assumed that acinar flow was kinetically reversible and that gas mixing by convective processes was minimal in this region. This understanding has been challenged by the work of Heyder et al. (10), who looked at the dispersion of aerosol boli inhaled at various lung depths. They showed that there was substantial aerosol mixing occurring at the alveolar level. This mixing could not be explained by the effect of particle intrinsic motions and, therefore, had to be explained by some mechanisms occurring deep in the lung. Later studies in which bolus inhalations were performed in microgravity also showed appreciable aerosol mixing in the alveolar region of the lung even in the absence of gravitational sedimentation (7, 8), reinforcing the concept of other means by which particles transfer from the inspired to the resident air.
Butler and Tsuda (2) and Tsuda et al. (13) suggested that the mixing of convective streamlines in the airways was much more complex than previously thought. Using flow visualization techniques, they showed that the reciprocal motion of the air in the airways wraps the streamlines around each other during tidal breathing. This new mixing mechanism was dubbed convective stretching and folding. The effect is not unlike that of the stretching and folding of pastry, with the effect being both to cause initially close streamlines to diverge from one another and to bring previously widely separated streamlines into close apposition with each other. As such, geometrically long diffusion distances are greatly reduced, and the effect is that of an increase in the apparent diffusion coefficient. The prediction that would be made from these theoretical arguments is that, in the presence of stretch and fold, deposition of aerosol by diffusion would be much greater than that predicted by current deposition models. These predictions of enhanced deposition correlate closely with our observations of higher than expected deposition of the smaller particle sizes in the microgravity environment (5).
To determine whether the phenomenon of stretch and fold is an operative mechanism in aerosol mixing in the human lung in vivo and whether this might be a factor to explain our laboratory's previous experimental results (5), we performed a series of bolus studies with a protocol designed in collaboration with Butler and Tsuda to induce a complex folding pattern within the confines of a controlled, invariant overall respiratory maneuver. Enhanced diffusion resulting from stretching and folding, if it occurs, is a mechanism that would be expected to take place mainly in the peripheral region of the lung where sedimentation is a dominant mechanism of transport. Thus, to avoid the confounding effect of gravitational sedimentation in the measurements, the experiments were performed in microgravity aboard the NASA Microgravity Research Aircraft.
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METHODS
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Equipment.
Aerosol bolus data were collected with the equipment shown in Fig. 1. Briefly, the system allowed the injection of an aerosol bolus with a half-width of 
70 ml at a given point in the inhalation by switching computer-controlled pneumatic valves. After the initial bolus inhalation maneuver (Fig. 2), a piston assembly connected to the sliding valve SV2 could be used to produce flow reversal (FR) maneuvers as described in Subjects and protocol below. Measurements of the aerosol concentration and the flow rate were provided by a photometer (model 993000, PARI) (16) and a pneumotachograph (Fleisch no. 1, OEM Medical), respectively. The photometer, pneumotachograph, and valves were heated to body temperature to prevent water condensation. A diffusion dryer was located between the photometer and the mouthpiece. It removed the water vapor from the exhaled air to avoid condensation on the lenses of the photometer. This equipment is the same as that used in previous studies (4, 7, 8), with the addition of the piston assembly.
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Fig. 1. Schematic representation of experimental system. One configuration of sliding valves (SV) SV1 and SV2 allowed the subject to breathe air from the room through a 2-way nonrebreathing valve (NRV) equipped with filters. In the other configuration of the valve (SV1), subject inspired aerosol bolus located between SV1 and SV3. A syringe assembly to produce the flow-reversal maneuvers was connected to one port of SV2. The breath hold in the absence of flow reversals was accomplished by maintaining the piston in a constant position. Measurement of aerosol concentration and flow rate was provided by a photometer and a pneumotachograph (Fleisch no. 1), respectively.
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Fig. 2. Lung volume history during the test. After some normal breaths, the subject exhaled to residual volume (RV) before inhaling to a volume of 1 liter above functional residual capacity (FRC) at 1 G (FRC1G) at a flow rate of 0.45 l/s. An aerosol bolus was introduced in the inhaled air at a volume of either 300 or 1,200 ml before the end of inspiration. The subject held his/her breath for 10 s while a number of small flow reversals was imposed using a piston assembly. The subject then exhaled to RV at a flow rate of 0.45 l/s. BH, breath hold; Vp, penetration volume.
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Aerosol generation.
The bolus tube was filled with aerosol containing monodisperse polystyrene latex particles (Duke Scientific). The particles were supplied in suspension (water), and the concentrate was diluted and dispensed via two Acorn II nebulizers (Marquest Medical Products). Before entering the bolus tube, the aerosol flowed through a heated hose and a diffusion dryer to remove water droplets so that the resulting aerosol was made of dry latex particles of uniform size. Precautions were taken during this process to ensure cleanliness of the aerosol being generated.
Two particle sizes, as provided by the manufacturer, were used in the study: 0.505 ± 0.010 and 1.03 ± 0.022 (SD) µm. For convenience, these are referred to as 0.5- and 1-µm-diameter particles, respectively. For both particle sizes, aerosol concentration was 104 particles/ml of gas. Previous size analyses (8) have shown that the number of doublets in the aerosol was <3% for 1-µm-diameter particles and <4.5% for 0.5-µm-diameter particles.
Data recording.
A laptop computer equipped with a 12-bit multifunction I/O card (National Instrument, DAQPad 6020E) was used for data acquisition. Signals from the photometer, a G sensor, and the pneumotachograph were sampled at 100 Hz. Custom software was developed for data acquisition by using National Instruments Lab Windows software.
Data were collected aboard the NASA Microgravity Research Aircraft. A typical flight consisted of a climb to an altitude of 10,000 m with the cabin pressurized to 600 Torr. A "roller coaster" flight profile was then performed. The aircraft was pitched up at 1.6 vertical acceleration (Gz) to a 45° nose-high attitude. Then the nose was lowered to abolish wing lift, and thrust was reduced to balance drag. A ballistic microgravity flight profile resulted and was maintained until the aircraft nose was 45° below the horizon. In this manner, microgravity (0 ± 0.003 Gz) was maintained for 27 s. A pullout averaging 1.6 Gz was maintained for 40 s, causing the nose to pitch up to a 45° nose-high attitude and allowing the cycle to be repeated.
Subjects and protocol.
Eight healthy subjects participated in the study. Four subjects also participated in previous studies aboard the NASA Microgravity Research Aircraft (4, 5, 7, 8), and we retained their subject numbers for comparison purposes. The relevant anthropometric data of the subjects are listed in Table 1.
After a few normal breaths, the subject exhaled to residual volume to ensure a known lung volume starting point (Fig. 2). The test breath consisted of an inspiration from residual volume to 1 liter above functional residual capacity measured previously in normal gravity at a flow rate of 0.45 l/s, a 10-s breath hold, and an expiration to residual volume, also at a flow rate of 0.45 l/s. A flowmeter provided visual feedback to the subject, who was well trained in the maneuver. During inspiration, an aerosol bolus of 70 ml was introduced at two different penetration volumes (Vp; 300 and 1,200 ml). Vp was defined as the volume of air inhaled from the mode of the aerosol bolus to the end of the inhalation.
During breath hold, a variable number of small, identical FRs was imposed on the subject using the piston assembly. Each FR consisted of a small inspiratory maneuver immediately followed by an expiratory maneuver, resulting in no overall change in lung volume. The FRs were performed using a crank system so that volume changes were approximately sinusoidal in nature. For a Vp of 300 ml, the piston produced a 100-ml inspiratory maneuver followed by a 100-ml expiratory maneuver in 1 s, providing a flow of 200 ml/s in each direction. For a Vp of 1,200 ml, the piston produced a 500-ml inspiratory maneuver followed by a 500-ml expiratory maneuver in 2 s, providing a flow of 500 ml/s in each direction. These flows were chosen to be compatible with the time constraints of the experiment in the aircraft and to maintain a low Reynolds number in the lung region reached by the bolus. Zero, one, four, and seven FRs were imposed for a Vp of 300 ml and zero, one, three, and four FRs for a Vp of 1,200 ml.
All tests were performed during the microgravity phase of the flights. The protocol was repeated three times for each Vp and each number of FRs. Data were obtained in eight subjects with 0.5-µm-diameter particles and in six subjects with 1-µm-diameter particles. The reduced number of subjects in the tests with 1-µm-diameter particles was due to subject unavailability and technical problems with the aircraft, which caused the cancellation of one flight. The protocol was approved both by the Human Research Protection Program at the University of California, San Diego, and by the Committee for the Protection of Human Subjects at the NASA Johnson Space Center, Houston, TX. Subjects signed a statement of informed consent.
Data analysis.
For each bolus test, we calculated the aerosol deposition (DE) and the aerosol bolus dispersion (H). Calculations were performed in a similar manner as in our laboratory's previous studies (4, 7, 8). Briefly, DE was calculated using the following equation
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where Nin and Nex are the number of particles in the inspired and expired bolus, respectively. Nin and Nex were calculated from the integration of the aerosol concentration as multiplied by the instantaneous flow rate. The integration was only done when the concentration exceeded 5% of the maximal expired concentration to reduce error due to the noise of the signal (7).
On a graph of aerosol concentration as a function of the respired volume, we computed the bolus half-width, which was defined as the difference in volume (in ml) between the two points of one-half the maximum concentration of the bolus. The change in half-width reflects H and was obtained by the following equation
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where Hin and Hex are the half-width of the inspired and expired boluses, respectively.
Statistical analysis.
For each experimental condition (particle size, Vp, and number of FRs) and for each subject, one single value for DE and H was determined and used in the statistical analysis. For each target Vp, there was some variability. Therefore, except for the few cases in which only one valid test was obtained per experimental condition, DE and H were determined at each target Vp by linear regression of the repeated measurements as a function of measured Vp. Linear regressions were performed separately for each subject and each experimental condition. By doing so, we eliminated the confounding effect of variation in Vp on DE and H. As an example, Fig. 3 shows the regression lines between repeated measurements (open circles) for each subject for tests performed at a Vp of 300 ml with 0.5-µm-diameter particles and one FR. Values of DE and H were then calculated from the regression lines for a Vp of 300 ml (closed triangles). Note that for subject 8 (S8; Fig. 3), only one valid test was performed for this experimental condition.
For each Vp and particle size, a one-way ANOVA for correlated samples was then performed to test for differences in deposition and dispersion between FRs. Post-ANOVA pairwise comparisons using Tukey's honestly significant difference test was performed for tests showing significant F ratios. Values are given as means ± SD, unless otherwise stated. Significant differences were accepted at the P < 0.05 level.
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RESULTS
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We collected data on eight subjects with 0.5-µm-diameter particles and on six subjects with 1-µm-diameter particles. Averaged over all the tests performed with 0.5-µm-diameter particles, measured Vp were 301 ± 102 and 1,146 ± 127 ml for Vp of 300 and 1,200 ml, respectively. For 1-µm-diameter particles, measured Vp were 301 ± 86 and 1,215 ± 97 ml for Vp of 300 and 1,200 ml, respectively.
Figure 4 shows H and DE of 0.5-µm-diameter particles as a function of the number of FR performed during the 10-s breath hold at Vp of 300 (closed symbols) and 1,200 ml (open symbols). Dispersion varied between 359 ml for FR = 0 and 448 ml for FR = 7 at a Vp of 300 ml and between 611 and 667 ml at a Vp of 1,200 ml. No significant differences in dispersion were found with FR at either Vp, except between FR = 0 and FR = 7 at a Vp of 300 ml (P < 0.05). Deposition varied between 29% for FR = 0 and 33% for FR = 7 at a Vp of 300 ml and between 51 and 56% at a Vp of 1,200 ml. No significant differences in deposition were found as a function of FR at either Vp.
Data obtained with 1-µm-diameter particles are shown in Fig. 5 in the same format as in Fig. 4. Dispersion varied between 325 ml for FR = 0 and 445 ml for FR = 7 at a Vp of 300 ml and between 578 and 680 ml at a Vp of 1,200 ml. Deposition varied between 33% for FR = 0 and 38% for FR = 7 at a Vp of 300 ml and between 56 and 57% at a Vp of 1,200 ml. No significant differences were found in dispersion or deposition as a function of FR at each Vp.
A strong correlation was found between deposition and dispersion irrespective of particle size and number of FRs. Figure 6 shows dispersion plotted as a function of deposition for both Vp, both particle sizes, and all FR conditions. The data showed that there is a strong linear relationship (r2 = 0.98) between deposition and dispersion.
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Fig. 6. Correlation between H and DE of aerosol bolus for 0.5 (circles)- and 1-µm-diameter particles (squares) at Vp = 300 (closed symbols) and 1,200 ml (open symbols). All data from the study are included and are the same as in Figs. 3 and 4. Linear regression line is also shown (solid line).
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DISCUSSION
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This study reports the effect of small FRs on aerosol mixing in the acinar region of the lung. These experiments were designed to further investigate the concept of stretch and fold introduced by Butler and Tsuda (2) and Tsuda et al. (13). Because the interpretation of the data relies greatly on this concept, it is described in detail below.
Mechanism of stretch and fold.
Stretch and fold addresses the mechanism of complex mixing that is thought to occur in the acinus as a result of the rhythmic expansion and contraction of complex alveolar structures. Because of the reciprocal motion of the air in the airways, the streamlines fold back on each other as tidal breathing continues. As such, previously long geometrical distances that would not be diffusively achievable are greatly reduced, and the effect is that of an increase in the apparent diffusion coefficient. Butler and Tsuda (2) and Tsuda et al. (13) first reported the existence of such complex stretch-and-fold mixing patterns in a rat lung filled with white silicone oil and ventilated with blue silicone oil for several tidal breaths. The experiment was performed at a very low Reynolds number to ensure that there were no inertial effects affecting the mixing pattern. After being ventilated, the silicone oil was allowed to polymerize and the lungs were sliced for examination. Lung sections clearly showed complex mixing patterns of white and blue silicone compounds.
The major finding of those studies was that the presence of even modest alveolar flow irreversibility led to a sudden increase in mixing that results from the coupling of diffusion with the mechanism of stretch and fold (2). Butler and Tsuda characterized stretch and fold by a convective length that decreases exponentially over time. Diffusion can be characterized by a diffusive length that is proportional to Dt, where D is the diffusion coefficient and t is time. For aerosols with low D, the t increase in mixing resulting from diffusion alone is too slow to effect significant mixing. Indeed, a unit density of a 0.5-µm-diameter particle will only move 20 µm, and a 1-µm-diameter particle 13 µm, in 1 s as a result of diffusion (1). Butler and Tsuda (2) demonstrated that a sudden increase in mixing occurred when the slowly increasing diffusive length scale approximately matched the rapidly decreasing convective length scale associated with the kinetics of folding. Using excised rat lungs, they showed that complete mixing was achieved within as few as three to five mechanical oscillations.
Recently, using the same visualization technique, Tsuda et al. (13) provided a more detailed description of the time evolution of the mixing patterns after one, two, three, and four tidal breaths in excised rat lungs. Interestingly, in the context of this study, they showed that a highly complex mixing pattern was already present after one tidal breath. During inspiration, because the interface between inhaled and resident air remained in contact at the tracheal walls (so-called no-slip condition), the front between tidal and resident air was stretched into the complex geometry of the lung. During expiration, because of the irreversibilities in the alveolar flow profile, the stretched front did not follow the same path as during inspiration, and each fluid element ended up at a location that differed from its initial position. As a result, the front between tidal and resident air consisted of a multitude of folds primarily in the axial direction (13).
Expectations and results.
Because Tsuda et al.'s experiment (13) strongly suggested that the kinematic irreversibilities that lead to the formation of complex convective mixing patterns originated from the acinus, our experiment was designed to study the mechanism of stretch and fold both at a shallow (Vp = 300 ml) and deep (Vp = 1,200 ml) acinar depth. Based on the Weibel symmetric model of the lung (15), in which the alveolar region spans generations 16–23, a Vp of 300 and 1,200 ml probes generations 18 and 21, respectively. At both Vp, the volume fluctuations generated by the FRs were such that the aerosol bolus was forced to traverse at least one generation of alveolated ducts, an important point since nonreversibility of flows at bifurcations is believed to contribute greatly to the mechanism of stretch and fold (12). Similar to Tsuda et al.'s experiment, the tests were performed at very low Reynolds numbers (0.11 and 0.03 at a Vp of 300 and 1,200 ml, respectively) to avoid any inertial effects on the mixing patterns. The low Reynolds numbers also ensured that there was little effect of changes in flow rates during the FR maneuvers, as the velocity profiles are kinematically determined by Stokes flow. Therefore, the precise waveform of flow rate during the FRs was a minor effect. Finally, by performing the tests in microgravity, we avoided the masking effect of sedimentation on the mechanism of stretch and fold. Our laboratory has shown previously that the sedimentation of particles is an important factor in the H measured in normal gravity (8).
We designed an experiment based on a single maneuver into which we induced small FRs to test the concept of stretch and fold in the human lung. Based on previous experimental studies performed in excised rat lungs, we hypothesized that, with every additional FR, aerosol mixing in the lung would slowly but steadily increase until a sharp transition in the extent of mixing occurred, reaching an almost complete state of mixing after which any additional FRs would have only minimal impact on the level of mixing. Such a sharp transition would be characterized by a sudden increase in H. We hypothesized that, because 0.5-µm-diameter particles diffuse more readily than 1-µm-diameter particles, the sharp transition would occur after a smaller number of FRs for 0.5- than for 1-µm-diameter particles. Finally, we hypothesized that such a sharp transition would also be accompanied by a significant increase in DE. Up to seven FRs were induced during the breath hold at a Vp of 300 ml and up to four at a Vp of 1,200 ml. We were precluded from performing more FRs by the limited time of microgravity available to us in the aircraft.
Our data showed that increasing the number of FRs had little effect on dispersion at either Vp and for both particle sizes (Figs. 4A and 5A). As expected, there was a slow increase in dispersion with increasing number of FRs. The only significant increase in H was found between zero and seven FRs at a Vp of 300 ml with 0.5-µm-diameter particles. However, no abrupt increases in dispersion were observed.
It should be noted that dispersion as measured in the aerosol bolus technique is mainly an indicator of axial mixing. Indeed, aerosol concentrations were measured at the mouth with light scattering photometry, a technique that uses a laser beam covering >70% of the cross section of the aerosol channel (16). Although this technique allows for recording of sharp concentration profiles, it does not allow us to distinguish between aerosol concentrations at different radial positions. Therefore, any radial mixing induced by the FRs will not be reflected in the measured dispersion. Radial mixing would, however, cause particles to migrate closer to airway and/or alveolar walls. In this situation, radial mixing would be expected to lead to an increase in DE even in the absence of a strong increase in axial dispersion. No such increase was observed in our data, which showed no significant differences in deposition with an increasing number of FRs at either Vp and for both particles sizes (Figs. 4B and 5B). The absence of an effect of radial mixing on deposition is also illustrated by the linear relationship between axial dispersion and deposition for all FRs. Such a linear relationship can also be observed in aerosol bolus tests performed without the inclusion of breath holds and FRs (4). A strong increase in deposition due to radial mixing would be characterized by a clear dissociation from the linear relationship shown in Fig. 6 toward higher levels of deposition.
Interpretation.
Our data showed a slow increase in dispersion as the number of FRs increased. These results suggest several potential interpretations. First, it may be that the phenomenon of stretch and fold did not occur within the number of FRs performed in this experiment. Second, it may be that the phenomenon had already occurred during the one breathing cycle that is included in the basic maneuver, without any subsequent additional FRs. In this case, the measured dispersion would reflect a high degree of mixing of the aerosol in the air spaces.
Third, it may be that the phenomenon of stretch and fold occurred during the FRs but that the methods we used were not able to detect such a mechanism. One basis for this interpretation may be that the measurements of dispersion and deposition were too noisy to detect the true signal. This is, however, unlikely because the data analysis was designed to minimize the error due to the noise of the signal (7, 14). Furthermore, our anticipation was that, if the phenomenon of stretch and fold did occur, the increase in dispersion at the mouth would be large and readily detectable.
Fourth, it may also be possible that the phenomenon of stretch and fold occurred on a small scale but was obscured by large-scale topographic differences in the lungs. If the dispersion of particles occurs because of changes in topographic differences in the lung, the exhaled concentration of particles would be expected to show a change in dispersion measured at the mouth. However, if the particles at a given point in the exhaled volume always come from the same lung region and complex mixing occurs within this lung region, then one might hypothesize that local mixing on a small scale will have little impact on the overall dispersion at the mouth. Nothing in Tsuda's et al. (13) experiments suggests that the phenomenon of stretch and fold is confined to a small region of the lung. Indeed, they showed complex mixing patterns at various locations in the rat lung. Therefore, we consider this an unlikely interpretation of our observations.
Fifth, cardiogenic mixing may also be a factor. The effect of cardiogenic mixing has been addressed in a previous study looking at the effect of breath holding on H and DE (4). In that study, our laboratory showed that the effect of cardiogenic mixing on aerosol mixing was limited. The data suggested that the effect was located mainly in the central airways and not in the periphery of the lung. We therefore think that a significant effect of cardiogenic mixing in our experiment is unlikely. Furthermore, because the overall breathing maneuver was invariant, except for changing the number of FRs, any effect of cardiogenic mixing is likely similar between experimental conditions.
In several aerosol bolus studies (7, 8, 10), it has been shown that there is substantial aerosol mixing occurring at the alveolar level. This mixing cannot be accounted for solely by the effect of particle intrinsic motions (inertia, gravitational sedimentation, and diffusion) assuming a reversible acinar flow, and H has been mainly attributed to convective mixing (10). In this context, convective mixing refers to the irreversible transfer of particles between inhaled and resident air. Such transfer results from dispersion processes induced by factors such as velocity patterns, airway and alveolar geometries, asymmetries between inspiratory and expiratory flow, nonhomogeneous ventilation of the lungs, and cardiogenic mixing.
Using a two-dimensional model of a six-generation structure of alveolated ducts, Darquenne and Prisk (6) studied the dispersion undergone by an aerosol bolus during its transport in the alveolar region of the lung and compared their predictions to experimental data (8). They showed that, for 0.5- and 1-µm-diameter particles, gravitational sedimentation accounted for 20 and 45% of overall measured dispersion. However, the total dispersion seen was much less than that observed in experimental data. Their model did not include the expansion and contraction of the air spaces during breathing and, therefore, could not simulate any potential geometric hysteresis that could lead to the phenomenon of stretch and fold. However, the mismatch between their predictions and experimental data (8) is another demonstration that mixing mechanisms other than those resulting from the particle intrinsic motion affect H deep in the lung. The difference between simulated and experimental data also suggests that a high degree of mixing occurs in the lung even in only one breath.
Our data strongly suggest that mixing resulting from kinematic interactions between inspired air and residual alveolar gas deep in the lung is already significant after one breathing cycle. The recent flow visualizations made by Tsuda et al. in the rat lungs (13) showed substantial mixing between inhaled and resident fluid after one breathing cycle and a complete mixing after four breathing cycles. However, the rate at which mixing occurs in the human lung is likely different from that observed in rat lungs filled with silicone oil. Indeed, the degree of both pressure and geometric hysteresis of lung units is closely correlated to the presence of surfactant. Liquid-filled lungs will therefore behave differently than air-filled lungs both in their pressure-volume curve and in their potential flow asynchrony. Geometric hysteresis (looping of surface area-to-volume ratio as a function of volume) has been measured by Miki et al. (11) in air-filled lungs, but to our knowledge nobody has ever measured geometric hysteresis or flow asynchrony in liquid-filled lungs. However, using a computational model, Denny and Schroter (9) showed that an alveolar duct filled with air presented a higher degree of geometric hysteresis than the same model filled with liquid.
Tsuda et al. (12) have demonstrated that the mechanism of stretch and fold can be generated by the geometric hysteresis of wall motions. It is likely that the higher degree of geometric hysteresis in air-filled lungs will induce a more rapid mixing of particles than what was observed in silicone-filled rat lungs. It is therefore reasonable to assume that the sudden burst in mixing generated by the mechanism of stretch and fold could occur during the first breathing cycle in humans, and it may well be that the dispersion we measured in this experiment reflects a close to complete mixing of aerosol in the lung.
In summary, we performed a series of bolus inhalations with a protocol designed to induce complex folding pattern in the human lung in vivo. Our data showed only a small increase in dispersion with increasing number of FRs. This suggests either that the phenomenon of stretch and fold did not occur within the number of FRs we performed or that the phenomenon had already occurred during the one breathing cycle included in the basic maneuver. Neither of these suggestions can be fully supported by previous published data. However, we speculate that the phenomenon of stretch and fold already occurred during the basic maneuver. Such a speculation is consistent with the high degree of dispersion and deposition observed previously in microgravity (4, 5, 7, 8). Our speculation is also consistent with the complex mixing patterns observed by Tsuda et al. in the rat lung after only one breathing cycle (13).
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GRANTS
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This work was supported by National Institute of Environmental Health Sciences Grant 1 RO1 ES-11184.
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ACKNOWLEDGMENTS
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We thank Jim Butler and Akira Tsuda for fruitful discussions that led to the design of this study and for their continuous scientific support. We also acknowledge the collaboration of John Yaniec and Noel Skinner from the KC-135 Reduced Gravity Program at NASA.
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FOOTNOTES
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Address for reprint requests and other correspondence: C. Darquenne, Physiology/NASA Laboratory 0931, Dept. of Medicine, UCSD, 9500 Gilman Dr., La Jolla, CA 92093-0931 (E-mail: cdarquenne{at}ucsd.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.
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REFERENCES
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- Brain JD and Valberg PA. Deposition of aerosol in the respiratory tract. Am Rev Respir Dis 120: 1325–1373, 1979.[Web of Science][Medline]
- Butler JP and Tsuda A. Effect of convective stretching and folding on aerosol mixing deep in the lung, assessed by approximate entropy. J Appl Physiol 83: 800–809, 1998.
- Darquenne C and Paiva M. One-dimensional simulation of aerosol transport and deposition in the human lung. J Appl Physiol 77: 2889–2898, 1994.[Abstract/Free Full Text]
- Darquenne C, Paiva M, and Prisk GK. Effect of gravity on aerosol dispersion and deposition in the human lung after periods of breath-holding. J Appl Physiol 89: 1787–1792, 2000.[Abstract/Free Full Text]
- Darquenne C, Paiva M, West JB, and Prisk GK. Effect of microgravity and hypergravity on deposition of 0.5- to 3-µm-diameter aerosol in the human lung. J Appl Physiol 83: 2029–2036, 1997.[Abstract/Free Full Text]
- Darquenne C and Prisk GK. Effect of gravitational sedimentation on simulated aerosol dispersion in the human acinus. J Aerosol Sci 34: 405–418, 2003.[CrossRef][Web of Science][Medline]
- Darquenne C, West JB, and Prisk GK. Deposition and dispersion of 1 µm aerosol boluses in the human lung: effect of micro- and hypergravity. J Appl Physiol 85: 1252–1259, 1998.[Abstract/Free Full Text]
- Darquenne C, West JB, and Prisk GK. Dispersion of 0.5–2 µm aerosol in micro- and hypergravity as a probe of convective inhomogeneity in the human lung. J Appl Physiol 86: 1402–1409, 1999.[Abstract/Free Full Text]
- Denny E and Schroter RC. Viscoelastic behavior of a lung alveolar duct model. ASME J Biomech Eng 122: 143–151, 2000.[CrossRef][Web of Science][Medline]
- Heyder J, Blanchard JD, Feldman HA, and Brain JD. Convective mixing in human respiratory tract: estimates with aerosol boli. J Appl Physiol 64: 1273–1278, 1988.[Abstract/Free Full Text]
- Miki H, Butler JP, Rogers RA, and Lehr J. Geometric hysteresis in pulmonary surface-to-volume ratio during tidal breathing. J Appl Physiol 75: 1630–1636, 1993.[Abstract/Free Full Text]
- Tsuda A, Otani O, and Butler JP. Acinar flow irreversibility caused by perturbations in reversible alveolar wall motion. J Appl Physiol 86: 977–984, 1999.[Abstract/Free Full Text]
- Tsuda A, Rogers RA, Hydon PE, and Butler JP. Chaotic mixing deep in the lung. Proc Natl Acad Sci USA 99: 10173–10178, 2002.[Abstract/Free Full Text]
- Verbanck S, Darquenne C, Prisk GK, Vincken W, and Paiva M. A source of experimental underestimation of aerosol bolus deposition. J Appl Physiol 86: 1067–1074, 1999.[Abstract/Free Full Text]
- Weibel ER. Morphometry of the Human Lung. New York: Academic, 1963.
- Westenberger S, Gebhart J, Jaser S, Knoch M, and Köstler R. A novel device for the generation and recording of aerosol micro-pulses in lung diagnostic. J Aerosol Sci 23: S449–S452, 1992.[CrossRef]
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ABSTRACT
METHODS
) are shown for each subject as well as the value of H and DE (
) calculated from the regression lines at the targeted Vp. Note that for subject 8 (S8) only one valid measurement was obtained for this experimental condition. See text for details.
, Vp = 300 ml; 
, Vp = 300 ml; 
, Vp = 1,200 ml. A: H. B: DE.