INTRODUCTION

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Data from the last three decades have suggested that the distal lung, which includes the airways < 2 mm and the lung parenchyma, significantly contribute to asthma pathogenesis. This concept was first evaluated in an animal model by Macklem and Mead (1) who showed that peripheral resistance (Rp) was too small to detect above 80% of vital capacity, but that it increased at lower volumes to 15% of the total lung resistance. These data confirmed work by Weibel (2) who demonstrated that the cross-sectional area of the small airways was significantly larger than that of the central airways. Thus, the distal airways were dubbed the "quiet zone" of the lungs by Mead and colleagues in 1970 (3).

Because of the challenges raised in evaluating the small airways of the lung in living humans, this region has not been studied at the same level of detail as the larger airways. However, pathologic data do exist from autopsy specimens (5) and they suggest that significant pathologic alterations occur in the distal lung in asthma. Recently, investigation of patients with chronic, stable asthma is starting to be performed with regard to the small airways and lung parenchyma (9). Nocturnal asthma (NA) is a very common aspect of asthma, affecting from 30 to 75% of asthmatics according to Turner-Warwick (12). The time of greatest lung function in NA has been shown to be 4:00 P.M., whereas the nadir is approximately 4:00 A.M. (13). These changes can have devastating consequences, as it has been documented that 70% of deaths and 80% of respiratory arrests caused by asthma occur during sleep-related hours (14). This circadian change in airway function has been linked to changes in airway inflammation, which have been shown to be increased at night in the airways of patients with NA (15). We have shown that NA is associated with increased influx of inflammatory cells into the distal airway, particularly lymphocytes, macrophages, and eosinophils (10, 11). Therefore, NA is characterized by increased nocturnal inflammation, with the distal lung exhibiting the greatest increase in inflammation from day to night, as compared with large airway inflammation.

However, the functional significance of this inflammation in living patients with asthma is not clear. Wagner and colleagues (16, 17), using an orthograde collateral ventilation technique employing a wedged bronchoscope in humans, showed that Rp was markedly increased in subjects with mild asthma as compared with nonasthma control subjects (16, 17). Moreover, the conductance (1/Rp) inversely correlated with whole-lung hyperresponsiveness (16). These investigators extended these observations by assessing small airway hyperresponsiveness by directly administering histamine and isoproterenol into the small airways using the wedged bronchoscope technique (17). Again, the baseline Rp was greater in asthmatics with normal spirometry as compared with normal control subjects. More histamine was required in normal subjects to cause a 100% increase in Rp (PC100) than in asthmatics. In asthmatics, the PC100 of the segment correlated with whole-lung responsiveness to histamine (r = 0.847, p < 0.05). Isoproterenol completely reversed the increase in Rp in normal control subjects, but not in the asthmatic subjects, possibly secondary to edema and airway closure.

As we have shown that parenchymal inflammation was increased at night in nocturnal asthma, we sought to determine the functional significance of this change. Employing the wedged bronchoscope technique, we investigated whether Rp would be greater at night in subjects with NA than in subjects with non-nocturnal asthma (NNA) and control subjects. Lastly, we also assessed the response of peripheral function to ₂-agonists in these three groups of subjects.

	METHODS

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Subjects

Ten asthmatic subjects with NA, and four with NNA, and four normal control subjects were recruited from the general Denver community. All asthmatic subjects met diagnostic criteria for asthma (18), exhibiting a methacholine PC₂₀ of less than 8 mg/ml, and they were maintained on inhaled ₂-agonists only. The group with nocturnal symptoms demonstrated a fall in peak expiratory flow rate (PEFR) of greater than 15% from bedtime to morning on at least four nights over a 7-d period of testing at home prior to study. The NNA and nonasthma control groups experienced an overnight fall in PEFR of 10% or less over 7 nights of testing. The nonasthma control groups also exhibited a methacholine PC₂₀ > 25 mg/ml. Exclusion criteria included use of leukotriene modifiers, theophylline preparations, cromolyn, nedocromil, inhaled or oral corticosteroids within the previous 6 wk, an upper respiratory tract infection within the previous 6 wk, immunotherapy within the previous 3 mo, cigarette use, and significant nonasthma pulmonary disease or other medical illnesses. Informed consent was obtained from all patients for this institutional review-board-approved protocol.

Protocol

Subjects underwent bronchoscopy with measurement of Rp at 4:00 P.M. and at 4:00 A.M. in a random order separated by approximately 1 wk. We chose these times because prior studies in nocturnal asthmatics have demonstrated that the greatest lung function occurs at approximately 4:00 P.M. and a nadir at 4:00 A.M. (13). In addition, we have shown that inflammation is significantly increased at 4:00 A.M. as compared with that at 4:00 P.M. (10, 15). Subjects presented to our laboratory at 9:00 P.M. prior to the 4:00 A.M. bronchoscopy. They underwent spirometry, and "lights out" occurred at 10:00 P.M.. They were awakened at 3:00 A.M. and spirometry and lung volumes via plethysmography were measured using techniques previously published (19). An esophageal balloon was inserted through one of the nares to measure esophageal pressure and ensure that all peripheral airway pressure measurements made during bronchoscopy were performed at end-exhalation or at functional residual capacity (FRC). The same routine took place prior to the 4:00 P.M. bronchoscopy, when subjects presented to our laboratory at 3:00 P.M. Prior to each bronchoscopy, subjects then received atropine, 0.4 mg intravenously, and anesthesia of the upper airway with 4% lidocaine. Subjects also received midazolam and fentanyl for sedation and cough suppression, respectively. With subjects in the supine position, the bronchoscope was inserted and wedged in the anterior segment of the right lower lobe. After clearing secretions within the instrument channel with a cytologic brush, a size 5 French double-lumen catheter (Baxter Healthcare Corp., Irvine, CA) was placed through the suction port of the bronchoscope. Warm, saturated 5% CO₂ in air at flows ranging from 100 to 1,000 ml/min exited the catheter through one lumen after passing through a mass flow meter (Sierra Instruments, Inc., Monterey, CA) and then through a heated respiratory humidifier (Bird Life Design, Carrollton, TX; Fisher & Paykel, Auckland, New Zealand). Kaminsky and colleagues (19), using a similar technique, confirmed that the gas exiting the catheter was indeed at 37° C. Pressure was measured through the second lumen at the tip of the bronchoscope using a transducer (Validyne Engineering Corp, Northridge CA), and continuous recordings of pressure, flow, time, and esophageal pressure were made using a chart recorder (Gilson Medical Electronics, Middleton, WI) and computer software system (AcqKnowledge; Biopac Systems, Inc., Goleta, CA). Pressure was recorded at each level of flow after the pressure had stabilized, usually within 30 to 60 s. Rp was defined as the pressure/flow averaged over three or more flow levels for each subject measured at FRC (end-exhalation). Because all of the airways leading from the wedged bronchoscope across the collateral airways and back out of the airways of the adjoining segments are exposed to the steady- state airflow, Rp represents the combined resistance of these airways. Flow rates were increased until the highest flow rate (1,000 ml/min) was achieved or an arbitrary pressure of 40 cm H₂O was observed.

At each flow rate, subjects were periodically instructed to stop breathing at FRC approximately three separate time points, which was confirmed by constant esophageal pressure. Flow was then stopped at FRC and the pressure was allowed to decay for approximately 10 s. This maneuver allowed us to analyze the pattern of decay in pressure and thus partition Rp into resistance of the large airways immediately distal to the bronchoscope and the small airways serving as the pathways for collateral flow out of the segment as described by Menkes and Traystman (20). After the initial drop in pressure (felt to be reflective of large airway resistance) was observed (if it was present), the final pressure achieved after the decay was termed the plateau pressure (Figure 1). A ~ 0.2 s time point was chosen as the beginning of the line fit because any initial pressure drop should have been completed by this time, as described by Smith and colleagues (21). We then fit a line to the logarithm of pressure between ~ 0.2 s and the time point at which the logarithm of pressure began to visually deviate from a straight line (usually 0.4 to 1 s), thereby restricting the analysis to the initial monoexponential decay of pressure. The early part of the curve after the initial pressure drop was analyzed, as the entire decay curve was not monoexponential, possibly because of a progressive increase in proximal airway as lung volume decreased (22, 23). We reasoned that the early part of the curve would reflect Rp, determined as the segment emptied passively through the collateral pathways. The pressure was determined to be at the plateau after it reached the lowest pressure during the decay for at least 5 s, but ideally 10 s. The time required for pressure to decay by 63% (1 to 1/e) after the initial drop was excluded and defined as the time constant (). The peripheral compliance of the segment (Cp) was calculated as /Rp as described by Woolcock and Macklem (24).

View larger version (18K): [in this window] [in a new window]   Figure 1.   Representative tracings from a subject with nocturnal asthma (NA) at 4:00 P.M. (top panel ) and at 4 A.M. (bottom panel ). The pressure tracing (Pb) is measured via a pressure transducer just outside the end of the bronchoscope and flow of warm, humidified air (flow at 300 ml/min at 4:00 P.M. and 250 ml/min at 4:00 A.M.) while the flow is continuous and during flow interruption at functional residual capacity, as illustrated by the esophageal tracing (Pes). The initial fall in pressure is appreciated at 4:00 A.M., followed a by decay in pressure until a plateau is reached.

Once the initial measurements were made, subjects received terbutaline, 0.3 mg subcutaneously, and measurements of Rp, plateau pressure, and time constant were made after a 5- to 10-min period similar to that described above. Subcutaneous terbutaline was chosen as Tashkin and colleagues (25) have shown that subcutaneous terbutaline improved radioxenon washout more significantly than did aerosolized terbutaline, consistent with bronchodilation of the large and small airways.

Statistical Analysis

The pressure-flow relationship was modeled using a mixed-effects model that accounted for correlation between repeated measurements made on the same subject (26, 27). If the interaction was significant, pairwise comparisons of least squares means were made within groups and times (28). This model allowed comparisons between subjects and groups and comparisons in response between A.M. and P.M. measurements. A mixed-effects model was also used to estimate differences in resistance, compliance, plateau pressure, and time constant, respectively, which included fixed effects for time and group and a random subject effect. Correlations between physiologic variables were performed using Pearson's correlation test. All tests were two-sided and conducted at the 5% significance level.

	RESULTS

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Subjects

Subject characteristics are shown in Table 1, and lung volume and specific conductance measurements are shown in Table 2. Note the significant overnight fall in FEV₁, measured from 10:00 P.M. to 4:00 A.M., in the NA group (Table 1). Regarding lung volume measurements, the percentage predicted thoracic gas volume (Vtg), TLC, and residual volume were all greater in the NA group as compared to the other groups at 4:00 P.M. and at 4:00 A.M., with the exception of Vtg, where it tended toward significance at 4:00 A.M. (Table 2). The specific conductance was lower in the NA group than in the other two groups at 4:00 A.M. (Table 2).

Peripheral Resistance and Plateau Pressure Measurements

The Rp values at 4:00 P.M. and at 4:00 A.M. in each of the three groups are shown in Figure 2. The subjects with NA exhibited an initial pressure drop at many (< 50%) flow rates during many (< 50%) of stop-flows, with a mean value of 27.6 ± 3.1 cm H₂O at 4:00 P.M. and 25.9 ± 4.0 cm H₂O at 4:00 A.M. (p = 0.88). This drop was also appreciated in one patient in the NNA group at 4:00 A.M. only (18.6 ± 1.5 cm H₂O averaged over four flow rates) but in none of the nonasthma control subjects. The Rp in the NNA and control groups appeared to be flow-dependent, whereas it was not flow-dependent in the NA group. In the NA group, lower flows (100 to 500 ml/min) were used to calculate Rp and Cp to avoid exceeding 40 cm H₂O for patient safety. The NA group exhibited the highest Rp values at 4:00 P.M. and at 4:00 A.M. as compared with the NNA and control groups, but all groups were significantly different from each other. At 4:00 P.M.: NA, 0.113 ± 0.02 cm H₂O/ml/ min; NNA:, 0.033 ± 0.005 cm H₂O/ml/min; Control subjects, 0.010 ± 0.001 cm H₂O/ml/min, p = 0.0001. At 4:00 A.M.: NA, 0.129 ± 0.023 cm H₂O/ml/min; NNA, 0.035 ± 0.007 cm H₂O/ ml/min; Control subjects, 0.009 ± 0.002 cm H₂O/ml/min; p = 0.0003 (Figure 2). None of the groups exhibited statistically significant differences in Rp between 4:00 P.M. and 4:00 A.M..

View larger version (24K): [in this window] [in a new window]   Figure 2.   The peripheral resistance (Rp) in control subjects, subjects with non-nocturnal asthma, and subjects with nocturnal asthma are shown at 4:00 P.M. (hatched bars) and 4:00 A.M. (closed bars). *p < 0.05 between the groups at 4:00 P.M. (nocturnal asthma > non-nocturnal asthma and control subjects); p < 0.05 between the groups at 4:00 A.M. (nocturnal asthma > non-nocturnal asthma and control subjects).

The plateau pressure measurements from 4:00 P.M. and 4:00 A.M. in each of the groups are shown in Figure 3. Subjects with NA demonstrated an initial fall in Rp at each flow rate during many (< 50%) of stop-flows, followed by a slower decay (Figure 1). This initial fall, felt to be reflective of increased Rp of the larger airways, was appreciated only in one of NNA subjects at 4:00 A.M. only, and in none of the control subjects. The plateau pressure increased significantly from 4:00 P.M. to 4:00 A.M., but only in the NA group (7.7 ± 0.9 cm H₂O at 4:00 P.M. versus 16.9 ± 4.6 cm H₂O at 4:00 A.M.; p = 0.0004). The plateau pressure was not flow-dependent in any of the groups.

View larger version (21K): [in this window] [in a new window]   Figure 3.   The plateau pressure in control subjects, subjects with non-nocturnal asthma, and subjects with nocturnal asthma is shown at 4:00 P.M. (hatched bars) and at 4:00 A.M. (closed bars). *p < 0.05 within the nocturnal asthma group.

Cp was decreased in the NA group as compared with that in the NNA and control groups at both 4:00 P.M. and 4:00 A.M. (4:00 P.M.: NA, 0.23 ± 0.08 ml/cm H₂O; NNA, 1.27 ± 0.43 ml/cm H₂O; Control subjects, 5.24 ± 1.67 ml/cm H₂O, p = 0.0003. 4:00 A.M.: NA, 0.25 ± 0.10 ml/cm H₂O; NNA, 1.29 ± 0.61 L/cm H₂O; Control subjects: 7.58 ± 4.17 ml/cm H₂₀, p = 0.003). Cp did not change significantly in either group from 4:00 P.M. to 4:00 A.M.

After subcutaneous terbutaline, the Rp decreased in both asthma groups, but it was statistically significant only at 4:00 A.M. (mean change in Rp after terbutaline within NA, 0.035 ± 0.008; p = 0.0001; NNA, 0.016 ± 0.004; p = 0.05) (Figure 4). There was no change in the initial pressure drop after terbutaline, and there was no significant change in Rp after terbutaline in the nonasthma control group. With regard to the plateau pressure, the NA group exhibited a significant reduction in the plateau pressure after terbutaline, but only at 4:00 A.M. (p = 0.043). There were no significant changes over time or after terbutaline within the NNA and control groups. There was no significant change in peripheral compliance (Cp) within any of the groups after terbutaline (data not shown).

View larger version (27K): [in this window] [in a new window]   Figure 4.   The change in peripheral resistance (Rp) and plateau pressure at 4:00 P.M. (hatched bars) and at 4:00 A.M. (closed bars) within each group: control, non-nocturnal asthma (NNA), and nocturnal asthma (NA). Values are calculated as preterbutalinepostterbutaline. *p < 0.05 within NNA group at 4:00 A.M. p < 0.05 within NA group at 4:00 A.M.; p < 0.05 within NA group at 4:00 A.M.

The Rp positively correlated with the residual volume at both 4:00 P.M. and 4:00 A.M. (Figure 5), with Pearson's correlation coefficient of 0.71 at 4:00 P.M. (p = 0.004) and 0.59 at 4:00 A.M. (p = 0.03).

View larger version (16K): [in this window] [in a new window]   Figure 5.   The correlations between peripheral resistance (Rp) and residual volume (RV) are shown at 4:00 P.M. and at 4:00 A.M. for all three groups combined.

	DISCUSSION

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We have shown that Rp and plateau pressure are increased and that Cp is reduced in subjects with nocturnal asthma when compared with those asthmatics without nocturnal worsening and with normal control subjects. The Rp was not flow-dependent in the NA group as compared with the NNA and control groups when there was flow dependency of Rp. The NA group demonstrated a significant drop in pressure during many (< 50%) of the stop-flows at each flow rate, but demonstrated by only one patient in the NNA group. We feel this is indicative of increased resistance in the larger airways just distal to the bronchoscope but proximal to the collateral airways, but it was not a common occurrence. When asthmatics and nonasthmatics were compared, our results confirmed those of Kaminsky and colleagues (22), who demonstrated that peripheral resistance and plateau pressure are higher and peripheral compliance is lower in asthmatics than in nonasthmatics. Although the peripheral resistance was higher at 4:00 A.M. than at 4:00 P.M. in the NA group, it did not reach statistical significance. Within the NA group only, the plateau pressure increased at 4:00 A.M. when compared with that at 4:00 P.M. and decreased after subcutaneous terbutaline. Peripheral compliance was significantly reduced in the NA group, but it did not change from 4:00 P.M. to 4:00 A.M.. Given our previous findings that parenchymal inflammation is increased in NA at night (10, 11), we conclude that the distal lung units, specifically the collateral channels, may be selectively altered by this cyclic inflammatory process observed in NA.

Before considering the implications of these results, a methodologic discussion merits comment. As in the report by Kaminsky and colleagues (22), we paid careful attention to pressure waveforms to assure a secure, airtight wedge and patent catheter by observing cardiogenic artifacts and pressure fluctuations with breathing. As discussed at length by Kaminsky and colleagues (22), we feel our results are consistent with a non-linear single compartment model because of the nonmonoexponential decay of pressure and a plateau pressure greater than zero. Based on this view, the higher Rp and plateau pressure of asthmatics compared with those of control subjects implies either narrower or fewer collateral channels. At night in the NA group, we hypothesize that the channels close off during segment emptying earlier than they do during the day, and also earlier than in the NNA group, resulting in higher plateau pressures at night in NA. The lack of change in Rp from 4:00 P.M. to 4:00 A.M. in the face of increasing plateau pressures may be due to a dominant component of large airway resistance demonstrated by the initial pressure drop during the majority of stop-flow maneuvers in the NA group at both time points, and in one NNA subject at 4:00 A.M.. Additionally, the 4:00 P.M. FEV₁ is lower in the NA group than in the NNA group, which may reflect increased large airway resistance (proximal to the bronchoscope) at both time points. This concept is also illustrated by the fall in FEV₁ and the fall in specific conductance, which may reflect changes in large airway physiology. The dissociation between the FEV₁ and Rp may also be due to the effect of deep inspiration prior to the measurement of FEV₁, where either airway or parenchymal hysteresis may dominate in a given subject (29). Another possibility is our sample size of 10 subjects with NA, as the Rp was higher at 4:00 A.M. than at 4:00 P.M., but it did not reach statistical significance. As vagal tone is increased at night (30) the use of atropine prior to bronchoscopy may have also contributed to lack of change in Rp from day to night.

The plateau pressure, which is the positive pressure that remains after flow through the bronchoscope was stopped at FRC, is felt to be reflective primarily of the small airways and collateral channels serving the segment. This distal area of the lung contains openings that allow communication between segments, as described by Menkes and Traystman (20). If these communicating small airways, or collateral channels, leading out of a segment of the lung parenchyma become occluded secondary to increased secretions, inflammatory cells, and/or because of surfactant dysfunction, then not all the gas diffuses, and the final pressure is positive. The significance of these collateral channels is that they do contribute to Rp, which correlates with RV. The higher the Rp, the higher the RV, suggesting that when these collateral channels close, air trapping, and thus RV, increases. It is possible that the collateral airway closure is occurring more commonly or earlier at 4:00 A.M., leading to increased plateau pressure without an increase in Rp, as large and small airway resistance is increased similarly at both time points. During the day, large airway narrowing is still present given the initial pressure drop and increased Rp. There is less collateral airway closure, resulting in a lower plateau pressure. These changes can occur despite a low peripheral compliance that does not change from 4:00 P.M. to 4:00 A.M., as the Cp is reflective of the distal lung parenchymal function, not including the collateral channels (22). In our subjects with NA, we have shown that parenchymal inflammation increases at night (10, 11) as compared with day. We hypothesize that increased inflammation and edema in this lung compartment results in earlier closure of collateral channels by affecting airway instability and surfactant function (see below).

The unique characteristics of the smallest airways (< 2 mm) and lung parenchyma make them susceptible to instability and airway closure. First, the small airways are less able to clear secretions because of lack of cilia and the lack of high gas velocity generated during cough. Normally, this is not a significant issue, but in asthma and in other obstructive lung diseases where small airway inflammation and goblet cell metaplasia occurs (31, 32), these factors become magnified. In addition, Michel and colleagues (33) have shown that pollen particles reach the small airways and alveoli, which may further increase the inflammatory response in the atopic asthmatic patient if clearance mechanisms in this part of the lung are not adequate. Given the small radius of curvature and high compliance of the small airways, as demonstrated by Martin and Proctor (34), these factors can lead to instability and airway closure at low lung volumes. In this setting, surfactant may confer stability by protecting against excessive change in radii with changes in volume, as shown by Macklem and colleagues (32). In asthma, surfactant function may be altered by inflammatory exudate or mucus, thus rendering the small airways prone to obstruction and closure. In fact, surfactant dysfunction has been described in asthma (35). If the stability of the peripheral airways were lost because of increased secretions and/or surfactant dysfunction, these events could lead to narrowing of the peripheral airways, airway closure, higher lung volumes, and gas trapping. Therefore, it is possible that the increased inflammation appreciated in nocturnal asthma could very well be manifested by increased plateau pressure. The lack of change in Rp from day to night may be due to the fact that large airway tone does not change appreciably from day to night, but collateral airway tone increases at night, demonstrated by the increased closing pressure. Peripheral compliance is lower in both asthmatic groups as compared with the control group, and does not change from day to night in NA. This observation also suggests that the dynamic area in NA may not be the parenchyma, but collateral channels.

The improvement in plateau pressure and Rp after subcutaneous terbutaline suggests that the small airways and collateral segments exhibit contractile elements that are responsive to ₂-agonists. In fact, Dolhnikoff and colleagues (38) illustrated this issue in lung tissue obtained from human subjects. They evaluated subpleural parenchymal strips from humans to determine dynamic measures of resistance and elastance and evaluated the presence of smooth muscle actin by immunohistochemistry. They found actin positivity in the small airways, alveolar ducts, and alveolar walls. Thus, these data are consistent with those of other studies (39, 40), and we suggest that the smooth muscle of the collateral channels may be activated at night in NA.

Airway remodeling may be an explanation for why the Rp and plateau pressure decreased after terbutaline, but the initial pressure drop did not change. As the initial pressure drop is possibly indicative of large airway resistance, the lack of response to a ₂-agonist suggests that the large airways may have been altered sufficiently by ongoing inflammation and wound repair that they are no longer responsive to bronchodilators. The distal collateral channels do respond to a ₂-agonist, suggesting that there are contractile elements within these channels that are capable of responding, and are not yet permanently altered.

In summary, our results reveal that Rp and plateau pressure are higher and Cp is lower in patients with asthma than in control subjects, which confirms results from previous studies (19, 22). One unique finding in patients with NA and in one subject with NNA is that there is also a significant component of large airway resistance, as shown by the initial pressure drop during many of the stop-flow maneuvers. The Rp and plateau pressure decreased with terbutaline in both asthma groups, suggesting a role for smooth muscle contraction in the pathogenesis of large and small airway resistance. Additionally, the lung parenchyma may be an active participant in asthma, given the significant reduction in compliance observed in both asthmatic groups compared with the normal control group. When the asthma groups were compared, the NA group demonstrated increased Rp, increased plateau pressure, and decreased Cp compared with the NNA group at both 4:00 P.M. and 4:00 A.M. Within both asthma groups, peripheral resistance and lung compliance did not change significantly between 4:00 P.M. and 4:00 A.M. However, the increase in plateau pressure at 4:00 A.M. as compared with that at 4:00 P.M. in NA suggests a loss or closure of collateral channels, possibly because of smooth muscle contraction, inflammation, and/or edema. Thus, the collateral channels of the lung parenchyma may be selectively altered at night in NA, given that the plateau pressure is reflective of this region of the lung as compared with Rp and Cp, which also include the large airways and the distal lung parenchyma, respectively. We conclude that the increased alveolar tissue inflammation observed at night in NA may have the physiologic result of early closure of these collateral channels, resulting in increased plateau pressure. This finding may have relevance regarding our current inhaled therapies, which, if they did not reach the distal lung, may explain the increased symptoms at night in NA.