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HIGHLIGHTED TOPICS
Airway Hyperresponsiveness: From Molecules to Bedside
Departments of 2Environmental Health Sciences and 1Anesthesiology and Critical Care Medicine, Bloomberg School of Public Health and School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205
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ABSTRACT |
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 TOP ABSTRACT HETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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high-resolution computed tomography; asthma; airway narrowing; airway closure; deep inspiration
Over the past decade, several direct methods of assessing airway pathology in asthma have been used. One such method is high-resolution computed tomography (HRCT) to visualize airway size in vivo. Although other imaging modalities have the potential to image airways in vivo, none presently has the convenience, the accessibility, and the resolution required to visualize the airways. HRCT allows the study of multiple individual airways during contraction to closure and relaxation in real time, as well as allowing study of changes in airway size with changes in lung volume in animals (8, 12, 18, 20) and in human subjects (5, 7, 17, 47, 53). There are no other methods that allow this kind of insight or investigation of airway behavior in vivo. In the following sections, we will document the capabilities of HRCT by briefly reviewing experimental results from several canine and human studies.
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HETEROGENEITY OF AIRWAY RESPONSIVENESS |
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TOPABSTRACTHETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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A key variable in any measure of airway responsiveness is the initial size
of the airway. It clearly will take much less shortening of airway smooth
muscle to cause a given change in airway resistance when the airway starts
from a smaller size. This effect is often neglected in assessment of airway
reactivity; however, using HRCT, we have observed substantial variability in
the baseline size of individual airways over extended periods of time. Because
we establish anatomic landmarks in each dog, it is straightforward to find the
same airway on any particular experimental day. We have followed these
baseline changes in dogs over the course of 
1 yr
(18). These results show a
surprising degree of airway variability in the individual airways over this
extended time period. Within an animal, an individual airway sometimes seemed
to show random variation, whereas on other dates most of the airways appeared
to change similarly. We also found no correlation between the magnitude of
variability in an individual airway and its location (right vs. left, anterior
vs. posterior, and proximal vs. distal) within the lung. Additionally, the
mode of challenge was also shown to be unimportant
(9). We know of no comparable
in vivo studies that examine the changes in individual airway size over time.
There are studies in humans and dogs that have shown reproducibility of
traditional pulmonary function tests over time
(24,
45,
52). However, these
measurements reflect a summation of hundreds or thousands of airways. Indeed,
if we did a simple average of all the airway areas measured in each dog, we
also found no significant changes over time in this mean. Thus mean values or
global pulmonary function measurements provide no insight into the extent of
individual airway variability. Although we still do not know the reasons for
this underlying variability, the only way to study such a potentially
important phenomenon is with functional imaging.
The ability of HRCT to pursue this investigation is shown in Fig. 1. Figure 1 shows the variability in baseline size of individual airways in five dogs, studied on two occasions, each separated by at least 2 wk. Airway size is presented as a percentage of each airway's maximally relaxed size, determined at the end of all experiments on each experimental day. This maximal size was shown to be constant over several months. As can be appreciated from Fig. 1, the range of baseline sizes can be quite large, with some airways residing near maximum and others near closure even within the same animal. The variability within an animal is as large as that between animals. Although heterogeneity of ventilation and perfusion have been examined in increasing detail, examination of heterogeneity in the anatomic and physiological functions of individual airways is still in its infancy, but there is substantial evidence suggesting that the pathology in asthmatic lungs is quite heterogeneous (38, 49). How this normal airway variability impacts on individual airway responsiveness and asthma remains to be determined.
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MAXIMAL CONTRACTION |
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TOPABSTRACTHETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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0.5 mm lumen). We
(14) have used this potential
to document effective airway closure in response to a spasmogen. This
observation of a closure in vivo is consistent with in vitro airway
experiments, in which the airways do not generally exhibit a plateau effect to
an agonist challenge but continue to constrict to increasing concentrations of
agonist until complete closure occurs
(1,
25). Although airway closure
can also sometimes be observed in vivo
(60) and in situ
(44) as well as in vitro,
these observations are in direct conflict with indirect measurements of airway
narrowing in vivo with commonly used pulmonary function tests such as
FEV1 or airway resistance. With these conventional global
measurements, there appears to be a plateau in the response. We have
interpreted these contrary results by concluding that any apparent limitation
in airway responses in vivo must be due to mechanisms not directly related to
limitations associated with airway smooth muscle contraction. The appearance
of a plateau in vivo (26,
43,
50,
59,
63) may result from elastic
loads provided by the surrounding lung parenchyma or by limitations in the
delivery of agonist to the airway smooth muscle. To investigate this question
of maximal narrowing in individual airways in vivo, HRCT was used to visualize
canine airways narrowed by two routes of agonist challenge. Airway narrowing
induced by methacholine (MCh) via the conventional aerosol route was compared
with that caused by local atomization of MCh directly to individual airways.
Local atomization of microboluses of agonist were delivered directly to the
epithelium of the same airway locations measured during the conventional
aerosol challenge. The atomization was accomplished with a specially designed
catheter that could be placed with bronchoscopic visualization to deliver
agonist to a region smaller than 1 cm in the axial direction
(14). Figures 2 and 3 demonstrate the localized action of histamine on airway constriction. Figure 2 shows a large cartilaginous airway that has closed following local challenge. Figure 3 shows the location of the catheter tip and the degree of constriction as a function of distance along the airway for three sequential increasing doses of histamine. Figure 3 provides several important insights into airway contraction in vivo. First, Fig. 3 clearly supports our ability to generate a very localized constriction with very little axial spreading of the constriction. It was actually quite remarkable to observe airway closure over a range of only a few millimeters, yet, just a few millimeters either side of closure, the airways were nearly 50% of maximal size. There is nothing in the literature that would have led to the prediction that airway closure could occur over so limited a region. This result suggests that there are few axial constraints limiting bronchoconstriction and that severe airway obstruction in asthma might possibly result from relatively few intense local effects.
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Second, because this airway was 9 mm in diameter when there was no
smooth muscle tone, it clearly documents that there is no limitation on the
ability of any intraparenchymal airway to completely close in vivo. This
observation is consistent with in vitro experiments and supports the idea that
the apparent plateau often seen on aerosol dose-response curves in vivo may be
an artifact of the methodology because it clearly does not reflect the ability
of airway smooth muscle to completely overcome elastic loads in vivo.
What could be responsible for such artifacts? We do not have a definitive answer, but, as shown in Fig. 4, even in our canine model, such apparent plateaus appear. Although the dose-response curves give the appearance of a plateau, the airway area continued to fall slightly even up to doses of 500 mg/ml. This value of 500 mg/ml was more than an order of magnitude greater than the largest doses normally given to human subjects. It is not possible to challenge with aerosol concentrations much above 500 mg/ml, both because solutions at higher concentrations are not stable at room temperature and begin to precipitate agonist and because systemic drug absorption can lead to cardiovascular instability. However, a 10 mg/ml concentration of MCh delivered locally via the catheter caused complete closure in 13 of 21 airways and extreme narrowing in the remaining 8 airways (Fig. 3). In the airways not initially closed by the 10 mg/ml dose via the catheter, the narrowing was comparable to that seen in the same airways at the 500 mg/ml dose of aerosol MCh. When the 50 mg/ml dose of MCh was delivered via the catheter to the eight airways that remained open after the initial 10 mg/ml dose, they also completely closed. Thus we think that the apparent plateau seen with aerosol challenges may simply reflect a limited ability to deliver higher doses to the airway smooth muscle.
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There has been extensive speculation about the interaction of the parenchyma and the airways. Macklem (39) has suggested that the forces of interdependence of the parenchymal attachments on the airway wall may be the cause of attenuated bronchoconstriction in vivo. This interaction also highlights another difference between whole lung challenge and the local challenge. In the whole lung challenge, the entire parenchyma is contracted as well as the airway, and this could lead to increased tethering forces on the airways. In an attempt to address this issue, we did another study to examine the effects of increased mechanical distending stress on the airways caused by increased positive end-expiratory pressure (PEEP) on preventing airway closure was investigated (10). Although the number of airways that remained open even with maximal stimulation increased significantly when PEEP was increased, airway closure still can occur even at the highest level of PEEP (P = 0.006). At 10 cmH2O, we found that 36% of the airways could still completely close.
These results demonstrate that, whereas lung inflation can limit the ability of airway smooth muscle to shorten, even relatively high levels of PEEP could not always prevent airway closure when there was sufficient stimulation to the airway smooth muscle. Increasing levels of PEEP shift the MCh dose-response curve to the right, indicating an attenuation of airway contraction by the increased lung inflation. The findings also put some constraints on how effective the contracted parenchyma must be if that is to play a role in limiting airway narrowing. The contracted parenchyma must generate an effective peribronchial pressure of greater than 10 cmH2O if it is to be the mechanism that limits closure with aerosol challenge. These results with PEEP also emphasize the heterogeneity in individual airway responses. Whether repeat stimulation with the same degree of lung inflation would close the same population of airways remains to be determined. HRCT is the most accurate method with which to address this question.
Both of these studies indicate that there is no limit to the ability of smooth muscle to shorten in vivo. If these findings can be extrapolated to humans, then several interpretations of these dose-response curves need to be reconsidered. It is often assumed that normal subjects show a maximal dose-response plateau, whereas asthmatic subjects do not (43, 63). However, if there is no limit of normal airways to narrow, then the difference only reflects a shift in the dose-response curve to MCh and not a qualitative difference in the degree of maximal shortening. We believe that if the airways were challenged with the method we used in dogs normal human airways might be capable of constricting to a much greater extent, with many airways even closing completely.
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EFFECTS OF DEEP INSPIRATION ON AIRWAY CONSTRICTION |
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TOPABSTRACTHETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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Mechanisms underlying the observation in this study may have important implications regarding human asthma. It is generally accepted that lung inflation distends the airways of animals and humans (12, 15–17). In airways with little smooth muscle tone, even moderate lung inflation readily distends airways to their maximal size, and this was shown to be true in experimental animal models even when airways were made edematous (16, 19). Also, in normal healthy human volunteers and mild asthmatic subjects, there were similar degrees of airway distension at TLC either at baseline or after mildly increased airway tone with aerosol MCh challenges (17).
One mechanistic consideration involves the interaction between recoil pressures of the airway smooth muscle and lung parenchyma following the DI. We know that, at the lower inflation pressures, the airways are less dilated. When the lung recoil pressure is decreased after the DI maneuver, this loss of lung recoil may then lead to a further decrease in airway luminal size. It is not entirely clear, however, why the paradoxical narrowing should take so long to develop. This delay suggests perhaps that some intrinsic properties of the smooth muscle contractile proteins might also be important. In a closely related recent study (6), shortening the time spent at maximal lung volume during a DI maneuver was shown to lead to a subsequent paradoxical contraction of airways. Thus it appears that, to obtain a normal airway dilation after a DI, one must effectively dilate the airways to some minimal size, either by increasing the peak inflation pressure or by lengthening the time at peak pressure. The details of this pressure-time interaction are not yet clear, but as briefly discussed below such a mechanism would seem to have considerable clinical relevance.
Several recent clinical investigations have focused on single or repetitive DIs as a means of preventing or reversing bronchoconstriction (21, 40, 54, 55). In general, the nature of the DIs in the clinical studies were not explicitly specified, but they were usually brief and sigh-like, typically on the order of only a few seconds. The above results may relate to the paradoxical airway narrowing sometimes seen in asthmatic individuals after a DI (3, 17, 21, 27, 28, 31, 48, 58, 62). Perhaps asthmatic airways are stretched too little during the maneuver and behave like the low-pressure groups in the present work.
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EFFECTS OF TIDAL STRETCH ON SUBSEQUENT RESPONSE OF AIRWAYS TO A DI |
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TOPABSTRACTHETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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The effect of rhythmic cycling in decreasing the smooth muscle tone has been shown in both in vitro (33, 37) and in vivo studies (22). Warner and Gunst (61) originally demonstrated that the rhythmic stretching associated with tidal breathing decreased not only the baseline lung resistance but also the response to MCh. Gunst's group later proposed a mechanistic explanation that involves changes in the plasticity of the smooth muscle cellular cytostructure (32, 57). Alternatively, in a series of papers by Fredberg et al. (29, 30), it was proposed that the steady-state muscle force would be determined by a balance between high- and low-energy cross-bridge dynamics and speculated that normal tidal breathing would provide a sufficient stress to keep the low-energy state from occurring in normal lungs.
We tested the validity of these in vitro models in an in vivo canine model using HRCT (42). With the use of a bronchial blocker, the right or left lung could be isolated and selectively ventilated. One lung was then randomized for subsequent ventilation. After 10 min of one-lung ventilation, both lungs were inflated to 30 cmH2O for 10 s; they were then allowed to passively expire to functional residual capacity. This was repeated with the alternate lung ventilated. After the 10-min period of ventilatory stasis in one lung, the subsequent DI led to an increase in airway area in the ventilated lung and a decrease in airway area of the unventilated lung. The correlations in Fig. 6 show that, on the ventilated side, lung volumes increased after a DI, concomitant with an increase in the mean airway. On the nonventilated side, lung volume decreased after a DI, concomitant with a decrease in mean airway area.
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These results clearly demonstrate that the airway response to a DI could be qualitatively changed by altering the pattern of normal tidal stresses. By eliminating tidal stresses in one lung, we were able to change the normal airway dilation that would occur in response to a DI to one of airway constriction. This change occurred after tone was induced in the airways with a continuous intravenous infusion of MCh. These observations are striking because they provide a potential mechanism that allows conversion of the normal airway dilation following a DI to that of constriction. All that was needed to cause this qualitative change was to minimize the tidal stresses for a period of time, which led to changes in the smooth muscle that now cause constriction after the DI. Although this qualitative change in the response to DI observed in the dog may well be related to the qualitative difference seen between asthmatic and normal humans, the mechanisms underlying the observation are still not completely clear. For example, the model of Fredberg et al. (29) argued that the stresses associated with normal tidal breathing were sufficient to keep the airway smooth muscle from attaining a low-energy latch state. Whereas our results appear to be consistent to what this model would predict, the situation in the intact living lung is more complex than just the response of smooth muscle in the airway wall. In situ, the final airway size depends on the resultant recoil pressure exerted by the surrounding lung (41). If the DI caused a normal reduction in lung elastic recoil, but has little direct effect on a stiff contracted airway, then the airway would end up smaller. Although changes in asthmatic lungs may not mimic the experimental protocol used, air trapping in the lungs of asthmatic subjects associated with bronchospasm could lead to increased lung volume and altered tidal stresses on the airways and parenchyma. Understanding the dose-time effect of these insidious changes may ultimately affect the way asthma is managed and treated.
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AIRWAY DISTENSION IN HEALTHY AND MILD ASTHMATIC SUBJECTS |
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TOPABSTRACTHETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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AIRWAY REMODELING AND DISTENSION IN SEVERE ASTHMA |
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TOPABSTRACTHETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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In ongoing work, we have attempted to address these issues in more severely asthmatic subjects, in which there may be chronic changes altering both the structure and distensibility of airways. Such changes should result in both decreased baseline function and an inability to fully distend the airways at TLC. We measured the ability of asthmatic subjects with varying degrees of baseline airway obstruction to distend their airways with a DI. This preliminary work shows that there is a significant decrease in airway distensibility in the severely obstructed subjects compared with those with either mild or moderate baseline obstruction (unpublished observations). Thus asthmatic individuals with greater airflow obstruction do have a decreased ability to distend their airways with lung inflation to TLC. Such compromised airway distensibility could result from increased stiffness of the airways from increased airway smooth muscle tone or secondary to airway remodeling and deposition of nondistensible elements such as collagen in the airway wall (51). Furthermore, although the previous study suggested that decreased parenchymal interdependence may not be important in mild asthma, it may assume increasing importance in the severe condition.
This new work in humans has also found that there are structural changes in airways that are consistent with decreased lung function even with no smooth muscle tone (unpublished observations). These results show that decreased FEV1 is correlated with smaller postalbuterol airway luminal area at TLC. One reason that we can reveal this expected relationship between luminal area and FEV1 is the ability of HRCT to measure the airway areas at TLC. Further precision can also be achieved because the dimensions at TLC used for the relationship to FEV1 were obtained after maximal relaxation with albuterol, thereby minimizing the size variability associated with different levels of baseline tone. This observation supports a potentially key role of airway remodeling on asthma severity and further supports this imaging methodology as a productive approach to examining the role of remodeling on airway obstruction and asthma severity.
In summary, we have shown the unique ability of HRCT to quantify static and dynamic changes in individual airways as small as 1 mm in diameter. Although several new insights into airway behavior in vivo have been obtained with this method, there are some clear limitations with its widespread use. Some of these include the amount of radiation given to subjects, the cost, the required supine position, and the inability to see the small membranous airways. The most promising approach for future mechanistic studies may result from combining HRCT with measurements of lung mechanics and classical pulmonary function tests.
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTHETEROGENEITY OF AIRWAY...MAXIMAL CONTRACTIONEFFECTS OF DEEP INSPIRATION...EFFECTS OF TIDAL STRETCH...AIRWAY DISTENSION IN HEALTHY...AIRWAY REMODELING AND DISTENSION...REFERENCES |
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, and a PGH2
analogue on airway diameters in dogs. J Appl Physiol
53: 1005-1014,
1982.
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R. H. Brown, D. B. Pearse, G. Pyrgos, M. C. Liu, A. Togias, and S. Permutt The structural basis of airways hyperresponsiveness in asthma J Appl Physiol, July 1, 2006; 101(1): 30 - 39. [Abstract] [Full Text] [PDF]
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),
35 cmH2O (
), and 45 cmH2O (
). For the larger
DI (45 cmH2O), the airway size remained above the baseline airway
area for the entire measurement period (*P < 0.0001).
In contrast, for the smaller (35 and 25 cmH2O) DIs, the airways
actively contracted to a smaller area than at the pre-DI baseline. At 5 min,
the airway area was 91 ± 3% of pre-DI airway area for the 35
cmH2O DI (#P < 0.0001) and 73 ± 1% for the 25
cmH2O DI (+ P < 0.0001). [From Brown et. al.
(
