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1 Department of Anesthesiology
and Critical Care Medicine,
2 Department of Radiology,
3 Division of Physiology, ABSTRACT Brown, Robert H., Wayne Mitzner, and Elizabeth M. Wagner.
Interaction between airway edema and lung inflation on
responsiveness of individual airways in vivo. J. Appl.
Physiol. 83(2): 366-370, 1997.
bradykinin; high-resolution computed tomography; hyper-
responsiveness; hyperreactivity; methacholine
INTRODUCTION INFLAMMATORY CHANGES in the airway wall are commonly
suggested as a primary cause of the increased airway responsiveness
seen in patients with asthma (4, 16). Mechanically, this could occur if
the inflammation included sufficient fluid leakage from the bronchial
vasculature to substantially thicken the airway wall. With a thicker
wall, a given degree of smooth muscle shortening could lead to
exaggerated luminal narrowing (15, 22). Although such a scenario seems
intuitively reasonable, there are little published data on which to
base quantitative estimates of this mechanism. In previous work in a
canine model in which airway edema was induced with systemic saline
volume loading, it was shown not only that there was a maximal limit to
the increase in wall thickness (~50%) but also that at this limit
the airway luminal area was decreased by only ~30% (8). One concern
with these experiments, however, was that the mechanism causing the edema might be quite different from what occurs with local inflammatory swelling of the airway wall. With inflammation, chemicals are released
that can cause the airway vascular permeability to increase, with
subsequent protein and plasma exudation (20). This inflammatory exudate
might be greater and more localized to the airway wall than edema
elicited with acute systemic saline volume loading. More recent studies
in a sheep model addressed this concern by generating airway edema with
the inflammatory mediator bradykinin (6, 29). In these
latter studies, a substantial increase in airway wall area was also
observed, but this increased thickness still caused only minor
decreases in luminal area.
It thus would seem that edema per se cannot lead to a substantial
degree of airway obstruction. The next logical question, whether this
increased wall thickness affects the airway responsiveness to agonist
challenge, has not been systematically studied. Although there are
theoretical reasons and some experimental evidence suggesting that
airway responsiveness is increased with airway wall thickening (7), the
influence of lung volume and agonist dose is unknown. In the present
study, we attempted to address these issues by measuring the
dose-response relationship to methacholine (MCh) of individual airways
in vivo before and after wall thickening caused by bradykinin at
different lung volumes. Results show a surprisingly small effect of
airway wall edema on airway responsiveness.
METHODS Our study protocol was approved by The Johns Hopkins Animal Care and
Use Committee. Anesthesia was induced in five sheep (25-35 kg)
with intramuscular ketamine (30 mg/kg) and subsequently maintained with
pentobarbital sodium (20 mg · kg
Inflammatory
changes and airway wall thickening are suggested to cause increased
airway responsiveness in patients with asthma. In five
sheep, the dose-response relationships of individual airways were
measured at different lung volumes to methacholine (MCh) before and
after wall thickening caused by the inflammatory mediator bradykinin
via the bronchial artery. At 4 cmH2O transpulmonary pressure
(Ptp), 5 µg/ml MCh constricted the airways to a maximum of 18 ± 3%. At 30 cmH2O Ptp, MCh resulted
in less constriction (to 31 ± 5%). Bradykinin increased airway
wall area at 4 and 30 cmH2O Ptp
(159 ± 6 and 152 ± 4%, respectively;
P < 0.0001). At 4 cmH2O Ptp, bradykinin decreased
airway luminal area (13 ± 2%; P < 0.01), and the dose-response curve was significantly lower (P = 0.02). At 30 cmH2O, postbradykinin, the maximal
airway narrowing was not significantly different (26 ± 5%;
P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation of
the MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effect
on the MCh-induced airway constriction. We conclude that inflammatory
fluid leakage in the airways cannot be a primary cause of airway
hyperresponsiveness.
1 · h1).
A tracheostomy was performed, the sheep were paralyzed with pancuronium
bromide (2 mg iv), and the lungs were mechanically ventilated with
100% oxygen at a rate of 15 breaths/min and a tidal volume of 12 ml/kg. A positive end-expiratory pressure of 5 cmH2O was applied. The left thorax
was opened at the fifth intercostal space, and heparin (20,000 U) was
administered. The esophageal and thoracic tracheal branches of the
bronchoesophageal artery were cut as previously described (32). The
bronchial branch was then cannulated with an 18-gauge angiocatheter and
perfused with a constant flow (0.6 mg · min1 · kg1)
of blood withdrawn from a femoral artery catheter by a variable-speed pump (Gilson, Villiers-Le-Bel, France). The vagus nerves were ligated
bilaterally to prevent reflex-mediated airway responses (31).
[T + 
(Ai/)]2,
where Ai is
luminal area and T is wall
thickness. A few of the walls of the smallest airways
could not be measured with this approach.
8, 2.5 × 107, 7.6 × 107, and 2.5 × 106 MCh, respectively.
After 10 min of MCh infusion, scans were acquired at static Ptp values
of 4 and 30 cmH2O in random order.
The subsequent MCh concentration was then administered.
After scans were acquired at the highest agonist dose, the MCh infusion
was stopped and the airways were allowed to recover (~30 min). A
second set of baseline images (baseline
2) were obtained. To determine whether airway wall
edema altered the degree of MCh-induced constriction, sheep were
administered a continuous infusion of bradykinin
(106 M) through the
bronchial artery at an initial rate of 2 ml/min for 10 min followed by
a maintenance dose of 1 ml/min, a dose previously shown to cause a
significant increase in airway wall thickness (6, 30). We have shown
that this dose of bradykinin has no direct airway smooth muscle
contractile effects in our sheep model (29).
During this infusion, scans were again acquired at static Ptp values of
4 and 30 cmH2O as described above.
Subsequently, the sheep were administered MCh in the same doses as
described above, and scans were again acquired at static Ptp values of
4 and 30 cmH2O.
Analysis.
Airway luminal area at 30 cmH2O
Ptp in the relaxed state after vagotomy was defined as 100% (maximal
area). Data are expressed as a percentage of maximal area.
The mean airway luminal areas for all airways in all the sheep (as
percentage of maximum) at initial baseline (baseline
1) and after recovery from MCh
(baseline 2) were compared by paired t-test. Paired
t-tests were also used to compare the
increases in wall area after bradykinin at each Ptp, the effective dose that caused a 75% decrease in luminal area from maximum
(ED75), and the maximal
contraction at the highest MCh dose before and after bradykinin
administration.
To compare the mean airway area after MCh with and without bradykinin,
generalized analysis of variance was used to control for repeated
measurements of the airways within each sheep and for repeated
measurements between sheep. The generalized analysis of variance was
performed separately for each lung volume studied, with the mean airway
luminal area (as a percentage of maximum) the dependent variable and
with dose, bradykinin, the different sheep, and the multiple airways
measured per sheep the independent variables.
RESULTS
In each sheep, 12-16 airways were identified and measured under the various conditions. The airways studied ranged in size from 2.5 to 12.8 mm in internal diameter after vagotomy at 4 cmH2O Ptp. There was no difference in airway luminal area as a percentage of maximum between the first and second baseline measurement at either 4 or 30 cmH2O Ptp (P = 0.19 and P = 0.23, respectively). The decrease in Ptp from 30 to 4 cmH2O caused an ~20% reduction in luminal area.
Bradykinin caused a significant increase in baseline airway wall area
at both 4 and 30 cmH2O Ptp. At 4 cmH2O Ptp, wall area was 159 ± 6% of baseline (P < 0.0001), and at
30 cmH2O Ptp, it was 152 ± 4%
of baseline (P < 0.0001). There was
no significant change in wall area with increased Ptp
(P = 0.25). Figure
1 shows the effect of bradykinin on the
relationship between wall area and relaxed airway luminal area at Ptp
of 4 cmH2O
(A) and 30 cmH2O (B). These plots show
that the increase in wall area with bradykinin administration occurred
over the entire range of airways studied.
, Wall areas for individual airways at each pressure before bradykinin; 
, wall areas for individual airways at each pressure after bradykinin. Plots show that
increase in wall area with bradykinin administration occurred over
entire range of airways studied.
Dose-response curves to MCh are shown in Fig.
2. At 4 cmH2O Ptp
(A), increasing doses of MCh
resulted in a constriction at maximal dose to 18 ± 3% of the
relaxed airway luminal area. At 30 cmH2O Ptp
(B), increasing doses of MCh
resulted in less of a constriction (to 31 ± 5% of maximum) at the
same maximal dose of 5 µg/ml. At 4 cmH2O Ptp, bradykinin
administration caused a small decrease (13 ± 2%) in baseline
airway luminal area (P < 0.01). This
caused the airway luminal area with MCh to be significantly lower at
this low level of inflation during bradykinin administration, reaching
a minimal luminal area of 13 ± 3%
(P = 0.02). At 30 cmH2O, bradykinin administration
had no effect on airway luminal area (P = 0.75); the maximal MCh dose
caused a decrease in luminal area to 26 ± 5%, which was not
significantly different from the comparable pre-bradykinin constriction
(P = 0.76). A comparison of the
average ED75 values showed no
significant difference with and without bradykinin at Ptp of 30 cmH2O (2.53 × 106 vs. 2.09 × 106, respectively;
P = 0.36) or a Ptp of 4 cmH2O (9.75 × 107 vs. 5.12 × 107, respectively;
P = 0.37).
, Vagotomy; , bradykinin.
Brackets indicate concentration. At 4 cmH2O Ptp
(A), increasing doses of
methacholine resulted in a maximal constriction to 18 ± 3% of
maximal airway luminal area. At 30 cmH2O Ptp
(B), increasing doses of
methacholine resulted in less of a constriction (to 31 ± 5% of
maximum) at same maximal dose. After bradykinin administration, dose-response curve was significantly lower at 4 cmH2O, reaching a minimal luminal
area at maximal constriction of 13 ± 3%
(P = 0.02). At 30 cmH2O, maximal methacholine dose
caused decrease in luminal area to 26 ± 5%, which was not
significantly different from comparable pre-bradykinin constriction
(P = 0.76).
DISCUSSION
Our results demonstrate the presence of substantial airway wall edema elicited by infusion of the inflammatory mediator bradykinin directly into the bronchial artery in vivo. Bradykinin caused an ~50% increase in wall area that was not altered by increasing Ptp to 30 cmH2O. That the wall area was not affected by lung inflation suggests that airway wall edema is neither relocated nor reabsorbed with lung inflation. Because lung inflation causes a decrease in interstitial pressure (28), this observation would suggest that either there is a uniform decrease in interstitial pressure or the resistance to fluid movement in the interstitium is sufficiently high that minimal movement can occur over the course of each experimental pressure change (~10 min).
We also found that this magnitude of airway wall edema had only a slight effect on the luminal area at low lung volume. At low lung volume, this 50% increase in wall area caused a 13% decrease in airway luminal area, and at high lung volume, luminal area was not affected by the edema. These observations are consistent with previous work examining the effects of lung volume on edematous airways by using HRCT (6). It was shown in this previous work that airway narrowing caused by wall edema at low lung volume could be reversed completely by lung expansion. This lung volume dependence of the effect of wall thickening may help explain some of the variability in previously published morphological work. Postmortem histological studies have generally found no significant changes in airway luminal dimensions with edema (2, 14, 21). However, because lungs are normally fixed in the fully inflated state, these negative results would be predicted from our present findings.
Another potential confounder regarding wall edema and luminal area may be airway size. In a morphometric study of small airways (<3 mm diameter) that had been fixed at 5 cmH2O Ptp, we showed that for a similar exposure to bradykinin to that used in the present study, there was a trivial effect on luminal narrowing (5%) (29). Edema fluid accumulated primarily external to the airway smooth muscle in these small airways. Thus the site of fluid accumulation as well as lung volume and airway size may impact whether wall thickening will alter baseline airway luminal area.
The major focus of the present study was to determine whether airway wall edema altered MCh-induced airway narrowing at different lung volumes. Our results showed only a minor effect of edema on the airway responsiveness to MCh. Only at a Ptp of 4 cmH2O was responsiveness to MCh slightly augmented, whereas at 30 cmH2O Ptp responsiveness was unchanged. To assess airway responsiveness it is customary to calculate an effective dose that caused a 50% decrease in airway luminal area (ED50). We could not do this in the present study because at the lower lung volumes the lowest MCh dose already decreased airway luminal area by >60%. We thus calculated an ED75 value. On the basis of this value, there was no appreciable difference in responsiveness to MCh before and after bradykinin infusion at either lung volume.
Our results suggest that the total amount of acute airway wall thickening per se is not a primary factor in the degree of agonist-induced luminal narrowing. We suggest that the potentiation of airway responsiveness by wall edema is dependent primarily on the extent to which the luminal area is decreased before agonist challenge. Therefore, any intervention that thickens the airway wall inside the airway smooth muscle or otherwise leads to a decreased lumen size would potentiate agonist-induced airway narrowing (15). In our present study, at high lung volume, despite an increase in wall area, there was no change in luminal area, and airway responsiveness to MCh was unaltered. Similarly, in a morphometric study of smaller airways in sheep exposed to bradykinin, despite increased wall area (30%) primarily external to smooth muscle layer, no changes in luminal area or airway reactivity were discerned (29). Hydrostatic edema in the airway wall of sheep induced by a prolonged period of hyperperfusion of the bronchial vasculature resulted in an increase in wall area external to airway smooth muscle. In that study, despite a 19% increase in airway wall area, no changes in luminal area, airway resistance, or airway reactivity were observed (3). Contrary to this theory that potentiation of airway responsiveness depends primarily on the extent of initial luminal narrowing is the work of Kimura and colleagues (17), who increased airway wall area by infusing a solution of dextran and bradykinin through the bronchial artery of dead cats. Histology showed an increase in wall area only outside the airway smooth muscle and no change in luminal area. However, they observed a significant shift in the dose-response curve to acetylcholine and an increase in the maximal dose (17).
Our previous work in sheep (6, 29) also contrasts with an investigation of an analogous question in dogs. In the canine study, peripheral infusion of saline sufficient to increase airway wall area by 16% not only caused a concomitant decrease in airway luminal area by 22% (7) but also caused a potentiation of histamine-induced airway reactivity. Reasons for this difference are not clear, but there were several methodological differences. Airway edema in the dog study was caused by acute systemic volume loading, a maneuver that necessarily caused pulmonary hypertension, possibly activating neural reflexes that can enhance the constrictor response (9). This is in contrast to the sheep studies where we selectively infused a mediator known to cause fluid extravasation in the airway blood vessels. Furthermore, the sheep were vagotomized to eliminate any potential reflex responses.
To quantify how the magnitude of wall swelling might alter the extent of luminal narrowing for a given degree of muscle shortening, we performed a geometric analysis on a nominal airway 5 mm in diameter with and an airway wall 1 mm thick, similar to what was done in a previous analysis of canine airways (7). The present analysis was done for two doses of MCh before and after bradykinin at 4 cmH2O Ptp. We assumed that the edema was relatively uniformly distributed in the airway wall, an assumption consistent with results from our previous analysis (7). With no edema, we found that the smallest dose of MCh decreased luminal areas to 50% of relaxed area. To achieve this degree of constriction required 24% muscle shortening. At the largest dose of MCh we found luminal areas to be 22% of relaxed area, and to achieve this degree of constriction required 41% muscle shortening. After the airways were made edematous by bradykinin, there was a luminal reduction to 87% of baseline, and with this reduced lumen the smallest dose of MCh caused a further decrease in luminal area to 47%. To achieve this increased degree of constriction required smooth muscle shortening of 20%, i.e., almost the same as before the bradykinin. At the largest dose of MCh after edema, the luminal area was decreased to 17% of relaxed area. To achieve this increased degree of constriction now required smooth muscle shortening of 40%, i.e., again almost the same as before the bradykinin. This simple geometric analysis thus provides additional support for the conclusion that the degree of smooth muscle shortening with MCh challenge was the same before and after the bradykinin-induced edema.
In this study we found that lung inflation was able to completely reverse bradykinin-induced airway luminal narrowing while having limited effectiveness at reversing MCh-induced airway narrowing, a finding consistent with previous work in sheep (6). How airways respond to distending forces via lung inflation depends on several factors, especially the extent to which the airway smooth muscle is contracted. There is clear evidence that given a sufficiently large contraction, some airway smooth muscle is very difficult to stretch. Previous work using HRCT to measure airway area showed increased Ptp had a minimal effect on the airway area of sheep when the smooth muscle was significantly constricted (6). Olsen et al. (24) showed very stiff pressure-area curves of isolated canine bronchi contracted with a high dose of acetylcholine (15 µg/ml). Even with a transmural pressure of 30 cmH2O, there was only minimal distension. Gunst et al. (12) similarly reported minimal distension in MCh-contracted canine airways with lung inflation in dogs. Murtagh et al. (23) showed that, with a large aerosol dose of MCh, sufficient to constrict in situ canine airways to ~25% of maximal caliber, pressures up to 96 cmH2O were required to pull open the airways.
In clinical asthma, the intrinsic forces of contraction may also be greater than that which lung inflation can overcome. This conjecture is supported by many observations showing that a deep inspiration does not relieve bronchoconstriction in asthmatic patients (10, 11, 25-27). Several authors have proposed that in asthma, edema fluid from inflammation and cellular infiltrate collects between the airway smooth muscle and the surrounding lung parenchyma and that this fluid should attenuate the forces of radial traction produced by increased lung volume and potentiate airway constriction (13, 18, 19). Our present findings in sheep do not support this mechanism. We found that, with an ~50% increase in airway wall area, the airway response to MCh was only minimally enhanced at low lung volume. And at high lung volume there was no effect at all of this substantial airway wall thickening. Because it is unlikely that airways can be acutely thickened much more than 50% (8) it would seem unlikely that edematous wall thickening per se could prevent a deep inspiration from distending airways of asthmatic individuals.
In summary, we found that the inflammatory mediator bradykinin produced a substantial airway wall thickening and a slight potentiation of the MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin caused a similar increase in wall thickness but had no effect on the MCh-induced airway constriction.
ACKNOWLEDGEMENTS
This work was supported by National Institutes of Health Grants HL-02795 and ES-03819 and by the American Heart Association.
FOOTNOTES
Address for reprint requests: R. H. Brown, The Johns Hopkins School of Hygiene and Public Health, Div. of Physiology/Room 7006, 615 North Wolfe St., Baltimore, MD 21205 (E-mail: rbrown{at}welchlink.welch.jhu.edu).
Received 6 January 1997; accepted in final form 17 April 1997.
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R. H. Brown and W. Mitzner Airway response to deep inspiration: role of inflation pressure J Appl Physiol, December 1, 2001; 91(6): 2574 - 2578. [Abstract] [Full Text] [PDF]
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 R. H. BROWN, N. SCICHILONE, B. MUDGE, F. B. DIEMER, S. PERMUTT, and A. TOGIAS High-Resolution Computed Tomographic Evaluation of Airway Distensibility and the Effects of Lung Inflation on Airway Caliber in Healthy Subjects and Individuals with Asthma Am. J. Respir. Crit. Care Med., March 15, 2001; 163(4): 994 - 1001. [Abstract] [Full Text]
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H. TIDDENS, M. SILVERMAN, and A. BUSH The Role of Inflammation in Airway Disease . Remodeling Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): S7 - 10. [Full Text] [PDF]
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E. M. Wagner and R. H. Brown Blood flow distribution within the airway wall J Appl Physiol, May 1, 2002; 92(5): 1964 - 1969. [Abstract] [Full Text] [PDF]
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L. S. King, S. Nielsen, P. Agre, and R. H. Brown Decreased pulmonary vascular permeability in aquaporin-1-null humans PNAS, January 22, 2002; 99(2): 1059 - 1063. [Abstract] [Full Text] [PDF]
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