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Department of Physiology, St. George's Hospital Medical School, London SW17 0RE, United Kingdom
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Duneclift, S., U. Wells, and J. Widdicombe. Estimation
of thickness of airway surface liquid in ferret trachea in vitro. J. Appl. Physiol. 83(3): 761-767, 1997.
The tracheae of ferrets and rabbits were mounted in vitro in
organ baths. While the tracheae were liquid filled, the permeability
coefficient ( P) was determined, and then while the
tracheae were air filled, the percent clearance for
99mTc-labeled
diethylenetriaminepentaacetic acid (DTPA) was determined. The thickness
of airway surface liquid (ASL) was estimated by three methods.
1) The initial concentration of
99mTc-DTPA and the total amount of
99mTc-DTPA (the sum of that
entering the outside medium, that draining from the trachea, and that
washed out at the end of 40 min) gave the initial volume of ASL and
thus its thickness. Mean values were 45.7 µm for the ferret and 41.9 µm for the rabbit. 2) Estimates of
ASL thickness at the end of the 40-min period, based on the final
99mTc-DTPA concentration and the
amount in the washout, were 42.9 µm for ferret and 45.4 µm for
rabbit. 3) The ratio of P
to percent clearance gave mean ASL thickness values of 49.2 µm for
the ferret and 40.3 µm for the rabbit. Thus three separate methods
for determining ASL thickness give very similar results, with means in
the range 40-49 µm. Administration of methacholine or atropine
to ferret tracheae did not significantly change ASL thickness.
airway mucus; airway permeability; airway clearance
INTRODUCTION MEASUREMENTS of the thickness of the airway surface
liquid (ASL) in the mammalian trachea and large bronchi give very
diverse results. All studies agree that there is periciliary liquid, or sol, of a depth equal to the length of the cilia, ~5-10 µm.
This depth of liquid may be maintained by capillarity (13, 15). However, the extent to which the cilia are overlaid by a layer of mucus
secretion or gel is controversial. There has been much discussion
whether the layer of gel is absent, continuous, or divided into
plaques. Early estimates suggested that the gel layer could be 5- to
30-µm thick (11, 17). However, recent physiological measurements give
values of total ASL thickness from 33 to 100-250 µm (7-9),
whereas electron-microscopic observations indicate that the ASL above
the cilia is as thin as 0.5-2 µm (1, 16).
A recent theoretical analysis (14) has described a way of assessing the
thickness of ASL by comparing different methods of measuring uptake of
a low-molecular-weight hydrophilic tracer from the airway lumen. These
results can be expressed either as the percentage of decrease in tracer
content per minute [percent clearance (%Cl)], i.e., the
flux of tracer from the airway lumen × 100 divided by the luminal
content of the tracer, or
or
as the permeability coefficient (P; in
cm/s) for the airway mucosa
where
dQ/dt is the rate of uptake of tracer
per second, Cin is the internal concentration of tracer,
C is the
concentration difference across the airway,
S is the surface area
(in cm2) of the airway, and
T is the ASL thickness (in cm). The
two equations can be combined to give
where
%Cl is reexpressed in %/s.
It is assumed that Cin = C, which is reasonable,
because for 99mTc-labeled
diethylenetriaminepentaacetic acid (DTPA), the concentration ratio
across the mucosa in the present experiments was 1,710 for the
air-filled tracheae after 40 min and 8,988 for the liquid-filled tracheae after 15 min.
It follows that, if P and %Cl can be measured on the same preparation, which has never yet been done, their ratio should give an estimate of ASL thickness. One purpose of this study was to conduct such an experiment. If the attempt were successful, it would give values for ASL thickness which, as indicated earlier, has not been unequivocally determined.
METHODS
Protocol. The experiment was divided into two parts. In the first part, the P of the tracheal wall to 99mTc-DTPA, a hydrophilic molecule with molecular mass of 492 Da, was measured. The lumen of the trachea was filled to the level of the carinal (upper) cannula with KH containing 99mTc-DTPA. The submucosal side was filled with 17 ml KH. After 15 min, a 0.5-ml sample of submucosal KH was taken. Then the luminal KH was withdrawn, its volume was measured, and it was replaced with fresh KH containing 99mTc-DTPA. The submucosal KH was also drained and replaced with fresh KH. This procedure was repeated for an additional five 15-min periods. In the second part of the experiment, the trachea was air filled for simultaneous measurement of %Cl and the P for 99mTc-DTPA. At 90 min (immediately after completion of the first part of the experiment), the lumen was drained and was left air filled. The organ bath was washed through with 50 ml KH and then refilled with 17 ml KH. Excess liquid from the air-filled lumen was gently withdrawn into the polyethylene tubing. The drainage time was ~5 min. The timer was reset to zero, and new polyethylene tubing was inserted into the Perspex cannula. A 0.5-ml submucosal sample was taken and replaced with 0.5 ml KH. Further luminal-drainage samples were collected in polyethylene tubing and sealed with bone wax. These and the submucosal samples were collected at 5, 10, 20, and 40 min. At 40 min (after both submucosal and luminal samples had been taken), the lumen of the trachea was washed out three times with 2-ml volumes of KH to collect the 99mTc-DTPA remaining in the lumen. Control measurements were made in eight ferret tracheae and six rabbit tracheae. In further ferret experiments, either methacholine (40 µM, n = 6) or atropine (100 µM, n = 6) was added to the submucosal KH at the start of the experiment and was present in all subsequent replacements of KH. Volume of drainage liquid. The volume of drained ASL in each luminal sample from the air-filled tracheae was estimated by the difference in the weight of the tubing containing ASL and the weight of the empty dry tubing. It was assumed that 1 µl ASL weighs 1 mg. Measurement of 99mTc-DTPA. The 99mTc-DTPA content of all samples (luminal, submucosal, and drainage) was measured by using a gamma counter (Beckman Gamma 5500). Because 99mTc-DTPA has a short half-life (6 h), corrections for radioactive decay were made to all samples. Drugs. Acetyl-
-methacholine chloride and atropine sulfate were both from
Sigma Chemical (Poole, UK). The composition of the KH solution was (in
mM) 120.8 NaCl, 4.7 KCl, 1.2 KH2PO4,
1.2 MgSO4 · 7H2O, 24.9 NaHCO3, 2.4 CaCl2, and 5.6 glucose.
P of liquid-filled trachea
(Pliq).
The P
(Pliq, in cm/s)
for 99mTc-DTPA was calculated for
the first part of the experiment with liquid-filled tracheae
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1 · s1),
and C is the concentration gradient of
99mTc-DTPA from the tracheal lumen
to the submucosal solution
(counts · min1 · ml1).
S, the surface area of the isolated
trachea (in cm2), was calculated
by measuring the length (L) and
diameter (D) of the trachea after
the experiment and by using the equation S = 
· D · L.
%Cl of air-filled trachea.
%Cl of 99mTc-DTPA was calculated
from the time constant (k) of the
decay in luminal 99mTc-DTPA
content over 40 min, and k was
calculated from the equation
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Qdr,
Qw, and Qout, respectively)
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Qout).
Experimentally, Qin 40 = Qw, but this value cannot be
used to determine the exponential loss of luminal
99mTc-DTPA into the external
medium or to calculate %Cl, because some of the
99mTc-DTPA is lost into the
drainage samples. However, correction for this loss can be made. The
percentage loss into the drainage over 40 min is the content of
99mTc-DTPA in the drainage samples
(Qdr) divided by the original luminal content of 99mTc-DTPA
(Qin 0) × 100. If
this loss had not taken place, the luminal content of
99mTc-DTPA and its output to the
external medium would have been proportionately higher. The value of
the external output of 99mTc-DTPA
(Qout) at the
end of the 40-min test period was therefore increased by the percent
loss of original luminal contents due to drainage, and
k,
t0.5, and %Cl
were calculated on this basis. Thus the value of
Qin 40 applied in the
exponential equation is a notional and corrected one.
After this correction, k is calculated
and converted to the half-time of decay of
99mTc-DTPA
(t0.5) by the
equation
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This
is the ratio of the output of
99mTc-DTPA into the external
medium over 40 min, divided by the integral over the same time of the
concentration of 99mTc-DTPA
(
dC/dt) in the lumen × S. The integral
was derived from the initial concentration of
99mTc-DTPA in the lumen, the same
as the luminal concentration when the liquid-filled trachea was
drained, and the luminal concentration at the end of the 40-min period.
The latter was obtained from the total
99mTc-DTPA in the final washouts,
assuming that ASL thickness was the same at the beginning and at the
end of the 40 min. It was also assumed that the decay in luminal
concentration was exponential.
ASL thickness of air-filled tracheae.
ASL thickness was estimated in three different ways.
1) Immediately after the trachea had
been drained, ASL thickness
(T0) was
calculated based on the assumption that the initial amount of tracer in
the lumen must equal the sum of the outputs of tracer into the external
medium, into drainage from the trachea, and into the final washout.
Therefore
|
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Qout,
Qdr, and
Qw are the total outputs over
40 min of the tracer into the external liquid, drainage, and final washout, respectively. Cin 0
was taken as the concentration of 99mTc-DTPA in the KH used
previously to fill the trachea. 2)
In 13 of the 30 experiments, enough ASL (>2.0 µl) was present in
the drainage sample collected at the end of 40 min to allow accurate measurement of 99mTc-DTPA
concentration (Cin 40).
This allowed calculations of ASL thickness at 40 min
(T40), based on
the assumption that the total 99mTc-DTPA in the ASL at that time
was the same as the 99mTc-DTPA
washed out. Thus
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RESULTS
5.35 × 107
cm/s for the ferret and 3.74 × 107 cm/s for the rabbit.
For the ferret, the corresponding values for methacholine and atropine
were 2.18 × 107 and 2.65 × 107 cm/s, respectively,
significantly smaller than for the controls.
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, Ferret controls; 
,
ferret methacholine; 
, ferret atropine; 
, rabbit. Line, line of
identity.
Table 2 gives the values of Tcalc derived from the Pliq and %Cl values in Table 1. The only significant difference was for methacholine-treated tracheae compared with controls.
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Table 2 includes values of the total volume (V) of ASL drained from the tracheae over the 40 min when they were air-filled (
Vdr). Methacholine increased
ASL drainage more than threefold, whereas atropine caused an
insignificantly smaller output compared with control. The output in the
rabbit was not significantly different from zero.
Table 1 also includes the means of estimated surface areas of the
tracheae and the calculated volumes of ASL at time
0 (V0), i.e.,
V0 = T0 · S.
There were no significant differences between the
V0 values for the groups, which is
to be expected since the values of
T0 and
S were similar.
DISCUSSION
The primary purposes of this research were 1) to determine values for ASL thickness (T0, T40) in ferret and rabbit tracheae and 2) to see whether determination of P and %Cl separately but simultaneously in the same preparation gave acceptable values for thickness based on the theoretical analysis (Tcalc; Ref. 14). The results for Tcalc, 49.2 µm for ferret controls and 40.3 µm for rabbits, were reasonably similar to those obtained by using the same method to calculate thickness from previous studies for the rabbit (46.0 µm) and for other species (14). It is clearly important that histological studies should be done to see whether, in the same preparation, morphological values for ASL thickness correspond to the physiological ones described in this paper.
P values
(Pliq) for
99mTc-DTPA (5.35 × 107 and 3.74 × 107 cm/s for ferret
controls and rabbit, respectively) were also similar to published
values [4.70 × 107 cm/s for ferret
tracheae (2) and 5.10 × 107 cm/s for sucrose in the
rabbit trachea (10)]. There seem to be no published values of
%Cl for 99mTc-DTPA for the
ferret, but for the rabbit the mean of nine studies gave a value of
0.82%/min (see Ref. 14 for review) compared with 0.58%/min in the
present study. The nine prior studies were in vivo, when the presence
of a subepithelial capillary vasculature might have led to a higher
%Cl.
We chose ferrets and rabbits because they have tracheae large enough to allow accurate analyses of 99mTc-DTPA movements and because previous experiments with the same preparation had shown that the tracheae remained viable over the time course of the experiments (2, 6). We wished to compare a species with copious submucosal glands (the ferret) with one that lacked these glands (the rabbit) (6). To see whether gland secretion and its inhibition affected ASL thickness, we stimulated and inhibited secretion with methacholine and atropine, respectively.
The preparation may not represent conditions in vivo in several respects. The tracheae were vertical, not horizontal, and the laryngeal end was at the bottom. This was so that any secretion during the 40-min air-filled period could freely collect at the bottom and be removed. On initially draining, some tracheal excess KH solution might be retained in the trachea, giving a high value of ASL thickness. The fact that T0 values were close to those of T40 suggests that this was not the case. More importantly, the ASL would have a different composition from that of naturally occurring ASL with a smaller content of mucus and surface-active substances, such as surfactant. However, although the rheology of the experimental ASL might be abnormal, its surface tension properties should not appreciably affect the results. In the circumferential direction, the surface tension would exert an inward pressure of ~0.02 cmH2O, assuming a surface tension the same as that of physiological saline, and considerably less if surfactant were present. Similar forces due to surface tension would be exerted in the longitudinal direction.
The calculations are based on several assumptions.
1) It is assumed that the changes in content and concentration of 99mTc-DTPA in the air-filled trachea are exponential over the 40-min period of measurements. This assumption applies to the 99mTc-DTPA passing into the external medium, to that collected by drainage, and to that present in the airway lumen.
An exponential relationship is axiomatic for the various changes in concentration and content of 99mTc-DTPA, based on the equation
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A further consideration is that if the decay in luminal concentration and content of 99mTc-DTPA is assumed to be linear rather than exponential, the mean error introduced is only 6.6%, which would correspond to an overestimate of P values for air-filled tracheae of the same percentage. The small size of this error is because the luminal concentration of 99mTc-DTPA remained high because the mucosa has a relatively low P to 99mTc-DTPA, with a high concentration gradient across the mucosa, so that averaged linear and exponential values across the mucosa were similar.
2) The second main assumption is that ASL thickness does not change during the 40 min of the air-filled tracheae experiments. This assumption applies to the calculation of Pair but not to the calculation of other parameters. Pair is calculated from luminal 99mTc-DTPA concentrations that, for the 40-min sample, require an assumption of luminal volume and, therefore, thickness. However, the assumption seems justified by two arguments. First, when T40 was measured, values were obtained that were not significantly different from those of T0, being on average only 9% greater. Second, if thickness had varied greatly during the 40-min experimental period, this would have resulted in calculated values of Pair much different from those of Pliq. For example, if thickness had considerably decreased due to uptake of water from the air-filled lumen, this would have increased the concentration of 99mTc-DTPA and resulted in faster afflux of 99mTc-DTPA. The calculated value for P would have been appreciably larger than that calculated on the basis of unchanged thickness. In practice, the values of Pair and Pliq were similar in size (Table 1). Conversely, it seems unlikely that thickness would increase appreciably during the 40-min period, since the initial draining of the trachea would leave a thickness dependent on forces unchanged throughout the 40 min. Additions to the ASL would drain out of the trachea, as happened in all 30 experiments except for one ferret control and three rabbit preparations.
3) We have assumed that S was constant throughout the experiments and was the same for liquid and air-filled tracheae. Air in the trachea might have allowed tracheal compression by external hydrostatic forces, and changes in smooth muscle tone might have changed gross tracheal circumference. External pressure in the air-filled tracheae was small, on average ~5 cmH2O, but both ferret and rabbit tracheae have strong cartilaginous structures, and large changes in volume and gross tracheal circumference seem unlikely. In addition, the epithelium is not compressible, so that, even if gross circumference changed, epithelial surface area should not be affected appreciably.
4) We had hoped to calculate thickness from the ratio of Pair and %Cl measured simultaneously in the air-filled trachea. However, to estimate the mean concentration of 99mTc-DTPA in the ASL during the 40-min period and therefore to calculate Pair, an assumption of a value for T40 was required. Therefore, this parameter could not be used to calculate thickness. Consequently, we calculated thickness from the ratio of Pliq for the liquid-filled tracheae and %Cl for the air-filled tracheae. There is no reason to believe that putting physiological liquid in the trachea will change P, and there was no systematic difference between Pair and Pliq (Table 1, Fig. 2).
The three methods of calculating thickness gave similar results (Table 1, Fig. 3), with the largest variation seen in the experiments with methacholine, which greatly increased total ASL. When all the results were pooled, T40 was on average 9% greater and Tcalc was 13% lower than T0.
The %Cl and k values for experiments with methacholine and atropine in the ferret are lower than those for the controls without drugs, and the corresponding t0.5 values are higher. However, because the P values were also lower in the two groups of experiments with drugs, the corresponding values for thickness were similar in the three groups of experiments.
The controls were the initial experiments done in this research, since
only after their completion was it decided to see whether methacholine
or atropine changed measured and calculated variables. The lower %Cl
and Pair values
for methacholine and atropine seem unlikely to be due to direct effects
of the drugs, because they should have opposite effects on the airway
epithelium and glands. It is more likely that conditions in different
batches of ferrets varied. A previous series of experiments with the
same model gave a mean P value for
99mTc-DTPA of 4.70 cm/s (2)
similar to the control values here. The gender of animals is known to
influence %Cl (3), the variable being more than twice as high for male
compared with female rats. Hormonal, environmental, and airway
pathological conditions could explain these differences, although there
is no reason to incriminate any particular factor in the present
experiments. What the results do show is that for the different batches
of ferrets and different experimental conditions, both %Cl and
P may vary systematically, which is not surprising, and thus
lead to similar calculated values for ASL thickness.
P values for the liquid-filled
tracheae were on average 6% smaller than for the air-filled tracheae
(Table 1, Fig. 2). With air in the lumen, there will be a hydrostatic
pressure across the airway mucosa, averaging 5 cmH2O for a 10-cm-long trachea. This might open paracellular pathways for the air-filled trachea and
lead to a tendency for liquid flux into airway lumen. However, it is
unlikely that this effect would be important in relation to
P. Calculations of the liquid flux in
guinea pig tracheae exposed to external pressures of 5 cmH2O suggest that the plasma flux equivalent would be 0.0074 µl · cm2 · min1
(5), assuming a surface area of 5 cm2, which would not appreciably
affect values of ASL thickness given in this paper. For dog tracheal
epithelial sheets, a submucosal pressure of 5 cmH2O did not change the rate of
efflux of
[14C]mannitol from
lumen to submucosal side (4). The general similarity of
Pair and
Pliq values
implies that the influence of a mean 5 cmH2O hydrostatic pressure due to
external KH solution was not important in determining
P and %Cl values.
Several forces determine ASL thickness. The influence of external
hydrostatic pressure has already been discussed. For the periciliary
layer, there will be a large force of capillarity that will prevent ASL
depletion from this layer (13, 15). However, the ciliary depth is only
7-10 µm, and much of the estimated ASL thickness must reside
elsewhere, presumably in the gel layer above the cilia. A
circumferential surface tension force drawing liquid into the airway
lumen, already mentioned as being ~0.02 cmH2O or less, would be
counterbalanced by any absorptive force taking liquid from the lumen.
The influence of active ion pumping in determining the thickness of ASL
may be a factor. Water flux into the lumen associated with increased
active ion pumping across dog tracheal epithelium gave a value of 0.137 µl · cm2 · min1
(12). This would correspond to thickness change of 1.4 µm · cm2 · min1
and a total liquid output of ~50 µl over 40 min. The fact that drainage volumes were considerably less than this value, and almost nonexistent in the rabbit in the absence of submucosal glands, suggests
that liquid changes due to active ion transport may not be important in
the preparation.
Methacholine increased the volume of drainage liquid more than threefold, presumably by secretion from submucosal glands. However, there was no significant difference from controls for T0 or T40. This suggests that secreted mucus is not retained in the ASL but is carried down by gravity and ciliary action and collected as drainage. Values of ASL thickness for the rabbit, which lacks submucosal glands (6), were similar to those of ferret controls, although the volume of liquid drained was only one-fifth. Thus the resting secretion of mucus in the ferret is not an important influence on ASL thickness in this model. In the presence of a rapid flow of mucus due to methacholine, the correction made to calculate internal 99mTc-DTPA content due to loss in the drainage liquid probably becomes less accurate. It may be significant that the three calculations of ASL thickness were closest in the rabbit, which has virtually no secreted mucus (Table 2, Fig. 3).
Our results should be compared with other measurements of ASL thickness. For a guinea pig trachea in vivo and in vitro, ASL thickness has been calculated, by means of surface probing, to be as high as 100-250 µm (7, 9). For the sheep trachea in vitro, a value of 33 µm has been obtained (8). These values include the thickness of periciliary liquid. Recent electron-microscopic studies have suggested that the ASL thickness above the periciliary liquid is 2 µm or less (1, 16). In these last experiments, it is possible that the surface gel had been cleared by mucociliary transport, which would only take 1-2 min for a 1-cm2 segment of trachea, whereas our experiments may have allowed for the accumulation of liquid above the periciliary layer. The administration of methacholine to the ox trachea in vitro increased the thickness of the liquid above the cilia from 2 to 30 µm (16) but made no difference in the ASL thickness (33 µm) in sheep trachea (8), as in the present experiments. Conventional and early studies with light microscopy suggested that there is an appreciable layer of liquid above the cilia (11, 17). For the particular model we have used, our results support this conclusion. It should be emphasized that even an ASL thickness of 40-50 µm is extremely thin compared with the total luminal diameter of the trachea of the ferret, which is ~6,000-8,000 µm.
The significance of the ASL thickness in the airways has been discussed elsewhere (14). Among its other properties, it determines the rate of uptake of drugs and agents from the airway lumen into the mucosa and thus is an important variable to be determined.
ACKNOWLEDGEMENTS
S. Duneclift and U. Wells were supported by the Wellcome Trust.
FOOTNOTES
Address for reprint requests: J. G. Widdicombe, Sherrington School of Physiology, UMDS, St. Thomas's Hospital, Lambeth Palace Rd., London SE1 7EH, UK.
Received 25 June 1996; accepted in final form 13 May 1997.
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