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Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Because the availability of transgenic mice
makes it possible to examine the contribution of single genes to in
vivo function, we developed a simple in situ mouse model that can be
used to quantify isosmolar alveolar epithelial fluid clearance (AFC). Mice were killed, a tracheostomy was done, and then a test solution of
a 5% isosmolar albumin solution with 0.1 µCi of
125I-labeled albumin was instilled
via the trachea into the distal air spaces of both lungs. After
instillation, the lungs were inflated to 7 cmH2O with 100%
O2 and maintained at 37°C by
placing the animals under an infrared lamp. AFC was measured by the
progressive increase in concentration of labeled and unlabeled protein
over 1 h. The results indicated the following.
1) Basal, unstimulated AFC in mouse
lungs was significantly faster than in ex vivo rat lungs (27 ± 5%
in in situ mice vs. 11 ± 3% in ex vivo rat lungs; P < 0.05).
2) Comparison of equivalent doses
(10
4 M) of 
-adrenergic
agonist (isoproterenol) and
2-adrenergic agonists
(terbutaline and salmeterol) indicated that stimulated clearance
occurred only in presence of isoproterenol.
3) Because atenolol, a specific
1-antagonist, abolished the
effect of isoproterenol, the -adrenergic stimulation appears to be
mediated by 1-receptors. The
rate of AFC in nonperfused mouse lungs was significantly faster than in
prior studies of nonperfused lungs in rats and sheep. Interestingly,
the stimulated clearance rate in mice was similar to the fast rates of
AFC that we recently reported in patients recovering from hydrostatic
pulmonary edema. This in situ model is a unique experimental
preparation that can be readily used to quantify isosmolar epithelial
fluid clearance in mice.
alveolar epithelium; -adrenergic agonists; pulmonary edema; sodium transport
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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BECAUSE ADVANCES in molecular genetics have facilitated
the isolation of cDNA and genes, the ability to assess the role of normal and mutated genes in transgenic mice has become an important approach for the analysis of gene function in vivo. However, specific animal models are needed to test the potential function of specific gene products. Our laboratory is particularly focused on developing methods to quantify alveolar epithelial fluid transport in the intact
lung. Recently, for example, we developed a fluorescence model in
isolated, perfused mouse lungs to measure osmotic water permeability
(5). The overall goal of the present study was to develop
an in situ mouse model to study isosmolar alveolar epithelial fluid
clearance (AFC). Because prior studies from our laboratory (25, 26) and
others (9) demonstrated that the rate of short-term AFC was not
adversely affected by the absence of perfusion or ventilation to the
lung, our first objective was to develop an in situ mouse model that
would be useful for quantifying isosmolar AFC over a 1-h period. Once
the model was successfully established, the second objective was to
determine the rate of basal AFC in the mouse. The third objective was
to determine the effect of -adrenergic stimulation on AFC in mice.
The fourth objective was to compare the basal and stimulated AFC data
in the nonperfused mouse lungs with our previously published data in
clearance rates in nonperfused lungs of sheep and rats as well as with
our recent data on clearance rates from patients during the resolution
of hydrostatic pulmonary edema.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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For all experiments, male c57 mice (Benton-Kingman, Fremont, CA) weighing 20-25 g were used. The mice were housed in air-filtered, temperature-controlled units with food and water. All of the procedures conformed to the guidelines of the University of California-San Francisco Committee on Animal Research.
Experimental Preparation
Mice were killed with an overdose of pentobarbital sodium (150 mg/kg ip). Within 2 min of death, the trachea was transected and cannulated with a 20-gauge trimmed Angiocath plastic needle (Becton Dickinson, Sandy, UT). The mice were maintained in a decubitus position throughout the experiment. Continuous positive airway pressure (CPAP) with 7 cmH2O with 100% O2 was delivered for the duration of the 1-h experiment, as has been done previously (25). This was done to avoid airway and alveolar collapse, to maintain a homogeneous instillate distribution, and to ensure adequate tissue oxygenation. Body temperature was maintained at 37-38°C with a thermostatically controlled pad. A temperature probe (Yellow Springs Instrument, Yellow Springs, OH) that was used to monitor core temperature throughout the experiment was inserted via a 0.5-cm incision into the abdominal cavity. In preliminary experiments, we found that additional thermal regulation could be achieved with an infrared lamp (Fisher, Santa Clara, CA) placed ~30 cm above the body. The lamp was cycled on and off to maintain the core temperature at 37-38°C.Preparation of Instillate
The instillate consisted of 5% BSA (Sigma Chemical, St. Louis, MO) with Ringer lactate, as previously published (10, 14, 23). We added 0.1 µCi of 125I-labeled albumin (Merck-Frosst, Montreal, PQ, Canada) to the instillate as an alveolar protein tracer. Amiloride, terbutaline, atenolol (Sigma Chemical), benzamil (Research Biochemicals International, Natick, MA), propranolol (SoloPak; SoloPak Laboratories, Elk Grove Village, IL), salmeterol (gift from Glaxo, Hertfordshire, UK), and isoproterenol (Sanofi Winthrop Pharmaceuticals, New York, NY) were added to the instillate in selected studies, as described in the specific protocol.General Protocol
For all studies, the following protocol was used. After we established the tracheostomy and inserted the temperature probe, the instillate (20 ml/kg; 0.51 ± 0.02 ml of an isosmolar 5% albumin Ringer lactate solution with 125I-labeled albumin) was delivered over 30 s into both lungs through the tracheal cannula. At the end of the experiment, 1 h after beginning the instillation, the lungs were removed through a median sternotomy. An alveolar fluid sample (0.1-0.2 ml) was aspirated with a small catheter (PE-10) and was centrifuged at 3,000 g for 10 min. The supernatant of the fluid was obtained for measurement of the total protein concentration and radioactivity. We reported in a prior study (3) that the concentration of the protein tracers in the liquid sampled by a small catheter wedged into the distal airways was the same as the concentration in an alveolar micropuncture sample.In preliminary studies, we determined that 0.5 ml was the optimal volume for the instillate, on the basis of the feasibility of recovering an adequate fluid volume for protein and radioactivity measurements after 1 h. Additional studies, using 0.3 or 0.4 ml as the instillate, were included for comparison with the 0.5-ml instillate group for basal clearance to determine whether the larger volume of instillate affected the rate of clearance.
Specific Protocol
Group 1: control studies (n = 6). We instilled 0.51 ± 0.02 ml of 5% albumin solution in Ringer lactate, with the protein tracer 125I-labeled albumin, into both lungs. Also, to be certain that the high rate of basal clearance was not simply a function of the 0.5 ml instilled volume, five additional mice were studied with lower instilled volumes (0.3 and 0.4 ml).
Group 2: effect of amiloride (103
M, n = 6) and benzamil (103 M, n = 5)
on AFC.
The effect of amiloride on alveolar fluid transport has been studied by
our laboratory (10, 14, 23) and by other investigators (1, 2,
6-8). The dose of 103
M amiloride was used in this study, because our objective was to have
an effective amiloride concentration of
104 M in the air spaces.
According to prior studies of amiloride-concentration measurements in
the air spaces of rabbit lung, amiloride declines by ~10-fold over 2 h (21). Therefore, the effective concentration over 1 h would be 2 × 104 M. Also,
because our instilled alveolar solution contained 5% albumin, we
empirically determined that another 50% reduction in functional
amiloride concentration (to
104 M) is caused by
nonspecific binding to albumin (11). Approximately 40-50% of
basal AFC in rats is inhibited by
103 M amiloride (10, 14).
Because amiloride at 104 M
may inhibit the
Na+-H+-antiporter
and the
Na+-K+-ATPase,
an additional set of experiments was carried out by using 103 M benzamil, a
Na+ channel blocker. These
experiments were performed only to eliminate the confounding effects of
nonspecific binding to albumin in Ringer's lactate solution.
Group 3: effect of propranolol on AFC
(n = 5).
Propranolol (104 M) was
added to the instillate to determine whether the high rate of basal AFC
in mice was mediated by stimulation of -Adrenergic receptors by
endogenous catecholamine release.
Group 4: terbutaline (n = 4) and
salmeterol studies (n = 5).
-adrenergic agonist therapy stimulates AFC in several species. We
used two 2-adrenergic receptor
agonists with markedly different potencies [apparent dissociation
constant = 50 nM for salmeterol and 5,500 nM for terbutaline
(16)] to determine whether 2-receptor stimulation
increases the rate of AFC. Terbutaline (104 M) or salmeterol
(104 M) was added to the
5% albumin instillate solution.
Group 5: isoproterenol studies (n = 4).
To determine the effect of isoproterenol
(1- and
2-adrenergic agonist) on AFC,
104 M isoproterenol was
added to the instillate.
Group 6: isoproterenol plus atenolol studies
(n = 4).
To determine whether the effect of isoproterenol was mediated by a
1-adrenergic receptor, we added
104 M of atenolol, a
1-adrenergic antagonist, to the
albumin solution with 104 M
isoproterenol.
Measurement of AFC
As in our previous studies (10, 14, 23), AFC was calculated by measuring the increase in albumin (either labeled or nonlabeled) concentration of the instilled albumin solution. AFC was calculated as AFC = (Vi × Fwi
Vf × Fwf) / (Vi × Fwi) × 100.
Fw is the water fraction of the initial (i) and the final (f ) alveolar fluid. The Fw is the volume of water per volume of solution measured by the gravimetric method. Vi is the volume of the initial alveolar fluid, and Vf, of the final. Vf (in ml) was estimated as Vf = (Vi × TPi × Fr) / TPf, where TP is the total protein concentration of the initial and final alveolar fluid. Fr is the fraction of alveolar tracer (125I-albumin) protein that remains in the lung at the end of the experiment.
Protein concentration was determined by the Biuret method with the use of spectrophotometry. The concentration of 125I-albumin was measured by gamma counting.
Measurement of Alveolar Barrier Integrity
As an index of alveolar barrier integrity, we used the residual 125I-albumin in the lung at the end of the experiment (10, 14, 22). In each experiment, >97% of the total radioactivity that was instilled at the beginning of the experiment was recovered from the final aspirate, lungs, and tracheal cannula. This indicates that the alveolar epithelial barrier remained largely intact even in the presence of 7 cmH2O CPAP.Statistical Analysis
The data are summarized as means ± SD. The one-way analysis of variance and Fisher's exact test were used to compare the different animal groups. We regarded a P value of <0.05 as statistically significant.| |
RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Basal AFC: Effect of Amiloride (103
M), Benzamil (103 M), and Propranolol
(104 M) on Basal Clearance
3 M benzamil,
AFC was significantly reduced by 30% over 1 h (final-to-instilled alveolar protein-tracer concentration ratio of 1.23 ± 0.03 in controls vs. 1.16 ± 0.03 with benzamil;
P < 0.05). In contrast, propranolol had no effect on basal AFC (final-to-instilled protein concentration ratio of 1.29 ± 0.03 with propranolol compared with 1.27 ± 0.05 in controls), indicating that there was no adrenergic stimulation in the basal condition.
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Basal unstimulated AFC in mice was 145% higher than the basal rate reported in ex vivo rat lungs over 1 h (25) and was much higher than the basal rate reported in nonperfused sheep lungs over 1 h (26) (Table 1). To be certain that the fast rate of clearance in mice was not a function of the larger instilled volume, additional studies were done in five mice with instillate volumes that were 20 or 40% smaller (0.4 or 0.3 ml, respectively). The final-to-instilled concentration ratios of alveolar protein tracer (125I-albumin) were similar with either 0.4 or 0.3 ml as the instillate volume. The combined data from these studies showed a final-to-instilled alveolar protein tracer-concentration ratio of 1.32 ± 0.05 compared with 1.23 ± 0.03 for the main experiments with the use of 0.5 ml as the instillate. Thus, AFC had a tendency to be slightly faster in the lower instillate volumes (34 ± 4%, as reflected by the rise in the alveolar protein tracer concentration), but the difference did not reach statistical significance.
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Stimulated AFC: Effect of Terbutaline
(104 M), Salmeterol
(104 M), and Isoproterenol
(104 M)
2-adrenergic agonist which has
100 times the receptor affinity of terbutaline (16), to the instilled
albumin solution did not increase AFC (final-to-instilled protein
concentration ratio of 1.22 ± 0.02 in the presence of terbutaline
and 1.21 ± 0.06 in the presence of salmeterol, compared with 1.23 ± 0.03 in the control studies). Thus, two independent
2-adrenergic agonists with
markedly different potencies did not stimulate AFC above the basal
rate. In contrast, isoproterenol markedly increased AFC (Figs. 1 and 2). This finding stimulated subsequent
studies to determine whether the effect of isoproterenol was mediated
by the 1-adrenergic receptor.
Atenolol (104 M) inhibited
the isoproterenol-induced increase in AFC (Fig. 2).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The continued development of transgenic mouse models requires new methods to evaluate lung function in newly expressed phenotypes. In particular, the ability of the air spaces to remain dry is necessary for effective gas exchange, a critical function that could be altered in transgenic mice (12).
The first objective was to develop a practical in situ mouse model that could be used by other investigators to study isosmolar AFC in the mouse lungs. It was possible to achieve this objective by adapting methods for the in situ mouse lung based on our prior experiments in other species (15, 26, 29), including human lungs (25).
The second objective of these experiments in this new model was to
characterize the isosmolar fluid transport properties of the alveolar
epithelium in mice. The ability to transport fluid out of the air
spaces was studied under basal conditions in the presence of amiloride
or propranolol, as well as with -adrenergic stimulation. AFC was
measured by the progressive increase in the protein concentration of a
5% albumin solution instilled into the distal air spaces of the lungs.
This method has proven to be reliable under normal (14) and even under
pathological conditions (10, 22, 23). Interestingly, basal AFC was
faster in the in situ mouse lungs than the basal rates reported in
several other species. In the in situ mouse lungs, basal AFC was 27 ± 5% of instilled fluid for 1 h. Protein concentration increased
from 5.1 ± 0.5 g/dl in the initial alveolar fluid to 6.4 ± 0.5 g/dl in final alveolar fluid (P < 0.05). In similar nonperfused preparations, the rate of clearance was
11 ± 3% of instilled fluid over 1 h in rats (25) and 24 ± 8% over 4 h in sheep (26).
Several potential mechanisms could explain the high basal clearance
rate in mice. First, an endogenous release of catecholamines accompanying the systemic hypotension from the barbituate overdose at
the time of death might increase AFC. Catecholamines are known to
stimulate AFC through the activation of both amiloride-sensitive Na+ channels (17, 18, 22) and the
Na+-K+-ATPase
in alveolar type II cells (30). Catecholamine stimulation operates via
-adrenergic stimulation, resulting in increased intracellular cAMP
levels leading to phosphorylation and activation of vectorial
Na+ transport (27). To test this
possibility, propranolol was administered with the 5% albumin solution
into the air spaces of the lungs. As we reported in other species (4,
14), propranolol had no effect on basal AFC.
A second explanation for the high basal clearance rate observed in mice could be the large volume of alveolar instillate relative to the body weight. Previous investigators have used different relative instillate volumes ranging from 1.5 to 17.0 ml/kg body weight (1, 19). In the present study, we used an instilled volume of 20 ml/kg body weight, because the larger instilled volume facilitated sampling of alveolar fluid at the end of the 1-h experiment. It seemed possible that the high basal rate of clearance we observed in mice compared with other species could be caused by the larger relative instillate volume that we used. To test this possibility, we carried out additional experiments, using different degrees of fluid filling of the lung (12 and 16 ml/kg body weight). Interestingly, not only was the larger relative instillate volume not responsible for the high basal rate observed in mice, it actually may have decreased the basal rate of clearance, because the rate was slightly faster with the lower instillate volumes. However, from a practical perspective, the 0.5-ml volume may be best for carrying out 1-h AFC experiments, because this volume allows for retrieval of a large enough air space sample to measure two independent markers of clearance (125I-albumin and total protein).
Finally, the nature of the nonperfused model itself could influence the basal rate of clearance. This was not the case in other larger animal models in which both perfused and nonperfused experiments have been carried out (15, 26). However, it cannot be ruled out in mice until a suitable in vivo model is developed that allows for adequate sampling of air space solutions at the end of 60-min experiments. Recent preliminary evidence from Icard et al. (13) indicates similar rates of clearance between the nonperfused mouse model in this study and their experiments with isolated, perfused mice lungs. Also, they reported that mice remove alveolar fluid twice as rapidly as rats normalized for the same quantity of lung tissue.
A novel observation in the present study is the finding that
1- and not
2-adrenergic stimulation
increased AFC. This finding was elucidated pharmacologically through
the use of a general -adrenergic agonist (isoproterenol), specific
2-adrenergic agonists (terbutaline and salmeterol), and a specific
1-antagonist (atenolol). This
observation is distinctly different from observations in rats (17, 31)
but similar to results that have been reported recently in guinea pigs
(20). The significance of this strain and/or
species specificity is not yet clear, although the data for guinea pigs
indicate that cAMP signaling in some species may be greater with
1- rather than
2-stimulation. The magnitude of
stimulation with isoproterenol was modest (40% over basal levels), perhaps partly because basal clearance is already high in mice.
To confirm that AFC is driven by active Na+ transport, amiloride or benzamil was used to inhibit Na+ uptake (and subsequent transepithelial transport) by alveolar type II cells. The inhibitory pattern observed is similar to what has been reported by others with respect to alveolar fluid and Na+ clearance (1, 2, 5, 7, 8, 10, 14). However, it is possible that factors such as changes in surface area could have accounted for some of the observed differences, although this effect would most likely be minor.
Benzamil or amiloride inhibited ~30-35% of basal AFC, slightly
less than percentages obtained in studies of rat lungs (1, 2, 5, 7, 8,
10, 14). This means that >50% of
Na+ reabsorption is amiloride
insensitive. The pathway for the amiloride-insensitive fraction of
transport has remained elusive. Recently, in situ hybridization of mRNA
encoding for nucleotide-gated cation channels was reported in alveolar
type I cells (28). If type I cells also participate in transepithelial
Na+ transport by means of
nucleotide-gated cation channels, these channels may contribute to
Na+ balance in the terminal parts
of the lungs. There are also new data that the
2-isoform of
Na+-K+-ATPase
is expressed in alveolar type I-like cells; these data raise the
possibility that these cells may participate in vectorial Na+ transport (24).
In summary, AFC can be quantified in an in situ mouse model over 1 h.
The basal clearance rates in mice are faster than those reported in
similar in situ experimental models in sheep and rats. Also, the
1-adrenergic receptor appears
to be responsible for a modest upregulation of AFC in mice. The fast
basal and stimulated rates are similar to the maximal AFC rates that
were recently reported in patients during the resolution of pulmonary
hydrostatic edema (32). This new murine model will be useful to
investigators in the field of alveolar epithelial fluid transport.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grant RO1-HL-51854. E. P. Carter was supported by a fellowship from the American Lung Association.
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FOOTNOTES |
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Address for reprint requests: M. A. Matthay, Cardiovascular Research Institute, Univ. of California San Francisco, Box 0130, San Francisco, CA 94143-0130 (E-mail: mmatt{at}itsa.ucsf.edu).
Received 14 August 1997; accepted in final form 9 January 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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