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J Appl Physiol 93: 1875-1880, 2002. First published August 2, 2002; doi:10.1152/japplphysiol.00275.2002
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Vol. 93, Issue 5, 1875-1880, November 2002

HIGHLIGHTED TOPICS
Lung Edema Clearance: 20 Years of Progress
Selected Contribution: Long-term effects of beta 2-adrenergic receptor stimulation on alveolar fluid clearance in mice

C. Sartori1,2, X. Fang1, D. W. McGraw3, P. Koch4, M. E. Snider4, H. G. Folkesson5, and M. A. Matthay1

1 Cardiovascular Research Institute, University of California, San Francisco, California 94143-0130; 2 Botnar Center of Clinical Research, CHUV, Lausanne, 1011 Switzerland; 3 Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0564; 4 Sepracor, Marlborough, Massachusetts 01752; and 5 Department of Physiology, Northeastern Ohio University College of Medicine, Rootstown, Ohio 44272-0095


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Stimulation of active fluid transport with beta -adrenergic receptor (beta AR) agonists can accelerate the resolution of alveolar edema. However, chronic beta AR-agonist administration may cause beta AR desensitization and downregulation that may impair physiological responsiveness to beta AR-agonist stimulation. Therefore, we measured baseline and terbutaline- (10-3 M) stimulated alveolar fluid clearance in mice that received subcutaneously (miniosmotic pumps) either saline or albuterol (2 mg · kg-1 · day-1) for 1, 3, or 6 days. Continuous albuterol administration increased plasma albuterol levels (10-5 M), an effect that was associated with 1) a significant decrease in beta AR density and 2) attenuation, but not ablation, of maximal terbutaline-induced cAMP production. Forskolin-mediated cAMP-release was unaffected. Continuous albuterol infusion stimulated alveolar fluid clearance on day 1 but did not increase alveolar fluid clearance on days 3 and 6. However, terbutaline-stimulated alveolar fluid clearance in albuterol-treated mice was not reduced compared with saline-treated mice. Despite significant reductions in beta AR density and agonist-mediated cAMP production by long-term beta AR-agonist exposure, maximal beta AR-agonist-mediated increase in alveolar fluid clearance is not diminished in mice.

pulmonary edema; acute lung injury; lung fluid balance; alveolar epithelium


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

PULMONARY EDEMA IS a life-threatening condition resulting from an imbalance between forces driving fluid into the air spaces and active transport mechanisms that remove edema fluid from the air spaces and interstitium of the lung. There is now strong evidence that vectorial sodium and chloride transport across the alveolar epithelium play important roles in creating the osmotic gradient that leads to water reabsorption in both the perinatal lung (13, 21, 34) and the adult lung (26, 36, 39).

Several studies have demonstrated that endogenous and exogenous beta -adrenergic receptor (beta AR) agonists (in particular but not exclusively beta 2AR-selective agonists) can markedly increase transepithelial sodium transport in vitro (26, 30) and upregulate alveolar fluid clearance both ex vivo in human lung (37) and in vivo when given acutely to animals (5, 16, 33). Consistent with these responses, both beta 1ARs and beta 2ARs have been detected on the alveolar epithelium (7). The stimulatory effect of beta AR agonists on ion and water transport is, at least partly, mediated by cAMP-dependent mechanisms (18), is partly inhibited by amiloride (5, 13, 17, 25, 26, 33, 34), and is not related to changes in the pulmonary blood flow that are simultaneously induced by these beta AR agonists (5).

Recent observations (2, 14, 38) have suggested that beta AR stimulation of alveolar fluid clearance may be of potential use for the treatment and prevention of pulmonary edema. Subacute or chronic beta AR agonist administration may however, lead to downregulation of beta ARs, as has earlier been shown in the airways (4). Few data are available that evaluate long-term effects of beta AR agonist administration on the capacity of the alveolar epithelium to respond to beta AR agonist stimulation, nor that assess whether downregulation of beta ARs would prevent or attenuate the beta -adrenergically mediated increases in alveolar fluid clearance (8, 31). Recent findings in rats demonstrated that desensitization of the alveolar fluid clearance response does not occur after 4 h of continuous epinephrine exposure (8), whereas isoproterenol when given over 48 h resulted in a downregulation of the alveolar epithelial beta ARs and an impaired response to additional air space beta AR stimulation (31).

To determine whether a similar phenomenon was present after a more prolonged exposure to systemic beta AR agonists and whether this functional impairment may be counterbalanced by a high dose of acute intra-alveolar administration of beta 2AR agonists, we measured total lung adrenergic-induced release of cAMP and beta AR density and compared both baseline and terbutaline-stimulated alveolar fluid clearance in ex vivo mice that received either saline or albuterol by continuous subcutaneous administration for 1, 3, or 6 days.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Male CD-1 mice weighing 25-35 g were used for all experiments. The mice were housed in air-filtered, temperature-controlled units (20 ± 2°C) and had food and water ad libitum. All procedures were approved by the University of California, San Francisco committee on animal research.

Albuterol Plasma Concentration Measurements

Plasma albuterol levels were measured by high-performance liquid chromatography. Albuterol levels reported in this study are the sum of the R- and S-enantiomer levels (15) and were measured by a technician blinded to the experimental condition at Sepracor (Marlborough, MA).

Lung cAMP Measurements

As previously described (33), duplicate samples of distal lung tissue (25-30 mg) were washed in ice-cold 0.9% NaCl with 1 mM isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor; Sigma Chemical, St. Louis, MO), then incubated in 0.25 ml of 5 mM Tris (Merck, Darmstadt, Germany) in 0.9% NaCl (pH 7.4), 1 mM IBMX, 0.1 mM ascorbic acid (Merck), and 0.1 mM HCl (Merck). Baseline cAMP content was determined after incubation of the sample at 4°C for 10 min, and baseline cAMP production was studied after 10 min of incubation at 37°C. Stimulation of cAMP generation was studied after the addition of either terbutaline (10-3 M, Sigma Chemical) or forskolin (10-4 M; Sigma Chemical) and incubation of the samples for 10 min at 37°C. All reactions were stopped with 0.25 ml of 10% trichloroacetic acid (Sigma Chemical). The samples were homogenized and centrifuged (4,000 g, 15 min at 4°C). The supernatants were extracted with ether (5:1) three consecutive times to remove the trichloroacetic acid. The remaining ether was evaporated in a 70°C water bath for 30 min. The samples were stored at -70°C until analysis. The cAMP content was determined with a radioimmunoassay (NEN-DuPont, Boston, MA). The cAMP content was normalized to milligrams of lung tissue, and the results were expressed as cAMP per milligram of lung tissue as previously done (33).

beta 2-Adrenoceptor Density

Lung membranes were prepared from mice by homogenizing the left lung in 10 ml of hypotonic lysis buffer (5 mM Tris, pH 7.4, 2 mM EDTA) containing the protease inhibitors leupeptin, aprotinin, benzamide, and soybean trypsin inhibitor (10 µg/ml each). The homogenate was centrifuged at 40,000 g for 10 min at 4°C. The supernatant was removed, and the pellets containing crude membrane particulates were resuspended in assay buffer (75 mM Tris, pH 7.4, 12.5 mM MgCl2, 2 mM EDTA). beta AR expression was determined by radioligand binding with [125I]iodocyanopindolol (ICYP, a nonselective beta AR antagonist), as described previously (28, 29).

Alveolar Fluid Clearance Measurements

Preparation of instillate. The instillate consisted of 5 g/100 ml bovine serum albumin (Sigma Chemical) in Ringer lactate adjusted to 330 mosmol/kgH2O with NaCl to be isosmolar with mouse plasma and 0.1 µCi of 131I-labeled albumin (Merck-Frosst, Montreal, Canada) as the labeled alveolar protein tracer (6). For measurements of stimulated alveolar fluid clearance, terbutaline (10-3 M, Sigma Chemical) was added to the instillate.

Surgical preparation. The mice were euthanized by an overdose of pentobarbital sodium (200 mg/kg ip). The trachea was dissected and cannulated with a 20-gauge, trimmed Angiocath plastic needle (Becton Dickinson, Sandy, UT). The lungs were kept inflated with 5 cmH2O continuous positive airway pressure and oxygenated with 100% oxygen throughout the experiment. The body temperature was maintained at 37-38°C, as done earlier (16).

General protocol. In all studies, 13 ml/kg of the instillate was delivered over 30 s into both lungs through the tracheal cannula. After 30 min, an alveolar fluid sample (0.05-0.10 ml) was aspirated with a 1-ml syringe directly connected to the 20-gauge Angiocath. The aspirate was weighed, and the radioactivity was measured in a gamma counter. Alveolar fluid clearance (% of instilled fluid volume) was calculated by measuring the increase in tracer-labeled albumin (131I-labeled albumin) concentration in the instilled solution. Because the initial volume of the instilled solution and the initial and final radioactivity of the samples were known, alveolar fluid clearance (AFC) could be determined by using the following mass-balance equation
AFC = (1 − radioactivity in the instilled sample/

radioactivity in the final sample) × 100
where AFC is expressed in percent of the initial volume of instillate that was cleared from the distal air spaces during the 30 min (8, 16).

Specific Protocols

Baseline and terbutaline-stimulated alveolar fluid clearance were determined in mice receiving either continuous albuterol administration (2 mg · kg-1 · day-1) or normal saline for 24 h (group 1: alveolar fluid clearance at day 1) via a miniosmotic pump (Alzet model 2001, Alzo, Palo Alto, CA) implanted subcutaneously after a rapid anesthesia with ketamine/xylazine (12). Similarly, baseline and terbutaline-stimulated alveolar fluid clearance were measured in mice that received either albuterol or normal saline for 72 h (group 2: alveolar fluid clearance at day 3) and 150 h (group 3: alveolar fluid clearance at day 6).

Statistical Analysis

The data are summarized as means ± SD. ANOVA and paired and unpaired t-tests were used for comparisons as appropriate. We regarded as significant differences with a P value of <0.05.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Albuterol Plasma Concentration

Continuous subcutaneous albuterol administration (2 mg · kg-1 · day-1) for 1, 3, and 6 days by an osmotic minipump provided a steady-state plasma albuterol concentration of ~11 ng/ml (or 10-5 M) on day 1 that persisted through day 6 (Fig. 1). Albuterol was not detected in control mice receiving continuous administration of normal saline.


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  		Fig. 1.   Albuterol plasma concentration in mice receiving a continuous subcutaneous albuterol administration (2 mg · kg-1 · day-1) or saline for 1, 3, and 6 days; n = 5 for each albuterol group, n = 3 for the saline group. There was no detectable albuterol in the plasma of mice receiving saline.

Total Lung cAMP Measurements and beta AR Density

Basal cAMP production in lung slices from mice that received systemic albuterol for 1, 3, or 6 days were not significantly different from that of the saline-treated control mice. Addition of terbutaline to the saline-treated lungs caused an approximately threefold increase (P < 0.05) in cAMP release (Fig. 2). Terbutaline also caused a significant increase in cAMP production in each of the albuterol treatment groups (days 1, 3, and 6). However, terbutaline-stimulated cAMP production in each of the albuterol-treated groups was ~40-50% lower than the agonist-stimulated levels achieved in the saline control groups (Fig. 2). In contrast, cAMP levels stimulated by forskolin (a direct activator of the adenylyl cyclase) were not different in the saline- and albuterol-treated mice (Fig. 2), indicating that systemic albuterol administration had no significant effect on beta AR-independent cAMP production.


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  		Fig. 2.   Baseline (open bars), terbutaline-stimulated (black bars), and forskolin-stimulated (shaded bars) cAMP release in total lung tissue of mice receiving either saline or albuterol for 1, 3, and 6 days. Values are means + SE. *P < 0.05 vs. saline. Values in controls at different time points were similar and therefore were pooled; n = 18 for controls, n = 6 for each albuterol group.

The attenuation of terbutaline-stimulated cAMP production in the albuterol treatment groups suggested the possibility that chronic beta AR agonist therapy was contributing to desensitization of the signal transduction pathway. Because downregulation (i.e., a decrease in receptor number) is one mechanism that may underlie such desensitization and has been observed for beta ARs in the lung, we compared beta AR density in whole lung homogenates from the saline- and albuterol-treated mice by radioligand binding with the nonselective beta AR antagonist 125ICYP. beta AR density in lungs from animals treated with albuterol for 1 and 3 days was decreased by ~25% (P <=  0.05) compared with saline treated-control mice and was decreased by ~50% in lungs from mice treated for 6 days (Fig. 3).


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  		Fig. 3.   beta 2-Adrenergic receptor number in total lung tissue of mice receiving either saline or albuterol for 1, 3, and 6 days. Bmax, maximal beta -adrenergic receptor number. *P < 0.05 vs. saline; n = 3 for each group.

Alveolar Fluid Clearance

We and others have previously shown that endogenous and exogenous beta AR-agonists significantly increase in vivo alveolar fluid clearance, suggesting that beta AR activation may serve a protective function in the setting of pulmonary edema. Whether this effect on alveolar fluid clearance wanes in the presence of chronic beta AR agonist exposure (i.e., tachyphylaxis), however, is unclear. We therefore measured alveolar fluid clearance in saline-treated mice and compared them to those in mice treated continuously with albuterol for up to 6 days. For each treatment group, alveolar fluid clearance was determined in the absence (basal alveolar fluid clearance) or presence of intra-alveolar terbutaline (stimulated alveolar fluid clearance). Compared with saline-treated controls, there was a small but significant increase in alveolar fluid clearance in mice treated with systemic albuterol for 1 day. However, basal alveolar fluid clearance rates in mice treated with albuterol for 3 and 6 days were not different from their respective controls (Fig. 4A).


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  		Fig. 4.   Basal (A) and terbutaline-stimulated (B) alveolar fluid clearance in mice under continuous saline (baseline; open bars) or albuterol (filled bars) administration for 1, 3, and 6 days. Intra-alveolar terbutaline administration significantly stimulated (P < 0.05) alveolar fluid clearance in all groups of mice compared with corresponding groups studied under baseline conditions (B vs. A). *P < 0.05 vs. saline; at least 6 mice for each group.

To determine whether the maximal response of alveolar fluid clearance stimulation by beta AR agonists was diminished, we added terbutaline directly to the alveolar instillate. Compared with the respective basal alveolar fluid clearance for each group, addition of terbutaline significantly increased alveolar fluid clearance in saline controls as well as the 1-, 3-, and 6-day albuterol treatment groups (P < 0.05 for all; Fig. 4, B vs. A). Thus, despite the reductions in beta AR number and agonist-stimulated cAMP production associated with chronic albuterol treatment, the magnitude of terbutaline-stimulated alveolar fluid clearance was not affected (Fig. 4B). Interestingly, there was even an apparent additive effect of albuterol and terbutaline in stimulating alveolar fluid clearance on days 1 and 3.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Although continuous albuterol administration induced a significant downregulation of the beta ARs in the lung and attenuated the terbutaline-induced release of cAMP, the sustained albuterol treatment over 6 days did not diminish the acute intra-alveolar beta AR agonist-mediated stimulation of alveolar fluid clearance. These findings represent new information that may have clinical as well as physiological relevance.

Continuous release of albuterol subcutaneously with a miniosmotic pump resulted in a sustained high plasma albuterol concentration throughout the entire experimental period. We thought it was important to directly measure albuterol plasma levels to ensure that the levels obtained were adequate to model the clinical setting, where critically ill patients may have elevated levels of endogenous catecholamines or receive high levels of systemic beta AR agonists.

Chronic albuterol administration resulted in downregulation of lung beta ARs, as demonstrated by a decrease in receptor number and attenuation of agonist-promoted cAMP release. To ensure that the effect of lung cAMP was due to beta AR stimulation, we added forskolin, a direct activator of the adenylyl cyclase. Forskolin generated similar concentrations of cAMP in all experimental groups, indicating that the receptor-signaling defect occurred upstream of the adenylyl cyclase.

Both beta 1AR and beta 2AR subtypes are present in the lung, whereas, to the best of our knowledge, no data exist that demonstrate presence of the beta 3AR subtype in the lung. ICYP is a nonselective beta AR antagonist that recognizes both subtypes and thus measures total beta AR density. However, the ratio of beta 1AR to beta 2ARs in mouse lung parenchyma (i.e., peripheral lung) is 28:72 in favor of the beta 2AR (20). Moreover, the majority of cells in peripheral lung are those of the alveolar wall where the receptor ratio is 18:82 in favor of the beta 2AR. Therefore, any change in total beta AR density in the peripheral mouse lung is most likely to represent changes in the beta 2AR subtype.

The decline in beta AR number that we observed with chronic beta -agonist administration is consistent with previously published data in other experimental studies (24, 32). In particular, a similar exposure to albuterol in rats was associated with a reduction in lung beta AR density comparable to the results in this study (12). Recent data in rats continuously infused with isoproterenol also demonstrated a similar downregulation of beta AR in the lung (31). Thus prolonged subcutaneous administration of beta AR agonists provides a simple and reliable method to induce beta AR tolerance in the lung, although some studies have indicated that these pulmonary receptors may be particularly resistant, compared with other tissues, to desensitization and/or downregulation (4).

Despite the rapid attainment of high, steady-state plasma albuterol concentrations after subcutaneous implantation of the miniosmotic pumps, albuterol therapy alone did not induce a sustained increase in cAMP release in the mouse lung. The lack of such an increase, which in another study was associated with a nonstimulated PKA activity (12), may have contributed to the relatively unaltered baseline alveolar fluid clearance in albuterol-treated mice compared with their controls. Consistent with recent data in rats (31), the failure of subcutaneous albuterol to stimulate alveolar fluid clearance at days 3 and 6 may be a manifestation of beta AR desensitization.

However, as shown by similar terbutaline-stimulated alveolar fluid clearance measurements between control mice and those treated with albuterol for 3 and 6 days, a key finding in this study was that the albuterol-induced downregulation and desensitization of lung beta ARs did not impair the acute stimulatory effect on alveolar fluid clearance induced by high-dose intra-alveolar beta AR agonists. These results are similar to the data demonstrating no influence of continuous systemic epinephrine administration for up to 4 h on beta AR stimulation of alveolar fluid clearance in rats (8), but they contrast with recent data in the rat showing that delivery of systemic isoproterenol for 48 h impaired the lung's ability to respond to air space beta AR agonist stimulation with an increase in alveolar fluid clearance (31). These differences may have resulted from use of different species and techniques, but they may also be due in part to the choice of agonist used for chronic administration. Whereas we used the beta 2AR-selective partial agonist albuterol, Morgan and colleagues (31) used the nonselective and full agonist isoproterenol. Interestingly, recent data suggest that partial agonists may induce less beta AR desensitization than full agonists (22). Thus the extent of desensitization that we observed may have been less than that which occurred in the study by Morgan et al., thus accounting for the observed differences in physiological tolerance reported.

Desensitization and/or downregulation of beta ARs may occur by two different mechanisms. One is short-term, within minutes or hours, involving phosphorylation of the beta AR and uncoupling from stimulatory G-proteins (23, 35). The second is a long-term mechanism that may occur within several hours or over days that may involve internalization and/or degradation of the beta ARs (3) and inhibition of beta AR gene expression and transcription (19). Taken together, our results suggest that, even if some receptor tolerance develops, acute intra-alveolar administration of relatively high doses of beta 2AR agonists can counteract such an effect and stimulate alveolar fluid clearance.

Another explanation may be that alveolar epithelial cells contain more beta ARs than necessary to achieve a given response (spare receptors). In such a setting, the number of receptors that remain functional after downregulation may still be sufficient to obtain adequate cAMP levels inside the epithelial cells to stimulate alveolar fluid clearance. Consistent with this hypothesis, alveolar type II cells have high levels of mRNA expression and high density of beta ARs, suggesting that part of the synthesized beta ARs may constitute a functional pool reserve (9, 40) that is rapidly available to counterbalance beta AR downregulation (5). Although our data show that the maximal cAMP response to terbutaline in albuterol-treated lung tissue was less than that of saline-treated control mice, thereby suggesting an element of desensitization, it is important to note that the increase in cAMP over unstimulated levels in the albuterol-treated groups was nevertheless significant despite the decrease in receptor number. Given that the in vivo alveolar fluid clearance response to terbutaline was not diminished by chronic albuterol treatment, our findings suggest that a maximal cellular response with regard to cAMP may not be necessary for maximal physiological responsiveness (i.e., an increased alveolar fluid clearance). An alternative explanation is that a cAMP-dependent pathway is not the only mechanism responsible for beta AR stimulation of alveolar fluid clearance (6, 17, 36).

These results may have potential clinical relevance. First, in humans, development of tolerance to beta AR agonists has become an important issue, particularly with the introduction of long-acting inhaled beta AR agonists for asthma treatment. Indeed, in normal healthy subjects, tolerance has been demonstrated after only 1 wk of continuous therapy with inhaled beta AR agonists (4). Of note, the systemic levels of beta -agonist in these studies were similar to a concentration in edema fluid that enhanced alveolar fluid clearance in patients with acute respiratory distress syndrome (1). However, whether clinically significant tolerance develops with regard to alveolar fluid clearance has been unclear. Second and more importantly, an intact epithelial function with preserved respiratory transepithelial sodium, chloride, and fluid transport functions is necessary for clinical improvement in patients recovering from acute lung injury (27, 41, 42). Stimulation of vectorial fluid transport by beta AR agonists contributes both to prevention and/or acceleration of the resolution of pulmonary edema in experimental acute lung injury models (see Refs. 2 and 39 for review), as well as in a clinical study in subjects who are prone to high-altitude pulmonary edema development (38).

If beta AR downregulation acts to limit agonist-stimulated fluid clearance, then other strategies, such as stimulation by dopamine or even gene therapy with Na-K-ATPase (11) or beta 2ARs (10) may be needed to counteract the lack of responsiveness. Our findings, however, suggest that, although beta AR downregulation may occur with chronic systemic agonist administration, the capacity of the alveolar epithelium to upregulate alveolar fluid clearance in response to intra-alveolar beta 2-agonists can be maintained.


    ACKNOWLEDGEMENTS

This study was supported by National Heart, Lung, and Blood Institute Grants HL-51854 and HL-51856 (to M. A. Matthay).


    FOOTNOTES

Address for reprint requests and other correspondence: M. A. Matthay, Cardiovascular Research Institute 505 UCSF, Parnassus Ave, San Francisco, CA 94143-0130 (E-mail: mmatt{at}itsa.UCSF.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

August 2, 2002;10.1152/japplphysiol.00275.2002

Received 29 March 2002; accepted in final form 18 July 2002.


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DISCUSSION
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J APPL PHYSIOL 93(5):1875-1880
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