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Alveolar Epithelial ß₂-Adrenergic Receptors

Their Role in Regulation of Alveolar Active Sodium Transport

Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Center for Translational Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Pulmonary, Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York

Correspondence and requests for reprints should be addressed to Gökhan M. Mutlu, M.D., Northwestern University Feinberg School of Medicine, Pulmonary and Critical Care Medicine, 240 East Huron, McGaw 2-2300, Chicago, IL 60611. E-mail: g-mutlu{at}northwestern.edu

Key Words: acute lung injury • acute respiratory distress syndrome • albuterol • alveoli • pulmonary edema

ß-Adrenergic receptors are present on airway smooth muscle and lung inflammatory cells where their roles in regulation of airway inflammation and smooth muscle tone are well described. ß-Receptors are also present in the alveolar epithelium. A growing base of knowledge indicates that alveolar epithelial ß-receptors regulate the active Na⁺ transport needed for clearance of excess fluid from the alveolar airspace. This appreciation has led to the possibility of ß-agonist treatment for pulmonary edema and acute lung injury.

Herein, we provide a summary of the mechanisms by which the lung clears excess fluid from the alveolar airspace and an overview of the structure and function of the ß₂-receptor. Thereafter, we review the role of this receptor in regulation of alveolar active Na⁺ transport in normal and injured lungs. Finally, limitations of ß₂-agonist therapy for pulmonary edema and lung injury are discussed.

PHYSIOLOGY OF PULMONARY EDEMA CLEARANCE

More than 20 years ago, Matthay and colleagues provided clear evidence that excess fluid is removed from the alveolar airspace via an active, energy-requiring process (1). Substantial subsequent data have generated a widely accepted paradigm in which excess alveolar fluid transits from the alveolar airspace along an osmotic gradient created by the active extrusion of Na⁺ from the airspace into the interstitium. This pathway includes gated ion channels along the apical/airspace aspect of alveolar epithelial cells that allow passive flux of Na⁺ and Cl^– into cells. Jiang and colleagues have suggested that Cl^– flux through cystic fibrosis transmembrane conductance regulator may create a transmembrane electrical gradient that favors Na⁺ flux into the cell (2). This theory suggests that the cystic fibrosis transmembrane conductance regulator is a key regulator of ion transport. Conversely, Lazrak and Matalon did not find evidence for apical membrane hyperpolarization in human lung epithelial cells (H441) (3). Thus, at this time, we can only surmise that there is probably coordinate regulation of Na⁺ and Cl^– flux across the apical cell membrane (4). Irrespective of any interrelationship between Na⁺ and Cl^– channels, transcellular (e.g., vectorial) movement of both of these ions requires the electrochemical gradient created by Na,K-ATPases, which actively extrude Na⁺ from the basolateral aspect of alveolar epithelial cells. Inhibition of Na⁺ entry or Na,K-ATPase activity markedly reduces vectorial Na⁺ and fluid flux, confirming that active transport is required for clearance of excess alveolar fluid. Although Cl^– channel blockade appears to have little effect on alveolar fluid clearance in normal lungs, cystic fibrosis transmembrane conductance regulator is necessary for acceleration of fluid clearance in the edematous lung (5).

It is important to emphasize that in vivo models of alveolar active Na⁺ transport measure clearance of fluid instilled into the airspace compartment. Thus, much of the available data regarding alveolar active Na⁺ transport may be more relevant to our understanding of how the lung deals with excess fluid (e.g., pulmonary edema) than maintenance of alveolar fluid content in the uninjured lung (6).

Cumulatively, these data emphasize that pulmonary edema is due to the combination of increased fluid flux into the alveolar airspace and reduced clearance capacity. Extensive investigations to identify methods to restore and enhance alveolar active Na⁺ transport have been undertaken. In the 1980s, it was noted that ß-agonists stimulate vectorial fluid movement in isolated rat alveolar epithelial cells (7), isolated rat lungs (8), and anesthetized sheep (9). These pioneering studies raised the possibility of use of ß-agonists to augment alveolar active Na⁺ transport during pulmonary edema.

Alveolar fluid clearance is reduced in many models of lung injury caused by impaired function of the transport proteins discussed previously here (10–12). This understanding provides rationale for development of tools and pharmacologic approaches to restore function of these transport proteins in the injured lung. Interestingly, several models of injury (subacute hyperoxia, bacterial pneumonia, and sepsis) are associated with increased fluid clearance (13). These findings may reflect the effects of serum catecholamines (14–16) and cytokines such as tumor necrosis factor- (15, 17), which upregulate active Na⁺ transport. Alternately, variances in active Na⁺ transport between models may be due to differences in extent and severity of epithelial/endothelial injury, the degree of local hypoxia, the formation of reactive oxygen and nitrogen species (inhibiting cAMP-mediated upregulation of transport), the duration, and the degree of the insult that causes lung injury.

ß-ADRENERGIC RECEPTORS

ß-Receptors are found throughout the body and are classified into four distinct subtypes, ß₁, ß₂, ß₃, and ß₄, on the basis of their function, agonist binding patterns, and genetics. There is 65 to 70% homology among the ß₁-, ß₂-, and ß₃-receptors. The ß₃-receptor is found primarily in adipocytes and has been noted in pulmonary endothelial cells. The recently proposed ß₄-receptor appears to be a state of ß₁-receptor confined to myocardial cells.

The presence of lung ß-receptors in airway smooth muscle cells has been long appreciated. Less appreciated is that the density of ß-receptors expression rises with increasing airway generation, with the greatest total amounts in the distal airways and alveoli (18). More than 90% of all ß-receptors in human lung are located in the alveoli where the ß₂-subtype predominates (70%) (19). ß₁- and ß₂-subtypes coexist and are distributed uniformly in the alveolar walls. Isolated rat alveolar type 2 cells possess ß₂-receptors, and inferential data from autoradiographic studies suggest their presence in the alveolar type 1 cells (19).

STRUCTURE AND FUNCTION OF ß₂-ADRENERGIC RECEPTOR

The ß₂-receptor is a 1,200 base pair, single-copy, intronless gene located on the long arm of human chromosome 5 that encodes a 413–amino acid protein with a molecular mass of approximately 46.5 kD. Like other G-protein–coupled receptors, the ß₂-receptor has seven-transmembrane domains, an extracellular amino terminus, an intracellular carboxyl terminus, three interconnecting extracellular loops, and three intracellular loops.

ß₂-Receptors exist in an equilibrium between at least two structural conformations: R (inactive) and R*(active) that are defined based on their ability to associate with the stimulatory heterotrimeric guanosine triphosphate binding protein, Gs. ß-Agonist binding to the receptor cleft produces a conformational change in the receptor shifting this equilibrium toward R*, causing exchange of guanosine diphosphate on Gs for guanosine triphosphate and dissociation of Gs from Gsß. The R conformation is stabilized by inverse agonists and does not activate Gs. Measurable levels of adenylyl cyclase activity in the absence of ligand suggest that ß₂-receptors have low levels of agonist independent basal activity caused by spontaneous conversion from R to the active, R*conformation (20). Data from cardiac myocytes and lung epithelial cells indicate that basal levels of ß₂-receptor driven adenylyl cyclase activity change in parallel with ß₂-receptor expression (6, 21, 22). The replacement of guanosine triphosphate by guanosine diphosphate causes G_s dissociation from the receptor and a switch to the inactivate conformation, R.

Phosphorylation of ligand-occupied receptors by G-protein–coupled receptor kinase 2 produces conformational changes that reduce receptor interactions with Gs and diminish its affinity for ligand, thereby shifting conformation toward the R state. G-protein–coupled receptor kinase 2 phosphorylation of ß₂-receptors also allows for binding of the receptor to ß-arrestins, which further attenuates G-protein–receptor interactions and promotes receptor endocytosis via clathrin-coated vesicles signaling (Figure 1). These recent findings are a paradigm shift away from traditional "turn key" models in which receptors are either on or off in the presence or absence of ligand.

View larger version (22K): [in this window] [in a new window]   Figure 1. The effects of interaction between ß2-adrenergic receptor and G-protein–coupled receptor kinase (GRK) leads to decreased interaction between the receptor and Gs protein. (A) R (inactive) state/unstimulated receptor. (B) Ligand engagement of receptor. (C) Phosphorylation of ligand activated receptor by GRK. (D) Binding of arrestin to the receptor decreasing the interaction of the receptor with Gs (*).

ß₂-Adrenergic Receptor–mediated Regulation of Alveolar Active Na⁺ Transport
In the 1980s, Goodman and colleagues noted that ß-agonists produced signs (dome formation) indicative of active transcellular ion flux in confluent monolayers of isolated rat alveolar epithelial cells (7). These studies and data from isolated rat lungs (8) and anesthetized sheep (9) offered the possibility that ß-adrenergic agonists might be useful for the treatment of pulmonary edema. Subsequent to these studies, mechanistic data have become available providing clues as to how ß-adrenergic agonists regulate key alveolar epithelial active Na⁺ transport proteins such as the amiloride-sensitive epithelial Na⁺ channel, cystic fibrosis transmembrane conductance regulator, and Na,K-ATPase.

Endogenous and exogenous catecholamines stimulate alveolar fluid clearance in newborn and adult animals via activation of ß-receptors. Both nonspecific (isoproterenol, epinephrine) and ß₂-receptor–specific agonists (procaterol, salmeterol, terbutaline) increase alveolar fluid clearance in normal rat (24), dog (25), sheep (26), guinea pig (27), and mouse lungs (28, 29) and in human lung tissue (30). Recent data from ß₁- and ß₂-receptor knockout mice suggest that ß₂-receptors are responsible for the bulk of the ß-receptor–sensitive alveolar active Na⁺ transport (6), although other data suggest that ß₁-adrenergic receptors can accelerate alveolar active Na⁺ transport (31).

ß-Receptor–mediated increases in alveolar active Na⁺ transport are likely due to direct and indirect upregulation of the epithelial Na⁺ channel, cystic fibrosis transmembrane conductance regulator, and Na,K-ATPase (8, 13, 27, 32, 33) (Figure 2). In vitro, ß-agonists stimulate both highly selective sodium-selective channels (via recruitment from intracellular pools to the apical cell membrane) and amiloride-sensitive, Na⁺-permeable, nonselective cation channels (via increased open state probability and mean open time) (4). These effects of ß₂-agonists and cAMP appear to be mediated via protein kinase A, which phosphorylates cytoskeleton proteins and promotes exocytosis to the cell membrane (34) and direct phosphorylation of epithelial Na⁺ channel ß and subunits. In addition to exocytosis from intracellular pools, ß₂-receptors increase the expression of epithelial Na⁺ channel -subunit mRNA and protein (35).

View larger version (26K): [in this window] [in a new window]   Figure 2. ß2-Adrenergic receptor-mediated increase in alveolar active Na+ transport is likely due to direct and indirect upregulation of key epithelial transport proteins, including epithelial Na+ channel (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR), and Na,K-ATPase. G = G protein; AC = adenylyl cyclase; PKA = protein kinase A. Scaffold/adapter proteins include ezrin-radixin-moesin binding phosphoprotein and A-kinase–anchoring proteins (i.e., Gravin).

The cAMP-mediated upregulation of Na⁺ flux across alveolar epithelial cells involves both Na⁺ and Cl^– conductive pathways (2, 39). Data from alveolar epithelial cells convincingly indicate that ß₂-receptor signaling increases Cl^– flux through the cystic fibrosis transmembrane conductance regulator (40, 41). Interestingly, cAMP produces an initial and rapid increase in Cl^– current, which precedes increases in amiloride-sensitive Na⁺ current offering the possibility that the cystic fibrosis transmembrane conductance regulator and/or Cl^– flux may regulate ß₂-receptor sensitive Na⁺ flux into the cell (42). Interestingly, cystic fibrosis transmembrane conductance regulator knockout mice (508 transgenics) have normal basal alveolar fluid clearance rates but are unable to upregulate alveolar active Na⁺ transport in response to edema formation. Importantly, ß-agonists do not increase alveolar fluid clearance in 508 transgenics to the same degree as wild-type mice, suggesting that much of the ß-adrenergic sensitive upregulation of alveolar active Na⁺ transport is affected via cystic fibrosis transmembrane conductance regulator and/or Cl^– flux (5).

An important unanswered question is why engagement of ß₂-receptors produces highly compartmentalized rather than widespread activation of cAMP-sensitive pathways. Several new clues in this regard suggest that the ß₂-receptor interacts with scaffold and adaptor proteins such as via ezrin-radixin-moesin–binding phosphoprotein 50 and A-kinase–anchoring proteins (i.e., Gravin) via its intracellular, carboxy-terminal end (reviewed in References 43 and 44). These proteins link the ß₂-receptor directly or indirectly via ezrin-radixin-moesin–binding phosphoprotein 50 to the cytoskeleton at the apical domain of the cell membrane. These proteins simultaneously bind protein kinase A, G-protein–coupled receptor kinases, ion channels (e.g., cystic fibrosis transmembrane conductance regulator), and phosphodiesterases. This macromolecular regulatory complex brings the receptor in close approximation to its principal effector molecule (protein kinase A) and downstream targets (cystic fibrosis transmembrane conductance regulator) as well as proteins that turn receptor signaling off (G-protein–coupled receptor kinase) and prevent diffusion of cAMP throughout the cell (phosphodiesterases). This highly regulated process compartmentalizes receptor signaling near the apical membrane and allows the cell to fine tune receptor function. A single study from airway epithelial cells suggests that ezrin-radixin-moesin–binding phosphoprotein 50-mediated interactions between the receptor and cystic fibrosis transmembrane conductance regulator are important for regulation of Cl^– transport in airway epithelial cells (Calu-3). Whether similar interactions are important to regulation of active Na⁺ transport in alveolar epithelial cells is not yet known.

Importance of the ß₂-Adrenergic Receptor in Alveolar Fluid Homeostasis
There is long-standing debate regarding whether ß₂-receptors are required for maintenance of alveolar fluid balance in the normal lung. Studies that attempted to answer these questions added ß-antagonists to the alveolar airspace during alveolar fluid clearance measurements (9, 25, 28–30, 45, 46). Most such studies reported no net effect on unstimulated alveolar fluid clearance (i.e., no ß-agonists). Likewise, studies using adrenalectomized animals (21, 29) or desensitization of ß-receptors by prolonged infusions of ß-agonists (47, 48) have reported no net effect on unstimulated alveolar fluid clearance. However, none of these models fully desensitized alveolar ß₂-receptor function or completely eliminated serum catecholamines. To overcome the limitations of these prior models, we measured alveolar fluid clearance in mice with targeted deletions of the ß₂-receptor (ß₂-knockout) or ß₁-receptor and ß₂-receptor (ß₁ß₂ knockout) (6). Lung water content in these knockout animals was normal. However, the ability of ß₂-knockout and ß₁ß₂-knockout mice to clear fluid instilled into their lungs was reduced by 32% and 45%, respectively, suggesting that loss of ß₂-receptor signaling explains the reduction in alveolar clearance in these mice. More importantly, these mice had more pulmonary edema and substantially decreased survival from acute lung injury (hyperoxia). These important new findings indicate that the ß₂-receptor, not the ß₁-receptor, function may not be required to maintain alveolar fluid balance in the uninjured lung but is essential for adaptation to pulmonary edema. Furthermore, these data indicate that other regulatory pathways are not sufficient to accelerate alveolar active Na⁺ transport mechanisms in the injured lung. These experiments emphasize the importance of epithelial ß₂-receptor signaling to regulation of alveolar active Na⁺ transport (6).

Limitations of ß₂-Agonist Therapy
Regulation of ß₂-receptors occurs primarily through phosphorylation-dependent loss of sensitivity to agonist. Desensitization encompasses loss of signaling on subsequent engagement by agonists (homologous desensitization), downregulation of membrane bound receptors, and inhibition/alteration of downstream effectors pathways (heterologous desensitization). These processes have been extensively studied in cardiac cells and airway smooth muscle cells. Proclivity for desensitization varies among tissues; for example, cardiac myocytes are readily desensitized, whereas airway smooth muscle cells may not have the necessary G-protein–coupled receptor kinases to affect receptor phosphorylation.

Data regarding desensitization of alveolar ß₂-receptor are limited. Morgan and colleagues have reported that sustained infusion of high-dose isoproterenol (400 µg/kg/hour) diminishes terbutaline-induced alveolar active Na⁺ transport in rats (48); however, other groups using albuterol have noted downregulation of receptor number but not loss of effect on alveolar active Na⁺ transport (47). More intriguingly, Morgan and colleagues have shown that sustained, high-dose albuterol infusion diminishes adenylyl cyclase and protein kinase A activity, providing the first evidence of heterologous receptor desensitization in the alveolar epithelium (48). It has been noted that transgenic and adenoviral-mediated overexpression of ß₂-receptor in the alveolar epithelium increase alveolar active Na⁺ transport (6, 21, 49), probably by increasing the number of R*state receptors in the cell membrane.

It is important to consider that some forms of acute lung injury (i.e., prolonged hemorrhagic shock, hyperoxia, ischemia reperfusion after lung transplantation, and ventilator-induced lung injury) have been associated with diminished ß-receptor function in experimental models (50–55). Restoration of ß-agonist–sensitive active Na⁺ transport with inhibition of inducible nitric oxide synthase (50) and N-acetylcysteine (53) in some of these models implicates oxidant and/or nitrosylation-dependent impairment of ß₂-receptor signaling. Nuclear factor-B–dependent activation of inducible nitric oxide synthase impairs the function of membrane proteins (i.e., adenylyl cyclase) involved in the ß₂-receptor-cAMP signaling pathway (50). These studies raise concern that acute lung injury may impair alveolar epithelial ß-receptor function, thereby limiting ß-agonist therapy for pulmonary edema. Whether these effects are solely due to defects in receptor signaling or some combination of diminished alveolar barrier function, loss of epithelial cells, or downregulation of transport protein function is not yet known.

CLINICAL IMPLICATIONS

Pulmonary edema clearance is impaired in animal models of hydrostatic pulmonary edema (56) and acute lung injury (57). The inability to upregulate mechanisms of pulmonary edema clearance is associated with increased risk of pulmonary edema in humans (58) and mortality from lung injury in animals (6). Correlative human data indicate that most patients with hydrostatic and noncardiogenic pulmonary edema have impaired alveolar fluid clearance (12, 59) and that loss of clearance capacity is associated with a high mortality rate (59). In a study of 79 patients with acute lung injury, 56% had impaired pulmonary edema clearance (based on changes in edema fluid protein measurements), whereas 32% had submaximal clearance, and only 13% had maximal clearance (59). Hospital mortality was 20% in patients with maximal clearance compared with 62% in patients with impaired or submaximal clearance. These data raise the possibility that reduced alveolar fluid clearance capacity may contribute to the mortality seen during acute lung injury. Unfortunately, available human studies do not clearly indicate whether reduced alveolar fluid clearance is a primary cause of respiratory failure or a reflection of severity illness.

Limited clinical data regarding the use of ß-agonists for pulmonary edema are available. Prophylactic salmeterol, a long-acting ß₂-agonist, has been shown to reduce the incidence of high-altitude pulmonary edema in mountain climbers (58). Recently, it has been reported that aerosol delivery of albuterol to the lungs of mechanically ventilated patients with respiratory failure produces clinically significant levels of this ß-agonist in lung edema fluid (60), and a recent pilot study showed a correlation of ß-agonist use with improved outcome in patients with acute lung injury (61). These studies and the large body of data presented previously here lend credence to the use of inhaled ß-agonists for pulmonary edema.

Transgenic overexpression of ß₂-receptor in alveolar type 2 cells increases alveolar fluid clearance in mice by approximately 40% (49). Adenoviral-mediated transfer of a human ß₂-receptor to the alveolar epithelium increases alveolar fluid clearance in normal rats and mice by upregulating the expression and/or function of amiloride-sensitive epithelial Na⁺ channels and Na,K-ATPases in the distal lung (6, 21). These effects were attributed, in part to, improved responsiveness to endogenous catecholamines. Importantly, overexpression of the ß₂-receptor in mouse lungs markedly improved survival of mice exposed to 100% oxygen. Whether overexpression can obviate homologous and heterologous desensitization remains to be established, however, these studies raise the possibility of "receptor therapies" to exploit the positive attributes of ß₂-receptor signaling in the alveolar epithelium.

Conclusions
ß₂-Receptor signaling is required for upregulation of pulmonary edema clearance. Data regarding its positive, protective effects on alveolar active Na⁺ transport in normal and injured lungs provide rationale for the use of ß-adrenergic agonists for the treatment of pulmonary edema. We anticipate that forthcoming studies will provide the clinical evidence to justify the use these established pharmaceuticals for pulmonary edema, be it cardiogenic or noncardiogenic.

FOOTNOTES

Supported by the American Heart Association, the Northwestern Memorial Foundation, and National Institutes of Health HL-66211 and HL-71042.

Conflict of Interest Statement: G.M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; W.J.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; P.F. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form April 7, 2004; accepted in final form September 21, 2004

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