Prolonged isoproterenol infusion impairs the ability of β<sub>2</sub>-agonists to increase alveolar liquid clearance

Morgan, Eric E.; Hodnichak, Cheryl M.; Stader, Sonya M.; Maender, Kay C.; Boja, John W.; Folkesson, Hans G.; Maron, Michael B.

doi:10.1152/ajplung.00381.2001

Cited by 31 publications

(56 citation statements)

References 38 publications

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“…Other groups tested the importance of ␤-receptor function to basal AFC with adrenalectomized animals 11,27 or through desensitization of ␤-receptors by prolonged infusions of ␤-agonists. [33][34][35] Invariably these studies noted no effect on unstimulated AFC. However, none of these models completely desensitized alveolar ␤ 2 AR function nor were they likely to eliminate cAMP production due to spontaneous receptor activation.…”

Section: Discussionmentioning

confidence: 76%

Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling

Mutlu

Dumasius

Burhop

et al. 2004

Circulation Research

101

108

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Abstract-Alveolar epithelial ␤-adrenergic receptor (␤AR) activation accelerates active Na ϩ transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechanisms are sufficient to regulate active transport is unknown. In this study, we report that mice with no ␤ 1 -or ␤ 2 -adrenergic receptors (␤ 1 AR Ϫ/Ϫ /␤ 2 AR Ϫ/Ϫ ) have reduced distal lung Na,K-ATPase function and diminished basal and amiloride-sensitive AFC. Total lung water content in these animals was not different from wild-type controls, suggesting that ␤AR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with ␤ 1 -but not ␤ 2 -adrenergic receptors to ␤ 1 AR Ϫ/Ϫ /␤ 2 AR Ϫ/Ϫ mice indicates that the ␤ 2 AR mediates the bulk of ␤-adrenergic-sensitive alveolar active Na ϩ transport. To test the necessity of ␤AR signaling in acute lung injury, Key Words: alveolar fluid clearance Ⅲ pulmonary edema Ⅲ ␤ 2 -adrenergic receptor Ⅲ adenovirus Ⅲ Na ϩ channel T he combined action of alveolar epithelial Na ϩ channels (ENaCs), the cystic fibrosis transmembrane conductance regulator (CFTR), Na,K-ATPases, and K ϩ channels creates the transepithelial Na ϩ gradient needed for the transit of excess fluid from the alveolar airspace. 1,2 The importance of these proteins to this energy-dependent (ie, active) process is evidenced by data showing that their inhibition reduces the lung's ability to clear excess alveolar fluid [3][4][5][6][7] and that their upregulation confers protection from acute injury. 4,8,9 Despite these extensive investigations, the mechanisms by which these proteins are upregulated in response to excess alveolar fluid (pulmonary edema) are not well resolved.One possible pathway for upregulation of alveolar-active Na ϩ transport is ␤-adrenergic receptor activation. Stimulation of alveolar epithelial ␤ARs by endogenous or exogenous catecholamines accelerates active Na ϩ transport in lung epithelial cells in vitro and in experimental in vivo systems by increasing the expression and/or function of epithelial transport proteins. 10 -12 Thus, this G protein-dependent pathway represents a mechanism by which the lung can alter its physiology to adapt to and protect itself from excess alveolar fluid. What is not known is if ␤AR signaling is essential for the regulation of alveolar active Na ϩ transport or whether other mechanisms (eg, intracellular osmo-, redox-, or chemosensitive regulators) can enhance alveolar active transport to clear pulmonary edema.The present study was structured to define what contribution alveolar epithelial ␤ARs make to active Na ϩ transport in the alveolar epithelium of normal mice and mice with acute lung injury caused by exposure to hyperoxia. Herein, we show that distal lung transport protein function and the lung's ability to clear excess alveolar fluid is highly dependent on Materials an...

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Section: Discussionmentioning

confidence: 76%

Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling

Mutlu

Dumasius

Burhop

et al. 2004

Circulation Research

101

108

View full text Add to dashboard Cite

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“…In these studies, the ␤ 2 -AR may be expressed in several cells in the distal airspaces of the lung. There was evidence that the ␤ 2 -AR overexpression was associated with increased levels of ENaC (␣-subunit) and Na Some recent studies suggest that prolonged exposure to exogenous catecholamines may impair the ability of the alveolar epithelium to remove alveolar edema fluid and that this impairment was associated with a reduction in epithelial ␤-receptor number (244). It is important to bear in mind that although a mild impairment was evident at clinically used doses, infused ␤-agonist as well as instilled ␤-agonist stimulated fluid clearance above baseline levels.…”

Section: Regulation Of ␤ 2 -Receptor Expressionmentioning

confidence: 99%

Lung Epithelial Fluid Transport and the Resolution of Pulmonary Edema

Matthay

Folkesson²,

Clérici³

2002

Physiological Reviews

Self Cite

609

649

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The discovery of mechanisms that regulate salt and water transport by the alveolar and distal airway epithelium of the lung has generated new insights into the regulation of lung fluid balance under both normal and pathological conditions. There is convincing evidence that active sodium and chloride transporters are expressed in the distal lung epithelium and are responsible for the ability of the lung to remove alveolar fluid at the time of birth as well as in the mature lung when pathological conditions lead to the development of pulmonary edema. Currently, the best described molecular transporters are the epithelial sodium channel, the cystic fibrosis transmembrane conductance regulator, Na+-K+-ATPase, and several aquaporin water channels. Both catecholamine-dependent and -independent mechanisms can upregulate isosmolar fluid transport across the distal lung epithelium. Experimental and clinical studies have made it possible to examine the role of these transporters in the resolution of pulmonary edema.

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“…Continuous stimulation with isoproterenol causes impairment in the ability of b-agonists to increase alveolar fluid clearance only when nonspecific b-agonists (isoproterenol) or high doses of a b 2 -agonist are used (119,120). Prolonged stimulation with a b-agonist impairs its ability to continue to up-regulate alveolar fluid clearance, likely due to reduction in receptor density (120) and impaired of post-receptor signaling (82).…”

Section: Limitationsmentioning

confidence: 99%

“…Prolonged stimulation with a b-agonist impairs its ability to continue to up-regulate alveolar fluid clearance, likely due to reduction in receptor density (120) and impaired of post-receptor signaling (82). A broad base of data supports b-agonist-induced attenuation of b 2 AR-mediated airway relaxation.…”

Section: Limitationsmentioning

confidence: 99%

Alveolar Epithelial β₂-Adrenergic Receptors

Mutlu

Factor²

2008

Am J Respir Cell Mol Biol

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b 2 -adrenergic receptors are present throughout the lung, including the alveolar airspace, where they play an important role for regulation of the active Na 1 transport needed for clearance of excess fluid out of alveolar airspace. b 2 -adrenergic receptor signaling is required for up-regulation of alveolar epithelial active ion transport in the setting of excess alveolar edema. The positive, protective effects of b 2 -adrenergic receptor signaling on alveolar active Na 1 transport in normal and injured lungs provide substantial support for the use of b-adrenergic agonists to accelerate alveolar fluid clearance in patients with cardiogenic and noncardiogenic pulmonary edema. In this review, we summarize the role of b 2 -adrenergic receptors in the alveolar epithelium with emphasis on their role in the regulation of alveolar active Na 1 transport in normal and injured lungs.Keywords: pulmonary edema; acute respiratory distress syndrome; acute lung injury; alveoli; albuterol b 2 -adrenergic receptors (b 2 AR) are present throughout the lung. In the alveolar airspace they are important for regulation of the active Na 1 transport needed for clearance of excess fluid out of alveolar airspace (1). Both experimental and limited clinical data suggest that b-adrenergic agonists working via the b 2 AR accelerate clearance of excess fluid from the alveolar airspace, creating the possibility of their use for treatment of pulmonary edema and acute lung injury (ALI).In this review, we summarize the role of b 2 -adrenergic receptors in the alveolar epithelium with emphasis on their role in regulation of alveolar active Na 1 transport in normal and injured lungs. We also overview data regarding b 2 -agonist therapy for pulmonary edema and lung injury. In the lung, b2-adrenergic receptor (b 2 AR) expression increases with each airway generation, with the greatest total amounts in the distal airways and alveoli (3). Greater than 90% of all b-adrenergic receptors in human lung are located in the alveoli (4). Although both b 1 and b 2 subtypes coexist and are distributed uniformly in the alveolar walls, the b 2 -subtype predominates (70%) (4). Isolated rat alveolar type II cells possess b 2 AR and data from autoradiographic and immunohistochemical studies support their presence in the alveolar type 1 cells (4, 5). -Adrenergic Receptor Structure and FunctionThe b 2 -adrenergic 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 (1). The b 2 -receptor is a prototypical G protein-coupled receptor (GPCR) with seven-transmembrane domains, an extracellular amino terminus, an intracellular carboxyl terminus, three interconnecting extracellular loops, and three intracellular loops.b 2 -adrenergic receptors exist in the plasma membrane in an equilibrium between at least two structural conformations; inactive and active forms that are defined based on their ability to associate with the stimulatory guano...

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Prolonged isoproterenol infusion impairs the ability of β₂-agonists to increase alveolar liquid clearance

Cited by 31 publications

References 38 publications

Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling

Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling

Lung Epithelial Fluid Transport and the Resolution of Pulmonary Edema

Alveolar Epithelial β₂-Adrenergic Receptors

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Prolonged isoproterenol infusion impairs the ability of β2-agonists to increase alveolar liquid clearance

Cited by 31 publications

References 38 publications

Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on β 2 -Adrenergic Receptor Signaling

Upregulation of Alveolar Epithelial Active Na + Transport Is Dependent on β 2 -Adrenergic Receptor Signaling

Lung Epithelial Fluid Transport and the Resolution of Pulmonary Edema

Alveolar Epithelial β2-Adrenergic Receptors

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Product

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Prolonged isoproterenol infusion impairs the ability of β₂-agonists to increase alveolar liquid clearance

Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling

Upregulation of Alveolar Epithelial Active Na ⁺ Transport Is Dependent on β ₂ -Adrenergic Receptor Signaling

Alveolar Epithelial β₂-Adrenergic Receptors