Alveolar Epithelial β₂-Adrenergic Receptors

Abstract

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...

Transforming Growth Factor β1 Inhibits Cystic Fibrosis Transmembrane Conductance Regulator-dependent cAMP-stimulated Alveolar Epithelial Fluid Transport via a Phosphatidylinositol 3-Kinase-dependent Mechanism

“…Short Time Exposure (5-30 min) to TGF-␤1 Induces a Heterologous Desensitization of the ␤ 2 AR via a PI3K-dependent Mechanism-Several studies have shown that ␤ 2 AR signaling in the distal lung epithelium is mediated by a cAMP-and PKAmediated mechanism (41). We found that exposure to TGF-␤1 significantly inhibited epinephrine-induced cAMP accumulation and PKA activity in rat ATII cell monolayers (Fig.…”

“…Prolonged exposure to TGF-␤1 had no effect on CPT-cAMP-stimulated Cl Ϫ transport across the apical membrane of ATII cell monolayers (data not shown), indicating that the TGF-␤1 prolonged inhibitory effect on Cl Ϫ transport is not downstream of cAMP generation. Previously published work has shown that cAMP plays a critical role in activating CFTR promoter and mRNA expression in lung epithelial cells (41). Thus, we also hypothesized that TGF-␤1 prolonged exposure to TGF-␤1 would result in a reduction in the PKA-dependent CFTR promoter activity and mRNA expression.…”

“…2). Previous studies have shown that both the chloride channel CFTR and the sodium channel ENaC present in the alveolar epithelium are under ␤-adrenergic control (41). Thus, although we found that short exposure to TGF-␤1 (5-30 min) does not inhibit the epinephrine-stimulated amiloride-sensitive I sc (data not shown), our results suggest that long term (6 -24 h) exposure to TGF-␤1 likely inhibits both the chloride channel CFTR and the sodium channel ENaC, explaining why we observed a near complete inhibition of ␤ 2 AR agonist-dependent stimulation of alveolar epithelial fluid transport in these experiments.…”

The Effect of Inhaled Salbutamol in Transient of Tachypnea of the Newborn: A Randomized Clinical Trial

“…Therefore, the disruption of this chain due to inadequate Na + transport, either because of decreased numbers of transporters or inactivation can lead to retention of fluid in alveolar space (14,15). Beta 2 adrenergic (beta 2 A) receptors are present throughout the lung, including the alveolar airspace, and play a pivotal role for regulation of the active Na + transport in ENaC and Na-KATPase (16). Experimental studies documented the therapeutic role for the beta 2 agonist in the treatment of pulmonary edema by accelerating the clearance of excessive fluid from the alveolar space by increasing the function of epithelial transport proteins (17,18).…”

Knockout Mice Reveal Key Roles for Claudin 18 in Alveolar Barrier Properties and Fluid Homeostasis

“…The importance of the Na pump in AFC has been directly demonstrated by increased AFC after overexpression of Na pump subunits (24)(25)(26)(27)(28). b-Adrenergic signaling has been reported to increase transcription and translation of Na pump subunit genes (29) and to mobilize intracellular Na pumps for insertion into the basolateral cell plasma membrane (30), making b-adrenergic signaling a plausible mechanism underlying increased expression of Na pump subunit mRNA and higher ouabain-sensitive ATPase activity observed in C18 KO lungs. These results suggest that elevated b2-adrenergic signaling in C18 KO mice results in increased CFTR, ENaC and Na pump activity, and higher AFC.…”