Postreceptor defects in alveolar epithelial β-adrenergic signaling after prolonged isoproterenol infusion

Morgan, Eric E.; Stader, Sonya M.; Hodnichak, Cheryl M.; Mavrich, Kate E.; Folkesson, Hans G.; Maron, Michael B.

doi:10.1152/ajplung.00339.2002

Cited by 17 publications

(39 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Theoretically, a potential limitation of b 2 -agonist therapy for treatment of pulmonary edema is receptor desensitization (a regulated process that leads to attenuation of the biologic effect of receptor during prolonged agonist exposure) and downregulation (a form of desensitization during which density/ number of receptors decreases), both of which will diminish the efficacy of b-agonist therapy (82,117,118).…”

Section: Limitationsmentioning

confidence: 99%

See 1 more Smart Citation

Alveolar Epithelial β₂-Adrenergic Receptors

Mutlu

Factor²

2008

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Alveolar fluid clearance was measured as previously described (33,34). Rats were anesthetized with pentobarbital sodium (60 mg/kg body wt ip; Nembutal, Ovation Pharmaceuticals, Deerfield, IL), and anesthesia was maintained with supplemental doses as needed.…”

Section: Alveolar Fluid Clearance Measurementsmentioning

confidence: 99%

β-Adrenoceptor stimulation of alveolar fluid clearance is increased in rats with heart failure

Maron

Luther²,

Pilati³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

Self Cite

View full text Add to dashboard Cite

We thus hypothesized that its function might be upregulated in rats with heart failure, a condition that severely challenges the lung's ability to maintain fluid balance. Heart failure was induced by left coronary artery ligation. Echocardiographic and cardiovascular hemodynamics confirmed its development at 16 wk postligation. At that time, alveolar fluid clearance was measured by an increase in protein concentration over 1 h of a 5% albumin solution instilled into the lungs. Baseline alveolar fluid clearance was similar in heart failure and age-matched control rats. Terbutaline was added to the instillate to determine whether heart failure rats responded to ␤-adrenoceptor stimulation. Alveolar fluid clearance in heart failure rats was increased by 194% after terbutaline stimulation compared with a 153% increase by terbutaline in control rats. To determine the mechanisms responsible for this accelerated alveolar fluid clearance, we measured ion transporter expression (ENaC, Na-KATPase, CFTR). No significant upregulation was observed for these ion transporters in the heart failure rats. Lung morphology showed significant alveolar epithelial type II cell hyperplasia in heart failure rats. Thus, alveolar epithelial type II cell hyperplasia is the likely explanation for the increased terbutaline-stimulated alveolar fluid clearance in heart failure rats. These data provide evidence for previously unrecognized mechanisms that can protect against or hasten resolution of alveolar edema in heart failure. albumin; terbutaline APPROXIMATELY FIVE MILLION Americans are living with heart failure, with 400,000 new cases diagnosed annually (18). A major clinical problem in heart failure is the development of pulmonary venous (and consequently, pulmonary capillary) hypertension, which ultimately may lead to pulmonary edema and impaired blood oxygenation. Recent studies have demonstrated that excess pulmonary edema fluid is cleared from the alveoli secondary to active transepithelial Na transport (14, 31). The alveolar epithelium plays a critical role during pulmonary edema recovery by actively absorbing Na (14, 31). ␤-adrenoceptor and dopamine receptor agonists increase Na transport and thus hasten the resolution of pulmonary edema (2, 6, 31). These observations have important clinical significance because they suggest that ␤-adrenoceptor-or dopamine receptor-agonist therapy might help patients to recover more rapidly from pulmonary edema (2, 16).Lungs of heart failure patients undergo extensive remodeling (18,25,26), resulting in architectural changes such as pulmonary artery and vein wall thickening, pulmonary arteriole muscularization, and capillary endothelial and alveolar epithelial basement membrane thickening (18). Collectively, such remodeling results in increased alveolocapillary barrier thickness, correlating with reduced microvascular fluid and protein permeabilities (11,20,45). In addition to the aforementioned changes, alveolar epithelial type II cell proliferation may occur in these lungs (25,26). Hence, the hypot...

show abstract

“…␤ 2 -AR can become desensitized as a result of prolonged exposure to exogenous ␤-agonists or high levels of endogenous catecholamines (9,32). We therefore examined the possibility that RSV infection might induce sufficient physiological stress to trigger activation of the adrenal medulla and thereby chronically elevate systemic endogenous catecholamine (norepinephrine and epinephrine) levels.…”

Section: Effect Of Protein Kinase a Activation On Afcmentioning

confidence: 99%

Respiratory syncytial virus induces insensitivity to β-adrenergic agonists in mouse lung epithelium in vivo

Davis¹,

Xu²,

Gao³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Davis IC, Xu A, Gao Z, Hickman-Davis JM, Factor P, Sullender WM, Matalon S. Respiratory syncytial virus induces insensitivity to ␤-adrenergic agonists in mouse lung epithelium in vivo. Am J Physiol Lung Cell Mol Physiol 293: L281-L289, 2007. First published April 13, 2007; doi:10.1152/ajplung.00458.2006 is the most common cause of bronchiolitis in infants and children worldwide. We wished to determine whether intratracheal administration of ␤-agonists improved alveolar fluid clearance (AFC) across the distal respiratory epithelium of RSV-infected mice. Following intranasal infection with RSV strain A2, AFC was measured in anesthetized, ventilated BALB/c mice by instillation of 5% BSA into the dependent lung. We found that direct activation of protein kinase A by forskolin or 8-bromo-cAMP increased AFC at day 2 after infection with RSV. In contrast, short-and long-acting ␤-agonists had no effect at either day 2 or day 4. Insensitivity to ␤-agonists was not a result of elevated plasma catecholamines or lung epithelial cell ␤-adrenergic receptor degradation. Instead, RSV-infected mice had significantly higher levels of phosphorylated PKC in the membrane fractions of their lung epithelial cells. In addition, insensitivity to ␤-agonists was mediated in a paracrine fashion by KC (the murine homolog of CXCL8) and reversed by inhibition of either PKC or G protein-coupled receptor kinase 2 (GRK2). These results indicate that insufficient response to ␤-agonists in RSV may be caused, at least in part, by impaired ␤-adrenergic receptor signaling, as a consequence of GRK2-mediated uncoupling of ␤-adrenergic receptors from adenylyl cyclase. paramyxovirus; protein kinase C; G protein-coupled receptor kinase 2; CXCL8 RESPIRATORY SYNCYTIAL VIRUS (RSV) is the most common cause of lower respiratory tract disease in infants and children worldwide (44), is a frequent initiator of acute asthma exacerbations in young children, and has a disease impact comparable to that of nonpandemic influenza A in the elderly (8). Approximately 2-3% of all cases of RSV bronchiolitis result in severe hypoxia or a need for parenteral fluid supplementation that necessitates hospitalization (44). ␤-agonists are frequently used to treat RSV bronchiolitis, primarily because of their perceived ability to relax airway smooth muscle and cause bronchodilation, with the ultimate aim of alleviating hypoxemia. However, it is not clear that these drugs are clinically effective: meta-analyses have shown little or no overall benefit, regardless of viral bronchiolitis severity (15,20). Their lack of efficacy has not been explained, although it has often been ascribed to difficulties associated with drug delivery to the small airways of young infants, particularly in the presence of bronchoconstriction and inflammatory exudates or airway obstruction (28). ␤-agonists increase total body oxygen consumption, thereby increasing oxygen demands in infants hospitalized for respiratory compromise, and can potentially exacerbate ventilation-perfusion mismatch by inducing vaso...

show abstract

Postreceptor defects in alveolar epithelial β-adrenergic signaling after prolonged isoproterenol infusion

Cited by 17 publications

References 22 publications

Alveolar Epithelial β₂-Adrenergic Receptors

Alveolar Epithelial β₂-Adrenergic Receptors

β-Adrenoceptor stimulation of alveolar fluid clearance is increased in rats with heart failure

Respiratory syncytial virus induces insensitivity to β-adrenergic agonists in mouse lung epithelium in vivo

Contact Info

Product

Resources

About

Postreceptor defects in alveolar epithelial β-adrenergic signaling after prolonged isoproterenol infusion

Cited by 17 publications

References 22 publications

Alveolar Epithelial β2-Adrenergic Receptors

Alveolar Epithelial β2-Adrenergic Receptors

β-Adrenoceptor stimulation of alveolar fluid clearance is increased in rats with heart failure

Respiratory syncytial virus induces insensitivity to β-adrenergic agonists in mouse lung epithelium in vivo

Contact Info

Product

Resources

About

Alveolar Epithelial β₂-Adrenergic Receptors

Alveolar Epithelial β₂-Adrenergic Receptors