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            -Adrenergic Receptor Overexpression Increases Alveolar Fluid Clearance and Responsiveness to Endogenous Catecholamines in Rats

Dumasius, Vidas; Sznajder, Jacob I.; Azzam, Zaher S.; Boja, John W.; Mutlu, Gökhan M.; Maron, Michael B.; Factor, Phillip

doi:10.1161/hh2201.100204

Cited by 93 publications

(94 citation statements)

References 40 publications

(43 reference statements)

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“…Thus, when delivered systemically, gene transfer is seen primarily to the pulmonary vascular endothelial cells, 6,7,9,35,36 whereas airway delivery results in transfer and expression in the epithelium. 9,10,35,37,38 One exception to this appears to be PEI, where it has been reported that intravenous delivery of PEI-DNA complexes can in fact lead to expression in alveolar epithelial type II cells. 3,39 By contrast, electroporation results in gene transfer to alveolar epithelial cells, as well as cells beyond the epithelial permeability barrier, including some smooth muscle and endothelial cells in focal areas of the lung.…”

Section: Discussionmentioning

confidence: 99%

Electroporation as a method for high-level nonviral gene transfer to the lung

et al. 2003

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Section: Discussionmentioning

confidence: 99%

Electroporation as a method for high-level nonviral gene transfer to the lung

et al. 2003

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“…Lung proteins were obtained by homogenizing lung tissue collected from the peripheral 1-2 mm of each lobe as previously described (21,22). BAL was performed through a 20-gauge angiocath ligated into the trachea via tracheostomy.…”

Section: Methodsmentioning

confidence: 99%

FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells

Lubarski-Gotliv

Asher

Dada

et al. 2016

Journal of Biological Chemistry

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The FXYD proteins are a family of small membrane proteins that share an invariant four amino acid signature motif F-X-Y-D and act as tissue-specific regulatory subunits of the Na,KATPase. FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing V max . However, unlike other family members FXYD5 appears to have additional functions, which cannot be readily explained by modulation of transport kinetics. Knockdown of FXYD5 in MDA-MB-231 breast cancer cells largely decreases expression and secretion of the chemokine CCL2 (MCP-1). A related effect has also been observed in renal cell carcinoma cells. The current study aims to further characterize the relationship between the expression of FXYD5 and CCL2 secretion. We demonstrate that transfection of M1 epithelial cell line with FXYD5 largely increases lipopolysaccharide (LPS) stimulated CCL2 mRNA and secretion of the translated protein. We have completed a detailed analysis of the molecular events leading to the above response. Our key findings indicate that FXYD5 generates a late response by increasing the surface expression of the TNF␣ receptor, without affecting its total protein level, or mRNA transcription. LPS administration to mice demonstrates induced secretion of CCL2 and TNF␣ in FXYD5-expressing lung peripheral tissue, which suggests a possible role for FXYD5 in normal epithelia during inflammation.FXYD is a family of type I plasma membrane proteins characterized by the extracellular motif Phe-Xxx-Tyr-Asp. All seven mammalian members of this family specifically interact with the Na,K-ATPase and they have been described to act as tissue specific regulators or auxiliary subunits of the Na,KATPase whose role is to adjust the pump's activity to the cell environment (1). FXYD5 (also termed dysadherin or RIC) is a structurally and functionally unique member of the FXYD family. As other FXYD proteins, FXYD5 specifically interacts with the Na,K-ATPase and alters its kinetics by increasing V max (2, 3). However, in addition to regulating Na,K-ATPase kinetics, FXYD5 appears to have other functions. FXYD5 has been identified as a cancer-associated protein whose expression inhibits E-cadherin and promotes metastasis (4). Clinical studies have demonstrated correlations between the abundance of FXYD5 and the progression of malignancies and survival chances of patients with various human cancers (for review see Ref. 5). Silencing FXYD5 decreases individual and collective cell motility, while its overexpression has the opposite effect (6 -8). In addition, the expression of FXYD5 has been associated with changes in cytoskeletal organization, altered cell shape and impairment of tight and adherence junctions (6 -10). The above observations are consistent with the fact that the extracellular domain of FXYD5 is much longer than that of other FXYD proteins and presumably undergoes excessive O-glycosylation (4, 11).Prev...

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“…Data supporting this conclusion come primarily from rat alveolar type II cells; however, the observation that alveolar type I cells have functional ion transporters and b 2 AR suggests similar regulation of ion transport in alveolar type I cells (5,56,57). Activation of b 2 -adrenergic receptor increases cellular Na,KATPase activity in alveolar epithelial cells in vitro and lung tissue (8,39,49,58). b 2 -adrenergic receptor-mediated shortterm regulation of Na 1 pumps occurs within minutes of receptor engagement via highly regulated recruitment of assembled Na,K-ATPases from intracellular compartments through phosphorylation of intermediary proteins and RhoA-kinase (49,59).…”

Section: Role Of Alveolar Epithelial B 2 -Adrenergic Receptorsmentioning

confidence: 95%

“…In the absence of agonist, the basal equilibrium favors the inactive conformation (6, 7). Spontaneous receptor activation explains the presence of basal b 2 AR-driven adenylyl cyclase activity in cells and observations of increased receptor function in the absence of agonist in models of b 2 AR overexpression (8)(9)(10). Engagement of the b 2 AR by a b 2 -agonist produces a conformational change shifting the equilibrium between receptor conformations toward the active form causing exchange of guanosine diphosphate (GDP) on Gsa for GTP and dissociation of Gsa from Gsbg.…”

mentioning

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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β ₂ -Adrenergic Receptor Overexpression Increases Alveolar Fluid Clearance and Responsiveness to Endogenous Catecholamines in Rats

Cited by 93 publications

References 40 publications

Electroporation as a method for high-level nonviral gene transfer to the lung

Electroporation as a method for high-level nonviral gene transfer to the lung

FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells

Alveolar Epithelial β₂-Adrenergic Receptors

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β 2 -Adrenergic Receptor Overexpression Increases Alveolar Fluid Clearance and Responsiveness to Endogenous Catecholamines in Rats

Cited by 93 publications

References 40 publications

Electroporation as a method for high-level nonviral gene transfer to the lung

Electroporation as a method for high-level nonviral gene transfer to the lung

FXYD5 Protein Has a Pro-inflammatory Role in Epithelial Cells

Alveolar Epithelial β2-Adrenergic Receptors

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β ₂ -Adrenergic Receptor Overexpression Increases Alveolar Fluid Clearance and Responsiveness to Endogenous Catecholamines in Rats

Alveolar Epithelial β₂-Adrenergic Receptors