Selected Contribution: Long-term effects of β<sub>2</sub>-adrenergic receptor stimulation on alveolar fluid clearance in mice

Sartori, Cláudio; Fang, Xiaohui; McGraw, Dennis W.; Koch, Patrick; Snider, Mary Ellen; Folkesson, Hans G.; Matthay, Michael A.

doi:10.1152/japplphysiol.00275.2002

Cited by 41 publications

(27 citation statements)

References 39 publications

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“…The b 2 -adrenergic receptor agonist, terbutaline, increased pleural isosmolar fluid absorption, which was inhibited by amiloride. Terbutaline has long been used clinically to effectively ameliorate pulmonary edema by up-regulating ENaC activity, and thereby expediting edematous liquid clearance (21,22). These observations support the scenario that ENaC channels are functionally expressed in pleural tissues and contribute to pleural fluid reabsorption.…”

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confidence: 65%

Expression and Regulation of Epithelial Na⁺ Channels by Nucleotides in Pleural Mesothelial Cells

Nie

Tucker²,

et al. 2009

Am J Respir Cell Mol Biol

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Pleural effusions are commonly clinical disorders, resulting from the imbalance between pleural fluid turnover and reabsorption. The mechanisms underlying pleural fluid clearance across the mesothelium remain to be elucidated. We hypothesized that epithelial Na 1 channel (ENaC) is expressed and forms the molecular basis of the amiloride-sensitive resistance in human mesothelial cells. Our RT-PCR results showed that three ENaC subunits, namely, a, b, g, and two d ENaC subunits, are expressed in human primary pleural mesothelial cells, a human mesothelioma cell line (M9K), and mouse pleural tissue. In addition, Western blotting and immunofluorescence microscopy studies revealed that a, b, g, and d ENaC subunits are expressed in primary human mesothelial cells and M9K cells at the protein level. An amiloride-inhibitable short-circuit current was detected in M9K monolayers and mouse pleural tissues when mounted in Ussing chambers. Whole-cell patch clamp recordings showed an ENaC-like channel with an amiloride concentration producing 50% inhibition of 12 mM in M9K cells. This cation channel has a high affinity for extracellular Na 1 ions (K m : 53 mM). The ion selectivity of this channel to cations follows the same order as ENaC: Li 1 . Na 1 . K 1 . The unitary Li 1 conductance was 15 pS in on-cell patches. Four ENaC subunits form a functional Na 1 channel when coinjected into Xenopus oocytes. Furthermore, we found that both forskolin and cGMP increased the short-circuit currents in mouse pleural tissues. Taken together, our data demonstrate that the ENaC channels are biochemically and functionally expressed in human pleural mesothelial cells, and can be up-regulated by cyclic AMP and cyclic GMP.

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mentioning

confidence: 65%

Expression and Regulation of Epithelial Na⁺ Channels by Nucleotides in Pleural Mesothelial Cells

Nie

Tucker²,

et al. 2009

Am J Respir Cell Mol Biol

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“…Neither terbutaline nor amiloride affected osmotic water movement. Terbutaline has long been used clinically to effectively ameliorate pulmonary edema by up-regulating ENaC activity and thereby expediting edematous liquid clearance [16,17]. These exciting observations support the scenario that ENaC channels are functionally expressed in pleural tissues and contribute to pleural fluid re-absorption.…”

Section: I-1 Amiloride-inhibitable Cation Channelsmentioning

confidence: 82%

Electrolyte and Fluid Transport in Mesothelial Cells

Ji¹,

Nie²

2008

JEBP

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Mesothelial cells are specialized epithelial cells, which line the pleural, pericardial, and peritoneal cavities. Accumulating evidence suggests that the monolayer of mesothelial cells is permeable to electrolyte and fluid, and thereby govern both fluid secretion and re-absorption in the serosal cavities. Disorders in these salt and fluid transport systems may be fundamental in the pathogenesis of pleural effusion, pericardial effusion, and ascites. In this review, we discuss the location, physiological function, and regulation of active transport (Na + -K + -ATPase) systems, cation and anion channels (Na + , K + , Cl − , and Ca 2+ channels), antiport (exchangers) systems, and symport (co-transporters) systems, and water channels (aquaporins). These secretive and absorptive pathways across mesothelial monolayer cells for electrolytes and fluid may provide pivotal therapeutical targets for novel clinical intervention in edematous diseases of serous cavities. Keywords mesothelioma; ion channel; permeability; effusion; filtration; ENaC Mesothelial cells are specialized epithelial cells that line the serous cavities, including the pleural, pericardial, and peritoneal cavities in addition to internal organs [1]. While the mesothelium was first described more than a century ago, one of its critical essential functions, namely, its active roles in transerosal transport, in particular, cavity fluid secretion and reabsorption, was long overlooked. Only in last two decades compelling evidence accumulated that mesothelial cells actively transport electrolytes and fluid and, in turn, regulate liquid volume within the cavities. The mesothelium, on the basis of recent increasing experimental evidence, both in vitro and in vivo, is less permeable to electrolytes than was previously assumed, with ion permeability characteristics similar to those in epithelia [2,3]. Herein this article we will review the expression and biophysical features of salt and fluid transport systems, both active and passive, that have been identified in mesothelial cells (Fig. 1, Tables 1 and 2). I. ION CHANNELS AND ATPASE I-1. Amiloride-Inhibitable Cation ChannelsThe epithelial sodium channel (ENaC), as a major pathway which participates in sodium movement across the apical membrane of polarized epithelial cells, has been cloned and characterized [4][5][6] ENaC subunits have been cloned to date, namely α-, β-, γ-, δ-, and ε-ENaC [7]. The biophysical properties of various ENaC channels depend on their subunit compositions. When expressed in oocytes one of "conductive" subunits (α, δ, and ε-ENaC) can form a channel sharing identical biophysical properties to three-subunit channels composed of both a "conductive" subunit and two "non-conductive" subunits, namely, β-and γ-ENaCs. When α-, β-, and γ-ENaC subunits are assembled together, the result is a 4-to 6-pS channel that is highly selective for Na + over K + . In contrast, two-subunit α β-and α γ-ENaC channels display diverse amiloride sensitivity, conductance, and Na + permeability [8]. ENaC is...

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“…However, most experimental studies suggest that down-regulation of b 2 -receptors is a minor factor (32,33). A fourth possibility is that there were differences between study groups in the proportions of patients with genetic variants that determine individual responses to b 2 -adrenergic stimulation in the distal lung epithelium, as reported in patients with asthma (34).…”

Section: Discussionmentioning

confidence: 99%

Randomized, Placebo-controlled Clinical Trial of an Aerosolized β₂-Agonist for Treatment of Acute Lung Injury

Lung¹

2011

Am J Respir Crit Care Med

396

166

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Rationale: b 2 -Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies. Objectives: This clinical trial was designed to test the hypothesis that an aerosolized b 2 -agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI). Methods: We conducted a multicenter, randomized, placebocontrolled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days. Measurements and Main Results: Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P ¼ 0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95% confidence interval for the difference, -4.0 to 14.7%; P ¼ 0.30). In the subset of patients with shock before randomization, the number of ventilator-free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different. Conclusions: These results suggest that aerosolized albuterol does not improve clinical outcomes in patients with ALI. Routine use of b 2 -agonist therapy in mechanically ventilated patients with ALI cannot be recommended. Clinical trial registered with www.clinicaltrials.gov (NCT 00434993).Keywords: pulmonary edema; acute respiratory distress syndrome; alveolar epitheliumIn patients with acute lung injury and the acute respiratory distress syndrome (ALI/ARDS), inflammation of the pulmonary circulation increases vascular permeability. Fluid leaks from blood vessels into the pulmonary interstitium and alveoli. Recovery from this form of acute respiratory failure requires that the pulmonary edema resolve. The resolution of alveolar edema is driven by active transport of sodium and chloride ions from the luminal space across both type I and type II alveolar epithelial cells, creating an osmotic gradient for the reabsorption of water (1-4). The rate of alveolar fluid transport is increased by endogenous or exogenous cyclic AMP stimulation, which increases ion transport through epithelial sodium channels and chloride channels such as the cystic fibrosis transmembrane regulator (5, 6). In the ex vivo human lung, the rate of alveolar fluid clearance can be doubled by treatment with a cyclic AMP b 2 -adrenergic receptor agonist (7,8).Alveolar epithelial fluid clearance is impaired during ALI/ ARDS, and decreased resolution of alveolar edema is associated with increased mortality (9, 10). There are several potential mechanisms of decreased...

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Selected Contribution: Long-term effects of β₂-adrenergic receptor stimulation on alveolar fluid clearance in mice

Cited by 41 publications

References 39 publications

Expression and Regulation of Epithelial Na⁺ Channels by Nucleotides in Pleural Mesothelial Cells

Expression and Regulation of Epithelial Na⁺ Channels by Nucleotides in Pleural Mesothelial Cells

Electrolyte and Fluid Transport in Mesothelial Cells

Randomized, Placebo-controlled Clinical Trial of an Aerosolized β₂-Agonist for Treatment of Acute Lung Injury

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Selected Contribution: Long-term effects of β2-adrenergic receptor stimulation on alveolar fluid clearance in mice

Cited by 41 publications

References 39 publications

Expression and Regulation of Epithelial Na+ Channels by Nucleotides in Pleural Mesothelial Cells

Expression and Regulation of Epithelial Na+ Channels by Nucleotides in Pleural Mesothelial Cells

Electrolyte and Fluid Transport in Mesothelial Cells

Randomized, Placebo-controlled Clinical Trial of an Aerosolized β2-Agonist for Treatment of Acute Lung Injury

Contact Info

Product

Resources

About

Selected Contribution: Long-term effects of β₂-adrenergic receptor stimulation on alveolar fluid clearance in mice

Expression and Regulation of Epithelial Na⁺ Channels by Nucleotides in Pleural Mesothelial Cells

Expression and Regulation of Epithelial Na⁺ Channels by Nucleotides in Pleural Mesothelial Cells

Randomized, Placebo-controlled Clinical Trial of an Aerosolized β₂-Agonist for Treatment of Acute Lung Injury