Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine*

Sakuma, Tsutomu; Gu, Xia; Wang, Zheng; Maeda, Shin; Sugita, Makoto; Sagawa, Motoyasu; Osanai, Kazuhiro; Toga, Hirohisa; Ware, Lorraine B.; Folkesson, G.; Matthay, Michael A.

doi:10.1097/01.ccm.0000201403.70636.0f

Cited by 47 publications

(35 citation statements)

References 22 publications

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“…On the basis of previous studies, this level of epinephrine should not have stimulated the resolution of alveolar edema (29,30). Baseline epinephrine levels were significantly higher in the albuterol-treated patients, although this difference was modest.…”

Section: Resultsmentioning

confidence: 83%

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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Section: Resultsmentioning

confidence: 83%

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

View full text Add to dashboard Cite

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“…In addition, changes in the activity or expression of ion transport mechanism could also modify the therapeutic effect of the betaadrenergic agonists. In recent experiments in which the expression of ENaC was decreased with small interfering RNA against alpha ENaC, there was not only a decrease in the amiloridesensitive alveolar liquid clearance but also an inhibition of terbutaline stimulation of alveolar liquid clearance (Folkesson, H. G. et al 2006). These results might explain the lack of stimulation of alveolar liquid clearance by beta-adrenergic agonist in ischemia-reperfusion injury (Sugita, M. et al 2003) since there was a significant decrease in ENaC expression in those lungs.…”

Section: Edema Clearance In Injured Lungsmentioning

confidence: 99%

Alveolar edema fluid clearance and acute lung injury

Berthiaume

Matthay

2007

Respiratory Physiology & Neurobiology

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139

127

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Although lung-protective ventilation strategies have substantially reduced mortality of acute lung injury patients there is still a need for new therapies that can further decrease mortality in patients with acute lung injury. Studies of epithelial ion and fluid transport across the distal pulmonary epithelia have provided important new concepts regarding potential new therapies for acute lung injury. Overall, there is convincing evidence that the alveolar epithelium is not only a tight epithelial barrier that resists the movement of edema fluid into the alveoli, but it is also actively involved in the transport of ions and solutes, a process that is essential for edema fluid clearance and the resolution of acute lung injury. The objective of this article is to consider some areas of recent progress in the field of alveolar fluid transport under normal and pathologic conditions. Vectorial ion transport across the alveolar and distal airway epithelia is the primary determinant of alveolar fluid clearance. The general paradigm is that active Na + and Cl − transport drives net alveolar fluid clearance, as demonstrated in several different species, including the human lung. Although these transport processes can be impaired in severe lung injury, multiple experimental studies suggest that upregulation of Na + and Cl − transport might be an effective therapy in acute lung injury. We will review mechanisms involved in pharmacological modulation of ion transport in lung injury with a special focus on the use of β-adrenergic agonists which has generated considerable interest and is a promising therapy for clinical acute lung injury.

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“…Human lung segments were prepared and AFC measurements were done as described previously (27,28). Briefly, the segmental bronchus was occluded by a 10-Fr.…”

Section: Ex Vivo Afc In Human Lungsmentioning

confidence: 99%

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels

Han

Nie²,

et al. 2011

Am J Respir Cell Mol Biol

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Salt absorption via alveolar epithelial Na 1 channels (ENaC) is a critical step for maintaining an airspace free of flooding. Previously, we found that 8-(4-chlorophenylthio)-guanosine-39,59-cyclic monophosphate-Na (CPT-cGMP) activated native and heterologous ENaC. To investigate the potential pharmacological relevance, we applied this compound intratracheally to human lungs and found that ex vivo alveolar fluid clearance was increased significantly. Furthermore, this compound eliminated self-inhibition in human lung H441 cells and in oocytes expressing human abg but not dbg channels. To further elucidate this novel mechanism, we constructed mutants abolishing (b DV348 and g H233R ) or augmenting (a Y458A and g M432G ) self-inhibition. The mutants eliminating self-inhibition lost their responses to CPT-cGMP, whereas those enhancing self-inhibition facilitated the stimulatory effects of this compound. CPT-cGMP was unable to activate a high P o mutant (b S520C ) and plasmin proteolytically cleaved channels. Our data suggest that elimination of self-inhibition of abg ENaC may be a novel mechanism for CPT-cGMP to stimulate salt reabsorption in human lungs.Keywords: lung fluid reabsorption; amiloride-sensitive sodium channel; CPT-cGMP; ENaC self-inhibition Epithelial Na1 channels (ENaC) in polarized absorptive tight epithelium are responsible for the transapical salt influx. Together with basolaterally located Na 1 /K 1 -ATPase, the vectorial solute/fluid transport pathway is crucial for maintaining luminal and body fluid volume (1-3). Five subunits have been cloned: a, b, g, d, and e ENaC. Luminal impermeable reagents and hormones have been confirmed to regulate salt reabsorption in lung, kidney, and colon.ENaC has long been proposed to function as a ligand-gated channel on the basis of observations of other ENaC/DEG family members (1, 4). Acid-sensing Na 1 channels, a branch of the ENaC/DEG super gene family, are gated by external protons. Another branch of channels, termed FaNaC, are manipulated by FMRFamide and related tetrapeptides (5). With respect to ENaC channels, a number of luminal reagents, including parachloromercuribenzoate; benzimidazoly-2-guanidinium; bumetanide; and H 1 , Zn 21 , and Ni 21 ions, have been reported to alter external Na 1 self-inhibition, a temperature-sensitive intrinsic phenomenon of ENaC (1, 4, 6-10). Recently, a small molecule (S6939), cpt-cAMP, halothane, glibenclamide, and extracellular chloride ions (Cl 2 ) have been shown to act as ligands to regulate heterologous ENaC (11-16). Among these, halothane and Cl 2 ions may activate ENaC by eliminating Na 1 self-inhibition (17, 18). We recently found that 8-(4-chlorophenylthio)-guanosine-39,59-cyclic monophosphate-Na (CPT-cGMP) stimulated human abg ENaC in oocytes in a PKG-independent and domain-specific manner (19). The underlying mechanisms are unknown.Several ectodomains have been reported to modify self-inhibition by unknown mechanisms. Given that self-inhibition is governed by the extracellular Na 1 concentrations, the extracellu...

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Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine*

Cited by 47 publications

References 22 publications

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

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

Alveolar edema fluid clearance and acute lung injury

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels

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Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine*

Cited by 47 publications

References 22 publications

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

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

Alveolar edema fluid clearance and acute lung injury

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na+ Self-Inhibition of Epithelial Na+ Channels

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

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

8-(4-Chlorophenylthio)-Guanosine-3′,5′-Cyclic Monophosphate-Na Stimulates Human Alveolar Fluid Clearance by Releasing External Na⁺ Self-Inhibition of Epithelial Na⁺ Channels