TGF-β directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury

Peters, Dorothea M.; Vadász, István; Wujak, Lukasz; Wygrecka, Małgorzata; Olschewski, Andrea; Becker, Christin; Herold, Susanne; Papp, Rita; Mayer, Konstantin; Rummel, Sebastian; Brandes, Ralf P.; Günther, Andreas; Waldegger, Siegfried; Eickelberg, Oliver; Seeger, Werner; Morty, Rory E.

doi:10.1073/pnas.1306798111

Cited by 116 publications

(124 citation statements)

References 71 publications

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“…Second, ENaC-γ activity and trafficking such as ion and fluid transport need to be evaluated. 53 Finally, the mechanism we demonstrated based on our in vitro study; it would be of interest to further substantiate our findings that miR-21/PTEN/AKT pathway contributes to the lung antiedema effects of LXA 4 in vivo.…”

Section: Discussionsupporting

confidence: 55%

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

Cai

et al. 2015

Laboratory Investigation

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Lipoxin A 4 (LXA 4 ), as an endogenously produced lipid mediator, promotes the resolution of inflammation. Previously, we demonstrated that LXA 4 stimulated alveolar fluid clearance through alveolar epithelial sodium channel gamma (ENaC-γ). In this study, we sought to investigate the mechanisms of LXA 4 in modulation of ENaC-γ in lipopolysaccharide (LPS)-induced inflammatory lung injury. miR-21 was upregulated during an LPS challenge and downregulated by LXA 4 administration in vivo and in vitro. Serum miR-21 concentration was also elevated in acute respiratory distress syndrome patients as compared with healthy volunteers. LPS increased miR-21 expression by activation of activator protein 1 (AP-1). In A549 cells, miR-21 upregulated phosphorylation of AKT activation via inhibition of phosphatase and tensin homolog (PTEN), and therefore reduced the expression of ENaC-γ. In contrast, LXA 4 reversed LPS-inhibited ENaC-γ expression through inhibition of AP-1 and activation of PTEN. In addition, an miR-21 inhibitor mimicked the effects of LXA 4 ; overexpression of miR-21 abolished the protective effects of LXA 4 . Finally, both AKT and ERK inhibitors (LY294002 and UO126) blocked effects of LPS on the depression of ENaC-γ. However, LXA 4 only inhibited LPS-induced phosphorylation of AKT. In summary, LXA 4 activates ENaC-γ in part via the miR-21/PTEN/AKT signaling pathway.

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Section: Discussionsupporting

confidence: 55%

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

Cai

et al. 2015

Laboratory Investigation

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“…2A) due to epithelial sodium channel activity, an effect previously reported in alveolar epithelia (22).…”

Section: Journal Of Biological Chemistry 25711supporting

confidence: 51%

Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone

Manzanares

Krick

Baumlin

et al. 2015

Journal of Biological Chemistry

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Background: TGF-␤ is associated with worse outcome in cystic fibrosis (CF). Results: TGF-␤ causes mucociliary dysfunction by reducing airway surface liquid (ASL) due to decreased apical BK channel activity and down-regulation of its ␥ subunit LRRC26. Conclusion:The TGF-␤ inhibitor pirfenidone reverses ASL loss via BK and LRRC26 rescue. Significance: Clinical trials could test the usefulness of pirfenidone in CF.

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“…Several cytokines present in the airspaces of patients with ARDS, including IL-1b, IL-8, and transforming growth factor-b, were shown to decrease vectorial fluid transport across alveolar epithelium by reducing the expression and function of Na/K-ATPase and ENaC (58)(59)(60)(61)(62). Viral infection with influenza was found to impair the function of ENaC.…”

Section: Resolution Of Lung Edema In the Injured Lung (Ards)mentioning

confidence: 99%

Resolution of Pulmonary Edema. Thirty Years of Progress

Matthay

2014

Am J Respir Crit Care Med

138

111

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In the last 30 years, we have learned much about the molecular, cellular, and physiological mechanisms that regulate the resolution of pulmonary edema in both the normal and the injured lung. Although the physiological mechanisms responsible for the formation of pulmonary edema were identified by 1980, the mechanisms that explain the resolution of pulmonary edema were not well understood at that time. However, in the 1980s several investigators provided novel evidence that the primary mechanism for removal of alveolar edema fluid depended on active ion transport across the alveolar epithelium. Sodium enters through apical channels, primarily the epithelial sodium channel, and is pumped into the lung interstitium by basolaterally located Na/K-ATPase, thus creating a local osmotic gradient to reabsorb the water fraction of the edema fluid from the airspaces of the lungs. The resolution of alveolar edema across the normally tight epithelial barrier can be up-regulated by cyclic adenosine monophosphate (cAMP)-dependent mechanisms through adrenergic or dopamine receptor stimulation, and by several cAMPindependent mechanisms, including glucocorticoids, thyroid hormone, dopamine, and growth factors. Whereas resolution of alveolar edema in cardiogenic pulmonary edema can be rapid, the rate of edema resolution in most patients with acute respiratory distress syndrome (ARDS) is markedly impaired, a finding that correlates with higher mortality. Several mechanisms impair the resolution of alveolar edema in ARDS, including cell injury from unfavorable ventilator strategies or pathogens, hypoxia, cytokines, and oxidative stress. In patients with severe ARDS, alveolar epithelial cell death is a major mechanism that prevents the resolution of lung edema.Keywords: acute respiratory distress syndrome; acute lung injury; alveolar epithelium; alveolar liquid clearance; pulmonary edemaThe physiological basis for the formation of pulmonary edema was established by 1980. Cardiogenic pulmonary edema develops because of elevated vascular pressures in the lung (1), hence the term hydrostatic lung edema. Noncardiogenic pulmonary edema, clinically recognized as the acute respiratory distress syndrome (ARDS), is primarily the consequence of an increase in lung vascular and epithelial permeability (2). Several experimental studies had reported that the combination of elevated vascular pressure and an increase in lung vascular permeability would increase the accumulation of pulmonary edema (3, 4). And, in fact, elevated lung vascular pressures do coexist with an increase in lung vascular permeability in some clinical conditions that lead to ARDS, including sepsis and major trauma, as demonstrated definitively in a National Heart, Lung, and Blood Institute-supported multicenter clinical trial (5).However, the mechanisms responsible for the resolution of pulmonary edema were not well understood until research in the 1980s identified the primary mechanism responsible for the resolution of alveolar edema-active ion transport across the a...

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TGF-β directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury

Cited by 116 publications

References 71 publications

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

Lipoxin A4 activates alveolar epithelial sodium channel gamma via the microRNA-21/PTEN/AKT pathway in lipopolysaccharide-induced inflammatory lung injury

Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone

Resolution of Pulmonary Edema. Thirty Years of Progress

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