Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone

Bossmann, Miriam; Ackermann, B.; Thomé, Ulrich; Laube, Mandy

doi:10.3390/ijms18081807

Cited by 6 publications

(4 citation statements)

References 47 publications

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“…It has been shown in human cell culture that dexamethasone regulates wild-type CFTR protein post-transcriptionally, enhancing maturation and expression [ 106 ], and induces SGK1, which selectively increases wild-type CFTR in the plasma membrane by inhibiting its endocytic retrieval from the membrane [ 107 ]. Additionally, dexamethasone stimulates CFTR activity through nongenomic signalling in rats [ 108 ].…”

Section: Mechanisms Of Acquired Cftr Dysfunctionmentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

et al. 2022

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The cystic fibrosis transmembrane conductance regulator (CFTR) is a crucial ion channel for transport of chloride and bicarbonate anions. Functional roles of CFTR have been identified in a broad range of cell types including epithelial, endothelial, immune, and structural cells. While CFTR has been investigated largely in the context of inborn dysfunction in cystic fibrosis (CF), recent evidence shows CFTR is also affected by acquired dysfunction in chronic obstructive pulmonary disease (COPD). In patients with COPD and smokers, CFTR impairment has been demonstrated in the upper and lower airways, sweat glands and intestines, suggesting both pulmonary and systemic defects. Cigarette smoke, a key factor in COPD development, is the major cause of acquired CFTR dysfunction. Inflammation, bacterial by-products, and reactive oxygen species can further impair CFTR expression and function. CFTR dysfunction could directly contribute to disease manifestation and progression of COPD including disturbed airway surface liquid homeostasis, airway mucus obstruction, pathogen colonisation and inflammation. Mucus plugging and neutrophilic inflammation contribute to tissue destruction, development of dysfunction at the level of the small airways and COPD progression. Acquired CFTR dysfunction in extra-pulmonary organs could add to common co-morbidities and the disease burden. This review explores how CFTR dysfunction may be acquired and its potential effects on patients with COPD, particularly those with chronic bronchitis. The development of CFTR potentiators and the probable benefits of CFTR potentiation to improve tissue homeostasis, reduce inflammation, improve host defence, and potentially reduce remodelling in the lungs will be discussed.

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Section: Mechanisms Of Acquired Cftr Dysfunctionmentioning

confidence: 99%

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

et al. 2022

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“…Western blot studies were performed as described elsewhere [ 43 ]. Phosphorylation of AKT was analyzed using antibodies against phospho-AKT at Ser473 (# 9271, Cell Signaling Technology, Inc.) and AKT (# 9272, Cell Signaling Technology, Inc., both kindly provided by A. Garten).…”

Section: Methodsmentioning

confidence: 99%

Albumin Stimulates Epithelial Na+ Transport and Barrier Integrity by Activating the PI3K/AKT/SGK1 Pathway

Laube

Thomé

2022

IJMS

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Albumin is a major serum protein and is frequently used as a cell culture supplement. It is crucially involved in the regulation of osmotic pressure and distribution of fluid between different compartments. Alveolar epithelial Na+ transport drives alveolar fluid clearance (AFC), enabling air breathing. Whether or not albumin affects AFC and Na+ transport is yet unknown. We therefore determined the acute and chronic effects of albumin on Na+ transport in fetal distal lung epithelial (FDLE) cells and the involved kinase pathways. Chronic BSA treatment strongly increased epithelial Na+ transport and barrier integrity in Ussing chambers. BSA did not elevate mRNA expression of Na+ transporters in FDLE cells after 24 h. Moreover, acute BSA treatment for 45 min mimicked the chronic effects. The elevated Na+ transport was caused by an increased maximal ENaC activity, while Na,K-ATPase activity remained unchanged. Acute and chronic BSA treatment lowered membrane permeability, confirming the increased barrier integrity observed in Ussing chambers. Western blots demonstrated an increased phosphorylation of AKT and SGK1, and PI3K inhibition abolished the stimulating effect of BSA. BSA therefore enhanced epithelial Na+ transport and barrier integrity by activating the PI3K/AKT/SGK1 pathway.

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“…FDLE cell inserts were placed on ice, and protein lysates prepared and analyzed as described elsewhere 30 . Phosphorylation of AKT was analyzed using antibodies against phospho-AKT at Ser473 (# 9271, Cell Signaling Technology, Frankfurt am Main, Germany), and AKT (# 9272, Cell Signaling Technology, both kindly provided by A. Garten).…”

Section: Methodsmentioning

confidence: 99%

Epidermal growth factor strongly affects epithelial Na+ transport and barrier function in fetal alveolar cells, with minor sex-specific effects

Laube

Dornis

Wenzel

et al. 2021

Sci Rep

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Male sex remains an independent risk factor for respiratory distress syndrome (RDS) in preterm infants. Insufficient Na+ transport-mediated alveolar fluid clearance contributes to RDS development and we previously demonstrated sex-specific differences in Na+ transport. The epidermal growth factor (EGF) is important during fetal lung development with possible influence on Na+ transport. Sex-specific effects of EGF during surfactant synthesis were shown. We thus determined whether EGF exerts sex-specific effects on Na+ transport in fetal alveolar cells. We analyzed sex-specific fetal distal lung epithelial (FDLE) cells exposed to EGF and related ligands with Ussing chambers, RT-qPCR and Western blots. EGF strongly reduced the epithelial Na+ channel (ENaC) mRNA levels in both male and female FDLE cells. This was corroborated by a markedly reduced ENaC activity, while amiloride-insensitive pathways as well as barrier function were raised by EGF. In contrast to chronic effects, acute effects of EGF were sex-specific, because Na+ transport was reduced only in males. AKT phosphorylation was elevated only in female cells, while pERK1/2 was increased in both male and female cells. EGF showed certain sex- and time-dependent effects in FDLE cells. Nevertheless, the results suggest that EGF is an unlikely cause for the sex-specific differences in Na+ transport.

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Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone

Cited by 6 publications

References 47 publications

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond

Albumin Stimulates Epithelial Na+ Transport and Barrier Integrity by Activating the PI3K/AKT/SGK1 Pathway

Epidermal growth factor strongly affects epithelial Na+ transport and barrier function in fetal alveolar cells, with minor sex-specific effects

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