Impairment of mucociliary clearance with reduced airway fluid secretion leads to
chronically inflamed airways. Cystic fibrosis transmembrane conductance regulator (CFTR) is
crucially involved in airway fluid secretion and dexamethasone (dexa) has previously been shown to
elevate CFTR activity in airway epithelial cells. However, the pathway by which dexa increases CFTR
activity is largely unknown. We aimed to determine whether the increase of CFTR activity by dexa
is achieved by non-genomic signaling and hypothesized that the phosphoinositide 3-kinase (PI3K)
pathway is involved in CFTR stimulation. Primary rat airway epithelial cells and human bronchial
submucosal gland-derived Calu-3 cells were analyzed in Ussing chambers and kinase activation was
determined byWestern blots. Results demonstrated a critical involvement of PI3K and protein kinase
B (AKT) signaling in the dexa-induced increase of CFTR activity, while serum and glucocorticoid
dependent kinase 1 (SGK1) activity was not essential. We further demonstrated a reduced neural
precursor cell expressed, developmentally downregulated 4-like (NEDD4L) ubiquitin E3 ligase
activity induced by dexa, possibly responsible for the elevated CFTR activity. Finally, increases of
CFTR activity by dexa were demonstrated within 30 min accompanied by rapid activation of AKT.
In conclusion, dexa induces a rapid stimulation of CFTR activity which depends on PI3K/AKT
signaling in airway epithelial cells. Glucocorticoids might thus represent, in addition to their
immunomodulatory actions, a therapeutic strategy to rapidly increase airway fluid secretion.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89018 |
| Date | 15 January 2024 |
| Creators | Bossmann, Miriam, Ackermann, Benjamin W., Thome, Ulrich H., Laube, Mandy |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 1807 |
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