Ursodeoxycholic acid inhibits ENaC and Na/K pump activity to restore airway surface liquid height in cystic fibrosis bronchial epithelial cells

Steroids ◽  
2019 ◽  
Vol 151 ◽  
pp. 108461 ◽  
Author(s):  
Magdalena S. Mroz ◽  
Brian J. Harvey
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Ursodeoxycholic Acid ◽  
Bronchial Epithelial Cells ◽  
Airway Surface Liquid ◽  
Bronchial Epithelial ◽  
Liquid Height ◽  
Pump Activity ◽  
Surface Liquid

scholarly journals Culture with apically applied healthy or disease sputum alters the airway surface liquid proteome and ion transport across human bronchial epithelial cells.

2021 ◽  
Author(s):  
Maximillian Woodall ◽  
Boris Reidel ◽  
Mehmet Kesimer ◽  
Robert Tarran ◽  
Deborah L Baines
Keyword(s):  
Epithelial Cells ◽  
Ion Transport ◽  
Short Circuit ◽  
Bronchial Epithelial Cells ◽  
Airway Surface Liquid ◽  
Human Bronchial Epithelial Cells ◽  
Bronchial Epithelial ◽  
Surface Liquid

Airway secretions contain many signalling molecules and peptides/proteins that are not found in airway surface liquid (ASL) generated by normal human bronchial epithelial cells (NHBE) in vitro. These play a key role in innate defence and mediate communication between the epithelium, immune cells and the external environment. We investigated how culture of NHBE with apically applied secretions from healthy or disease (Cystic Fibrosis, CF) lungs affected epithelial function with a view to providing better in vitro models of the in vivo environment. NHBE from 6-8 different donors were cultured at air-liquid interface (ALI), with apically applied sputum from normal healthy donors (NLS) or CF donors (CFS) for 2-4 hours, 48 hours or with sputum reapplied over 48 hours. Proteomic analysis was carried out on the sputa and on NHBE ASL before and after culture with sputa. Transepithelial electrical resistance (TEER), short circuit current (Isc) and changes to ASL height were measured. There were 71 proteins common to both sputa but not ASL. The protease:protease inhibitor balance was increased in CFS compared to NLS and ASL. Culture of NHBE with sputa for 48 hours identified additional factors not present in NLS, CFS or ASL alone. Culture with either NLS or CFS for 48 hours increased CFTR activity, calcium activated chloride channel (CaCC) activity and changed ASL height. These data indicate that culture with healthy or disease sputum changes the proteomic profile of ASL and ion transport properties of NHBE and this may increase physiological relevance when using in vitro airway models.

scholarly journals High-Throughput Surface Liquid Absorption and Secretion Assays to Identify F508del CFTR Correctors Using Patient Primary Airway Epithelial Cultures

2019 ◽  
Vol 24 (7) ◽  
pp. 724-737 ◽  
Author(s):  
Allison Berg ◽  
Shawn Hallowell ◽  
Mark Tibbetts ◽  
Chad Beasley ◽  
Tracy Brown-Phillips ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
High Throughput ◽  
High Throughput Screening ◽  
Bronchial Epithelial Cells ◽  
Cellular Systems ◽  
Primary Cells ◽  
Bronchial Epithelial ◽  
Epithelial Cultures ◽  
Surface Liquid

High-throughput screening for drug discovery is increasingly utilizing cellular systems of high physiological relevance, such as patient primary cells and organoid cultures. We used 3D-cultured cystic fibrosis patient bronchial epithelial cells to screen for new small-molecule correctors of the disease-causing F508del mutation in CFTR. Impaired mucociliary clearance due to insufficient airway hydration is a hallmark of cystic fibrosis and we used a simple measure of surface liquid levels to quantify F508del CFTR correction in cultured bronchial epithelial cells. Two robust assay formats were configured and used to screen more than 100,000 compounds as mixtures or individual compounds in 96-well format. The corrector discovery success rate, as measured by the number of hits confirmed by an electrophysiology assay on patient primary bronchial epithelial cells, was superior to screens in cell lines expressing recombinant F508del CFTR. Several novel corrector scaffolds were discovered that when combined with the clinical corrector VX-809 delivered combination responses greater than double that of VX-809 alone. This work exemplifies the advantages of a disease-relevant readout and 3D-cultured patient primary cells for the discovery of new drug candidates.

Interaction of environmental Burkholderia cenocepacia strains with cystic fibrosis and non-cystic fibrosis bronchial epithelial cells in vitro

Microbiology ◽  
2012 ◽  
Vol 158 (5) ◽  
pp. 1325-1333 ◽  
Author(s):  
Annamaria Bevivino ◽  
Luisa Pirone ◽  
Ruth Pilkington ◽  
Noemi Cifani ◽  
Claudia Dalmastri ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Bronchial Epithelial Cells ◽  
Burkholderia Cenocepacia ◽  
Bronchial Epithelial
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