Cystic Fibrosis Transmembrane Conductance Regulator

Publication Title: 
Drugs of Today (Barcelona, Spain: 1998)

Cystic fibrosis (CF) is a life-shortening disorder that affects over 30,000 people in the U.S. and 70,000 worldwide. CF is caused by mutations in the CFTR gene, which codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is a chloride and bicarbonate channel and regulates several ion transporters at the epithelial cell membrane, controlling hydration or ionic composition of epithelial secretions. Management of CF is currently supportive, but recent advances in drug development have focused on therapies that assist mutant CFTR function.

Author(s): 
McPhail, G. L.
Clancy, J. P.
Publication Title: 
American Journal of Respiratory Cell and Molecular Biology

Cystic fibrosis (CF) is characterized by prolonged and excessive inflammatory responses in the lung and increased activation of NF-kappaB. Parthenolide is a sesquiterpene lactone derived from the plant feverfew, which has been used in folk medicine for anti-inflammatory activity. Several studies suggest that this compound inhibits the NF-kappaB pathway, but the exact site is controversial. We hypothesized that parthenolide might ameliorate the excessive inflammatory response in CF models by inhibiting activation of NF-kappaB.

Author(s): 
Saadane, Aicha
Masters, Sophia
DiDonato, Joseph
Li, Jingfeng
Berger, Melvin
Publication Title: 
Free Radical Biology & Medicine

In cystic fibrosis reduced CFTR function may alter redox properties of airway epithelial cells. Redox-sensitive GFP (roGFP1) and imaging microscopy were used to measure the redox potentials of the cytosol, endoplasmic reticulum (ER), mitochondria, and cell surface of cystic fibrosis nasal epithelial cells and CFTR-corrected cells. We also measured glutathione and cysteine thiol redox states in cell lysates and apical fluids to provide coverage over a range of redox potentials and environments that might be affected by CFTR.

Author(s): 
Schwarzer, Christian
Illek, Beate
Suh, Jung H.
Remington, S. James
Fischer, Horst
Machen, Terry E.
Publication Title: 
American Journal of Physiology. Lung Cellular and Molecular Physiology

Activation of an innate immune response in airway epithelia by the human pathogen Pseudomonas aeruginosa requires bacterial expression of flagellin. Addition of flagellin (10(-7) M) to airway epithelial cell monolayers (Calu-3, airway serous cell-like) increased Cl(-) secretion (I(Cl)) beginning after 3-10 min, reaching a plateau after 20-45 min at DeltaI(Cl) = 15-50 microA/cm(2). Similar, although 10-fold smaller, responses were observed in well-differentiated bronchial epithelial cultures.

Author(s): 
Illek, Beate
Fu, Zhu
Schwarzer, Christian
Banzon, Tina
Jalickee, Stephen
Miller, Sheldon S.
Machen, Terry E.
Publication Title: 
Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology

Little is known about the relationship between CF transmembrane conductance regulator (CFTR) gene expression and the corresponding transport of Cl. The phenotypic characteristics of polarized DeltaF508 homozygote CF bronchial epithelial (CFBE41o-) cells were evaluated following transfection with episomal expression vector containing either full-length (6.2kb) wild type (wt) and (4.7kb) DeltaF508CFTR cDNA.

Author(s): 
Illek, Beate
Maurisse, Rosalie
Wahler, Logan
Kunzelmann, Karl
Fischer, Horst
Gruenert, Dieter C.
Publication Title: 
Free Radical Biology & Medicine

Pyocyanin (N-methyl-1-hydroxyphenazine), a redox-active virulence factor produced by the human pathogen Pseudomonas aeruginosa, is known to compromise mucociliary clearance. Exposure of human bronchial epithelial cells to pyocyanin increased the rate of cellular release of H(2)O(2) threefold above the endogenous H(2)O(2) production.

Author(s): 
Schwarzer, Christian
Fischer, Horst
Kim, Eun-Jin
Barber, Katharine J.
Mills, Aaron D.
Kurth, Mark J.
Gruenert, Dieter C.
Suh, Jung H.
Machen, Terry E.
Illek, Beate
Publication Title: 
Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology

The flavone apigenin has been previously selected as a potent pharmacological activator of the CFTR Cl(-) channel, however, its utility for the activation of CFTR in vivo is expected to be limited because flavonoids are readily metabolized. We therefore investigated the poorly metabolizable methylether of apigenin, 5,7,4'-trimethoxyflavone (TMF) as a CFTR activator using transepithelial short-circuit current measurements, whole cell and single cell patch clamp techniques, and nasal potential difference (PD) measurements.

Author(s): 
Fischer, Horst
Illek, Beate
Publication Title: 
American Journal of Rhinology & Allergy

BACKGROUND: Chronic rhinosinusitis (CRS) occurs at high frequency in patients with cystic fibrosis, suggesting that the cystic fibrosis transmembrane conductance regulator (CFTR) chloride (Cl) ion channel might be involved in the development of chronic sinusitis in the general population. CFTR Cl ion transport controls the hydration of mucosal surfaces and promotes effective mucociliary clearance. Altered ion transport and, hence, disrupted mucociliary function, could play a role in the pathogenesis of sinus disease.

Author(s): 
Cho, Do-Yeon
Hwang, Peter H.
Illek, Beate
Publication Title: 
American Journal of Respiratory Cell and Molecular Biology

Therapies to correct the ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) folding defect require sensitive methods to detect channel activity in vivo. The β₂ adrenergic receptor agonists, which provide the CFTR stimuli commonly used in nasal potential difference assays, may not overcome the channel gating defects seen in ΔF508 CFTR after plasma membrane localization. In this study, we identify an agent, quercetin, that enhances the detection of surface ΔF508 CFTR, and is suitable for nasal perfusion.

Author(s): 
Pyle, Louise C.
Fulton, Jennifer C.
Sloane, Peter A.
Backer, Kyle
Mazur, Marina
Prasain, Jeevan
Barnes, Stephen
Clancy, J. P.
Rowe, Steven M.
Publication Title: 
Protein engineering, design & selection: PEDS

Post-translational modifications (PTMs) play a crucial role during biogenesis of many transmembrane proteins. Previously, it had not been possible to evaluate PTMs in cystic fibrosis transmembrane conductance regulator (CFTR), the epithelial ion channel responsible for cystic fibrosis, because of difficulty obtaining sufficient amounts of purified protein. We recently used an inducible overexpression strategy to generate recombinant CFTR protein at levels suitable for purification and detailed analysis.

Author(s): 
McClure, Michelle
DeLucas, Lawrence J.
Wilson, Landon
Ray, Marjorie
Rowe, Steven M.
Wu, Xiaoyun
Dai, Qun
Hong, Jeong S.
Sorscher, Eric J.
Kappes, John C.
Barnes, Stephen

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