scholarly journals Defective Ion Channel in Cystic Fibrosis: Current Development in Treatment of Cystic Fibrosis

2020 ◽  
pp. 28-34
Author(s):  
Ngoga Godfrey ◽  
M. M. Ganyam ◽  
G.O. Ibiang ◽  
C. A. Difa ◽  
Nelson Christian
Keyword(s):  
Cystic Fibrosis ◽  
Ion Transport ◽  
Ion Channel ◽  
Lung Disease ◽  
Defense Mechanisms ◽  
Respiratory Infections ◽  
The Body ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Airway Defense

Cystic fibrosis is an inherited disorder that causes severe damage to the lungs, digestive system and other organs in the body. Cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the production of mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery. But in people with cystic fibrosis, a defective gene in CFTR causes the secretions to become sticky and thick. Instead of acting as a lubricant, the secretions plug up tubes, ducts and passage ways, especially in the lungs and pancreas. This mucus leads to the formation of bacterial microenvironments known as biofilms (a niche that harbors bacteria; Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa ) that are difficult for immune cells and antibiotics to penetrate. Viscous secretions and persistent respiratory infections repeatedly damage the lung by gradually remodeling the airways, which makes infection even more difficult to eradicate. CFTR, a Cl– selective ion channel, is a prototypic member of the ATP-binding cassette transporter super family that is expressed in several organs. Understanding how these complexes regulate the intracellular trafficking and activity of CFTR provides a unique insight into the aetiology of cystic fibrosis and other diseases associated to it. Cystic fibrosis patients exhibit lung disease consistent with a failure of innate airway defense mechanisms. The link between abnormal ion transport, disease initiation and progression is not fully understood, but airway mucus dehydration seems paramount in the initiation of CF lung disease. New therapies are currently in development that target the ion transport defects in CF with the intention of rehydrating airway surfaces.

scholarly journals Vx-809/Vx-770 treatment reduces inflammatory response to Pseudomonas aeruginosa in primary differentiated cystic fibrosis bronchial epithelial cells

2018 ◽  
Vol 314 (4) ◽  
pp. L635-L641 ◽  
Author(s):  
Manon Ruffin ◽  
Lucie Roussel ◽  
Émilie Maillé ◽  
Simon Rousseau ◽  
Emmanuelle Brochiero
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Respiratory Infections ◽  
Bronchial Epithelial Cell ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Bronchial Epithelial ◽  
Primary Bronchial Epithelial Cell ◽  
Beneficial Impact

Cystic fibrosis patients exhibit chronic Pseudomonas aeruginosa respiratory infections and sustained proinflammatory state favoring lung tissue damage and remodeling, ultimately leading to respiratory failure. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) function is associated with MAPK hyperactivation and increased cytokines expression, such as interleukin-8 [chemoattractant chemokine (C-X-C motif) ligand 8 (CXCL8)]. Recently, new therapeutic strategies directly targeting the basic CFTR defect have been developed, and ORKAMBI (Vx-809/Vx-770 combination) is the only Food and Drug Administration-approved treatment for CF patients homozygous for the F508del mutation. Here we aimed to determine the effect of the Vx-809/Vx-770 combination on the induction of the inflammatory response by fully differentiated primary bronchial epithelial cell cultures from CF patients carrying F508del mutations, following exposure to P. aeruginosa exoproducts. Our data unveiled that CFTR functional rescue with Vx-809/Vx-770 drastically reduces CXCL8 (as well as CXCL1 and CXCL2) transcripts and p38 MAPK phosphorylation in response to P. aeruginosa exposure through a CFTR-dependent mechanism. These results suggest that ORKAMBI has anti-inflammatory properties that could decrease lung inflammation and contribute to the observed beneficial impact of this treatment in CF patients.

Cystic fibrosis transmembrane conductance regulator modulators for cystic fibrosis: a new dawn?

2021 ◽  
pp. archdischild-2020-320680
Author(s):  
Claire Edmondson ◽  
Christopher William Course ◽  
Iolo Doull
Keyword(s):  
Cystic Fibrosis ◽  
Life Expectancy ◽  
Respiratory Infections ◽  
Autosomal Recessive Disorder ◽  
Societal Implications ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Potent Effect ◽  
Major Barrier ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is the most common life-limiting inherited condition in Caucasians. It is a multisystem autosomal recessive disorder caused by variants in the gene for cystic fibrosis transmembrane conductance regulator (CFTR) protein, a cell-surface localised chloride channel that regulates absorption and secretion of salt and water across epithelia. Until recently, the treatment for CF was predicated on ameliorating and preventing the downstream symptoms of CFTR dysfunction, primarily recurrent respiratory infections and pancreatic exocrine failure. But a new class of therapy—the CFTR modulators, which treat the basic defect and decrease the complications of CF, leads to significantly improved pulmonary function, decreased respiratory infections and improved nutrition. The newest agent, a combination of elexacaftor, tezacaftor and ivacaftor, will be suitable for approximately 90% of all people with CF and is likely to decrease the morbidity and significantly increase the life expectancy for most people with CF. The major barrier to their widespread introduction has been their cost, with many countries unwilling or unable to fund them. Nevertheless, such is their therapeutic efficacy and their likely potent effect on life expectancy that their advent has wider societal implications for the care of children and adults with CF.

Glutathione permeability of CFTR

1998 ◽  
Vol 275 (1) ◽  
pp. C323-C326 ◽  
Author(s):  
Paul Linsdell ◽  
John W. Hanrahan
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Ion Channel ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Transmembrane Conductance ◽  
High Concentrations ◽  
Cystic Fibrosis Transmembrane ◽  
Glutathione Transport

The cystic fibrosis transmembrane conductance regulator (CFTR) forms an ion channel that is permeable both to Cl− and to larger organic anions. Here we show, using macroscopic current recording from excised membrane patches, that the anionic antioxidant tripeptide glutathione is permeant in the CFTR channel. This permeability may account for the high concentrations of glutathione that have been measured in the surface fluid that coats airway epithelial cells. Furthermore, loss of this pathway for glutathione transport may contribute to the reduced levels of glutathione observed in airway surface fluid of cystic fibrosis patients, which has been suggested to contribute to the oxidative stress observed in the lung in cystic fibrosis. We suggest that release of glutathione into airway surface fluid may be a novel function of CFTR.

scholarly journals A Novel Cystic Fibrosis Gene Mutation C.4242+1G>C in an Omani Patient: A Case Report

2021 ◽  
Vol 36 (2) ◽  
pp. e243-e243
Author(s):  
Said Al Balushi ◽  
Younis Al Balushi ◽  
Moza Al Busaidi ◽  
Latifa Al Mutawa
Keyword(s):  
Cystic Fibrosis ◽  
Gene Mutation ◽  
Digestive System ◽  
The Body ◽  
Cystic Fibrosis Gene ◽  
Cftr Gene ◽  
Sweat Test ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that affects multisystems in the body, particularly the lungs and digestive system. We report a case of an Omani newborn who presented with meconium ileus and high suspicion of CF. Thus, full CFTR gene sequencing was performed, which revealed a homozygous unreported C.4242+1G>C novel gene mutation. Both parents were found to be heterozygous for this mutation. This case sheds light on the importance of the extensive genetic testing of typical CF cases in the absence of family history or during neonatal presentations, especially when the sweat test cannot be performed and the diagnosis can be challenging.

scholarly journals The CFTR and ENaC debate: how important is ENaC in CF lung disease?

2012 ◽  
Vol 302 (11) ◽  
pp. L1141-L1146 ◽  
Author(s):  
James F. Collawn ◽  
Ahmed Lazrak ◽  
Zsuzsa Bebok ◽  
Sadis Matalon
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Bacterial Infections ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Ongoing Debate ◽  
The Subject ◽  
Cystic Fibrosis Transmembrane ◽  
Epithelial Sodium Channel Enac

Cystic fibrosis (CF) is caused by the loss of the cystic fibrosis transmembrane conductance regulator (CFTR) function and results in a respiratory phenotype that is characterized by dehydrated mucus and bacterial infections that affect CF patients throughout their lives. Much of the morbidity and mortality in CF results from a failure to clear bacteria from the lungs. What causes the defect in the bacterial clearance in the CF lung has been the subject of an ongoing debate. Here we discuss the arguments for and against the role of the epithelial sodium channel, ENaC, in the development of CF lung disease.

scholarly journals An Overview on Cystic Fibrosis

1970 ◽  
Vol 7 (5) ◽  
pp. 80-91
Author(s):  
Swetha Reddy Swetha Reddy Singireddy1 ◽  
Susmitha Varagandhi ◽  
Aishwarya Goud Jagiri ◽  
Rohith Kumar Kadarla
Keyword(s):  
Cystic Fibrosis ◽  
Pulmonary Function ◽  
Respiratory Infections ◽  
Severe Disease ◽  
Transmembrane Conductance Regulator ◽  
Net Benefit ◽  
Transmembrane Conductance ◽  
Oral Rehydration ◽  
Inhaled Antibiotics ◽  
Good Nutrition

Cystic fibrosis is an autosomal recessive disease. It is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene on chromosome 7 that codes for a protein transmembrane conductance regulator (CFTR) protein which functions as a transmembrane cAMP-activated chloride channel.  CFTR also affects other ion channels, most notably blocking the influx of sodium into the cell through the epithelial sodium channel. The CFTR abnormality has been shown to produce a number of changes in the airway, including acidification and decreased water and ion transit. A pulmonary exacerbation of CF is usually identified by an increase in cough and sputum and a decrease in pulmonary function. Disease manifests in many organs, but most notably the upper and lower airways, pancreas, bowel, and reproductive tracts. Pulmonary function testing is a major tool for evaluating and monitoring disease state and progression in CF. Spirometry is the commonly used pulmonary function test. Management of CF requires good nutrition and appropriate supplementation of vitamins and pancreatic enzymes. The Cystic Fibrosis Foundation recommends the following treatments as having a high certainty of substantial net benefit, grade A, for moderate-to-severe disease: inhaled tobramycin, dornasealfa, ivacaftor, and inhaled aztreonam. Preventing or treating intestinal blockages—oral rehydration and osmotic laxatives (incomplete blockage) and hyperosmolar contrast enemas (complete DIOS). Antibiotics are the major components of CF treatment and are administered chronically (e.g. inhaled antibiotics, macrolides used for their immunomodulatory properties) or intermittently to prevent, eradicate, control or treat respiratory infections. Lumacaftor (200 mg) + ivacaftor (125 mg), Orkambi, is the first approved CFTR corrector and potentiator combination therapy. Keywords: 

scholarly journals A Developmental Role of the Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Lung Disease Pathogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena N. Huang ◽  
Henry Quach ◽  
Jin-A Lee ◽  
Joshua Dierolf ◽  
Theo J. Moraes ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Anion Channel ◽  
Airway Disease ◽  
Genetic Mutation ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Disease Pathogenesis ◽  
Cftr Protein

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein is a cAMP-activated anion channel that is critical for regulating fluid and ion transport across the epithelium. This process is disrupted in CF epithelia, and patients harbouring CF-causing mutations experience reduced lung function as a result, associated with the increased rate of mortality. Much progress has been made in CF research leading to treatments that improve CFTR function, including small molecule modulators. However, clinical outcomes are not necessarily mutation-specific as individuals harboring the same genetic mutation may present with varying disease manifestations and responses to therapy. This suggests that the CFTR protein may have alternative functions that remain under-appreciated and yet can impact disease. In this mini review, we highlight some notable research implicating an important role of CFTR protein during early lung development and how mutant CFTR proteins may impact CF airway disease pathogenesis. We also discuss recent novel cell and animal models that can now be used to identify a developmental cause of CF lung disease.

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