A physiologically-motivated model of cystic fibrosis liquid and solute transport dynamics across primary human nasal epithelia

AbstractCystic fibrosis (CF) disease is caused by mutations affecting the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel expressed in the mucosal side of epithelial tissue. In the airway, dysfunctional CFTR results in a transepithelial osmotic imbalance leading to hyperabsorption of airway surface liquid mucostasis, chronic inflammation, and eventual respiratory failure. Human nasal epithelial cell cultures from healthy and CF donors were used to perform studies of liquid and solute transport dynamics at an air/liquid interface in order to emulate the in vivo airway. Then, these results were used to inform a quantitative systems pharmacology model of airway epithelium describing electrically and chemically driven transcellular ionic transport, contributions of both convective and diffusive paracellular solute transport, and osmotically driven transepithelial water dynamics. Model predictions showed CF cultures, relative to non-CF ones, have increased apical and basolateral water permeabilities, and increase paracellular permeability and transepithelial chemical driving force for a radiolabeled tracer used to track small molecule absorption. These results provide a computational platform to better understand and probe the mechanisms behind the liquid hyperabsorption and small molecule retention profiles observed in the CF airway.
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research

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Source: Archivos Espanoles de Urologia - Category: Urology & Nephrology Tags: Arch Esp Urol Source Type: research
Conclusions: S. aureus SAgs belonging to the EGC are highly prevalent in CF clinical isolates. The greater prevalence in these SAgs in CF airway specimens compared to skin isolates suggests that these toxins confer selective advantage in the CF airway.
Source: Genes - Category: Genetics & Stem Cells Authors: Tags: Article Source Type: research
ConclusionThe eastern and the northern provinces have the highest prevalence of CF, with the c.2988+1G>A (3120+1G>A) and c.1418delG (p.Gly473GlufsX54) variants showing the highest distribution in the Saudi CF population, which may reflect the effect of consanguinity within the same tribe. Proper family screening and counseling should be emphasized.
Source: International Journal of Pediatrics and Adolescent Medicine - Category: Pediatrics Source Type: research
ConclusionsThe present protocol based on the entire CFTR gene together with informative SNPs outside and inside the gene can be applied to diagnose all CF mutations at preimplantation stage.
Source: Journal of Assisted Reproduction and Genetics - Category: Reproduction Medicine Source Type: research
(University of California - San Diego) People with cystic fibrosis who carry genetic variants that lowerRNF5 gene expression have more mutant CFTR protein on cell surfaces. Even if the CFTR protein isn't fully functional, it's better than none, and may explain why some with cystic fibrosis are less prone to infection than others.
Source: EurekAlert! - Biology - Category: Biology Source Type: news
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Source: The Clinical Respiratory Journal - Category: Respiratory Medicine Authors: Tags: BRIEF REPORT Source Type: research
The CF community is currently celebrating the approval of CFTR modulators for individuals with specific CFTR mutations. Once a modulator has been approved by regulators for the treatment of individuals with CF and relatively common CFTR mutations (e.g., G551D or F508del), the community's next challenge is to objectively assess efficacy of that treatment in individuals with CFTR mutations of such rarity that traditional, parallel-group, randomized controlled trials are not feasible. When efficacy is further demonstrated in rare mutation groups, expanding the labels of approved drug to these ultra-orphan subpopulations is es...
Source: Journal of Cystic Fibrosis - Category: Respiratory Medicine Authors: Source Type: research
Bone mineral density (BMD) has been positively associated with lung function in patients diagnosed with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. However, t...
Source: BMC Pulmonary Medicine - Category: Respiratory Medicine Authors: Tags: Research article Source Type: research
Cystic Fibrosis (CF) is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is an ATP- and PKA-dependent chloride channel, regulating chloride and bicarbonate ion flux across apical membranes of polarized epithelial cells [1 –3]. To date, over 2000 mutations have been reported in the CFTR gene (CFTR1 database, http://www.genet.sickkids.on.ca). Around 10% of these mutations result in the formation of premature termination codons (PTCs) and prevent synthesis of full length CFTR mRNA and protein.
Source: Journal of Cystic Fibrosis - Category: Respiratory Medicine Authors: Source Type: research
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Source: Daily Express - Health - Category: Consumer Health News Source Type: news
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