Am J Respir Cell Mol Biol
September 2024
The COVID-19 pandemic has underscored the impact of viral infections on individuals with cystic fibrosis (CF). Initial observations suggested lower COVID-19 rates among CF populations; however, subsequent clinical data have presented a more complex scenario. This study aimed to investigate how bronchial epithelial cells from CF and non-CF individuals, including various CF transmembrane conductance regulator (CFTR) mutations, respond to infection with SARS-CoV-2 variants and SARS-CoV.
View Article and Find Full Text PDFAlthough substantial advances have been obtained in the pharmacological treatment of cystic fibrosis (CF) with the approval of Kaftrio, a combination of two correctors (VX-661, VX-445) and one potentiator (VX-770), new modulators are still needed to rescue F508del and other CFTR mutants with trafficking defects. We have previously identified PP compounds based on a tricyclic core as correctors with high efficacy in the rescue of F508del-CFTR on native epithelial cells of CF patients, particularly in combination with class 1 correctors (VX-809, VX-661). Compound PP028 was found as a lead candidate for the high rescue of F508del-CFTR and used for mechanistic insight indicating that PP028 behaves as a class 3 corrector, similarly to VX-445.
View Article and Find Full Text PDFOver the past few years, l-iminosugars have revealed attractive pharmacological properties for managing rare diseases including Cystic Fibrosis (CF). The iminosugar -butyl-l-deoxynojirimycin (l-NBDNJ, -), prepared by a carbohydrate-based route, was herein evaluated for its anti-inflammatory and anti-infective potential in models of CF lung disease infection. A significant decrease in the bacterial load in the airways was observed in the murine model of chronic infection in the presence of l-NBDNJ, also accompanied by a modest reduction of inflammatory cells.
View Article and Find Full Text PDFTMEM16 proteins, also known as anoctamins, are a family of ten membrane proteins with various tissue expression and subcellular localization. TMEM16A (anoctamin 1) is a plasma membrane protein that acts as a calcium-activated chloride channel. It is expressed in many types of epithelial cells, smooth muscle cells and some neurons.
View Article and Find Full Text PDFPatients with cystic fibrosis (CF) experience severe lung disease, including persistent infections, inflammation, and irreversible fibrotic remodeling of the airways. Although therapy with transmembrane conductance regulator (CFTR) protein modulators reached optimal results in terms of CFTR rescue, lung transplant remains the best line of care for patients in an advanced stage of CF. Indeed, chronic inflammation and tissue remodeling still represent stumbling blocks during treatment, and underlying mechanisms are still unclear.
View Article and Find Full Text PDFBackground: People with cystic fibrosis (pwCF) are considered at risk of developing severe forms of respiratory viral infections. We studied the consequences of COVID-19 and virus-host cell interactions in CF vs. non-CF individuals.
View Article and Find Full Text PDFCystic fibrosis (CF) is caused by defective Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) proteins. CFTR controls chloride (Cl) and bicarbonate (HCO ) transport into the Airway Surface Liquid (ASL). We investigated the impact of F508del-CFTR correction on HCO secretion by studying transepithelial HCO fluxes.
View Article and Find Full Text PDFF508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients.
View Article and Find Full Text PDFCystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The 2789+5G>A CFTR mutation is a quite frequent defect causing an aberrant splicing and a non-functional CFTR protein. Here we used a CRISPR adenine base editing (ABE) approach to correct the mutation in the absence of DNA double-strand breaks (DSB).
View Article and Find Full Text PDFPharmacological modulators of the Ca signaling cascade are important research tools and may translate into novel therapeutic strategies for a series of human diseases. We carried out a screening of a maximally diverse chemical library using the Ca-sensitive Cl channel TMEM16A as a functional readout. We found compounds that were able to potentiate UTP-dependent TMEM16A activation.
View Article and Find Full Text PDFBackground: Cystic fibrosis is caused by mutations impairing expression, trafficking, stability and/or activity of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The G1244E mutation causes a severe gating defect that it is not completely rescued by ivacaftor but requires the use of a second compound (a co-potentiator). Recently, it has been proposed that the corrector elexacaftor may act also as a co-potentiator.
View Article and Find Full Text PDFBackground And Purpose: Pharmacological inhibitors of TMEM16A (ANO1), a Ca -activated Cl channel, are important tools of research and possible therapeutic agents acting on smooth muscle, airway epithelia and cancer cells. We tested a panel of TMEM16A inhibitors, including CaCC -A01, niclosamide, MONNA, Ani9 and niflumic acid, to evaluate their possible effect on intracellular Ca .
Experimental Approach: We recorded cytosolic Ca increase elicited with UTP, ionomycin or IP uncaging.
The fluid covering the surface of airway epithelia represents a first barrier against pathogens. The chemical and physical properties of the airway surface fluid are controlled by the activity of ion channels and transporters. In cystic fibrosis (CF), loss of CFTR chloride channel function causes airway surface dehydration, bacterial infection, and inflammation.
View Article and Find Full Text PDFHere, we present a standardized protocol for isolation, maintenance, and polarization of the respiratory epithelial primary cells from patient samples acquired from nasal brushing, polyp specimens, or lung explants. This protocol generates a clearly defined polarized layer of epithelial cells on filters, with a good number of ciliated cells and a thin layer of mucus. We detail the steps for samples prepared from patients with cystic fibrosis as well as from subjects without cystic fibrosis.
View Article and Find Full Text PDFIon channels are potentially exploitable as pharmacological targets to treat asthma. This study evaluated the role of KCa3.1 channels, encoded by , in regulating the gene expression of mouse airway epithelium and the development of asthma traits.
View Article and Find Full Text PDFCystic fibrosis (CF) is a multi-organ genetic disease caused by loss of function of CFTR, a cAMP-regulated chloride channel expressed in epithelial cells. In airway epithelia, CFTR-dependent chloride secretion is required to humidify mucosal surface and to allow efficient mucociliary clearance. In CF patients, CFTR deficit causes chronic bacterial infections and airway obstruction by mucus accumulation.
View Article and Find Full Text PDFLoss-of-function mutations of the gene cause cystic fibrosis (CF) through a variety of molecular mechanisms involving altered expression, trafficking, and/or activity of the CFTR chloride channel. The most frequent mutation among CF patients, F508del, causes multiple defects that can be, however, overcome by a combination of three pharmacological agents that improve CFTR channel trafficking and gating, namely, elexacaftor, tezacaftor, and ivacaftor. This study was prompted by the evidence of two CF patients, compound heterozygous for F508del and a minimal function variant, who failed to obtain any beneficial effects following treatment with the triple drug combination.
View Article and Find Full Text PDFMutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease. Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity.
View Article and Find Full Text PDFCystic fibrosis (CF) is caused by loss of function of the CFTR chloride channel. A substantial number of CF patients carry nonsense mutations in the gene. These patients cannot directly benefit from pharmacological correctors and potentiators that have been developed for other types of CFTR mutations.
View Article and Find Full Text PDFChloride transport across cell membranes is broadly involved in epithelial fluid transport, cell volume and pH regulation, muscle contraction, membrane excitability, and organellar acidification. The human genome encodes at least 53 chloride-transporting proteins with expression in cell plasma or intracellular membranes, which include chloride channels, exchangers, and cotransporters, some having broad anion specificity. Loss-of-function mutations in chloride transporters cause a wide variety of human diseases, including cystic fibrosis, secretory diarrhea, kidney stones, salt-wasting nephropathy, myotonia, osteopetrosis, hearing loss, and goiter.
View Article and Find Full Text PDFDeletion of phenylalanine at position 508 (F508del) in the CFTR chloride channel is the most frequent mutation in cystic fibrosis (CF) patients. F508del impairs the stability and folding of the CFTR protein, thus resulting in mistrafficking and premature degradation. F508del-CFTR defects can be overcome with small molecules termed correctors.
View Article and Find Full Text PDFBackground: New drugs that target the basic defect in cystic fibrosis (CF) patients may now be used in a large number of patients carrying responsive mutations. Nevertheless, further research is needed to extend the benefit of these treatments to patients with rare mutations that are still uncharacterized in vitro and that are not included in clinical trials. For this purpose, ex vivo models are necessary to preliminary assessing the effect of CFTR modulators in these cases.
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