scholarly journals A molecular atlas of proximal airway identifies subsets of known airway cell types revealing details of the unique molecular pathogenesis of Cystic Fibrosis

2020 ◽  
Author(s):  
Gianni Carraro ◽  
Justin Langerman ◽  
Shan Sabri ◽  
Zareeb Lorenzana ◽  
Arunima Purkayastha ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Autosomal Recessive Disorder ◽  
Cell Types ◽  
Airway Disease ◽  
Transmembrane Conductance Regulator ◽  
Basal Cells ◽  
Airway Epithelial ◽  
Polarized Epithelia ◽  
End Stage

Introduction/AbstractCystic fibrosis (CF) is a lethal autosomal recessive disorder that afflicts in excess of 70,000 people globally. People with CF experience multi-organ dysfunction resulting from aberrant electrolyte transport across polarized epithelia due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CF-related lung disease is by far the most significant determinant of morbidity and mortality. In this study we report results from a multi-institute consortium in which single cell transcriptomics were applied to define disease-related changes to the proximal airway of CF donors (n=19) undergoing transplantation for end-stage lung disease compared to the proximal airway of previously healthy lung donors (n=19). We found that all major airway epithelial cell types were conserved between control and CF donors. Disease-dependent differences were observed, including an overabundance of epithelial cells transitioning to specialized ciliated and secretory cell subtypes coupled with an unexpected decrease in cycling basal cells. This study developed a molecular atlas of the proximal airway epithelium that will provide insights for the development of new targeted therapies for CF airway disease.

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.

scholarly journals Update on Calcium Signaling in Cystic Fibrosis Lung Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Alessandro Rimessi ◽  
Veronica A. M. Vitto ◽  
Simone Patergnani ◽  
Paolo Pinton
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Immune Cells ◽  
Cell Function ◽  
Autosomal Recessive Disorder ◽  
Airway Epithelial ◽  
Cystic Fibrosis Lung Disease ◽  
Relevant Role ◽  
Intracellular Organelles

Cystic fibrosis (CF) is an autosomal recessive disorder characterized by mutations in the cystic fibrosis transmembrane conductance regulator gene, which causes multifunctional defects that preferentially affect the airways. Abnormal viscosity of mucus secretions, persistent pathogen infections, hyperinflammation, and lung tissue damage compose the classical pathological manifestation referred to as CF lung disease. Among the multifunctional defects associated with defective CFTR, increasing evidence supports the relevant role of perturbed calcium (Ca2+) signaling in the pathophysiology of CF lung disease. The Ca2+ ion is a critical player in cell functioning and survival. Its intracellular homeostasis is maintained by a fine balance between channels, transporters, and exchangers, mediating the influx and efflux of the ion across the plasma membrane and the intracellular organelles. An abnormal Ca2+ profile has been observed in CF cells, including airway epithelial and immune cells, with heavy repercussions on cell function, viability, and susceptibility to pathogens, contributing to proinflammatory overstimulation, organelle dysfunction, oxidative stress, and excessive cytokines release in CF lung. This review discusses the role of Ca2+ signaling in CF and how its dysregulation in airway epithelial and immune cells contributes to hyperinflammation in the CF lung. Finally, we provide an outlook on the therapeutic options that target the Ca2+ signaling to treat the CF lung disease.

scholarly journals Chlorzoxazone or 1-EBIO increases Na+absorption across cystic fibrosis airway epithelial cells

2001 ◽  
Vol 281 (5) ◽  
pp. L1123-L1129 ◽  
Author(s):  
Lin Gao ◽  
James R. Yankaskas ◽  
Catherine M. Fuller ◽  
Eric J. Sorscher ◽  
Sadis Matalon ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Short Circuit ◽  
Fold Increase ◽  
Short Circuit Current ◽  
Airway Disease ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Cystic Fibrosis Airway ◽  
Cf Transmembrane Conductance Regulator

Previous studies demonstrated that chlorzoxazone or 1-ethyl-2-benzimidazolinone (1-EBIO) enhances transepithelial Cl− secretion by increasing basolateral K+ conductance ( G K) (Singh AK, Devor DC, Gerlach AC, Gondor M, Pilewski JM, and Bridges RJ. J Pharmacol Exp Ther 292: 778–787, 2000). Hence these compounds may be useful to treat cystic fibrosis (CF) airway disease. The goal of the present study was to determine whether chlorzoxazone or 1-EBIO altered ion transport across ΔF508-CF transmembrane conductance regulator homozygous CFT1 airway cells. CFT1 monolayers exhibited a basal short-circuit current that was abolished by apical amiloride (inhibition constant 320 nM) as expected for Na+ absorption. The addition of chlorzoxazone (400 μM) or 1-EBIO (2 mM) increased the amiloride-sensitive I sc ∼2.5-fold. This overlapping specificity may preclude use of these compounds as CF therapeutics. Assaying for changes in the basolateral G K with a K+ gradient plus the pore-forming antibiotic amphotericin B revealed that chlorzoxazone or 1-EBIO evoked an ∼10-fold increase in clotrimazole-sensitive G K. In contrast, chlorzoxazone did not alter epithelial Na+ channel-mediated currents across basolateral-permeabilized monolayers or in Xenopus oocytes. These data further suggest that alterations in basolateral G K alone can modulate epithelial Na+ transport.

Role of CFTR in Airway Disease

1999 ◽  
Vol 79 (1) ◽  
pp. S215-S255 ◽  
Author(s):  
JOSEPH M. PILEWSKI ◽  
RAYMOND A. FRIZZELL
Keyword(s):  
Lung Disease ◽  
Mucociliary Clearance ◽  
Airway Disease ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Gene Encoding ◽  
Water Secretion ◽  
Cf Transmembrane Conductance Regulator

Pilewski, Joseph M., and Raymond A. Frizzell. Role of CFTR in Airway Disease. Physiol. Rev. 79, Suppl.: S215–S255, 1999. — Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), which accounts for the cAMP-regulated chloride conductance of airway epithelial cells. Lung disease is the chief cause of morbidity and mortality in CF patients. This review focuses on mechanisms whereby the deletion or impairment of CFTR chloride channel function produces lung disease. It examines the major themes of the channel hypothesis of CF, which involve impaired regulation of airway surface fluid volume or composition. Available evidence indicates that the effect of CFTR deletion alters physiological functions of both surface and submucosal gland epithelia. At the airway surface, deletion of CFTR causes hyperabsorption of sodium chloride and a reduction in the periciliary salt and water content, which impairs mucociliary clearance. In submucosal glands, loss of CFTR-mediated salt and water secretion compromises the clearance of mucins and a variety of defense substances onto the airway surface. Impaired mucociliary clearance, together with CFTR-related changes in the airway surface microenvironment, leads to a progressive cycle of infection, inflammation, and declining lung function. Here, we provide the details of this pathophysiological cascade in the hope that its understanding will promote the development of new therapies for CF.

Differential expression of ORCC and CFTR induced by low temperature in CF airway epithelial cells

1995 ◽  
Vol 268 (1) ◽  
pp. C243-C251 ◽  
Author(s):  
M. E. Egan ◽  
E. M. Schwiebert ◽  
W. B. Guggino
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Incubation Temperature ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Channel Activity ◽  
Patch Clamp Recording ◽  
Cl Channel ◽  
Channel Expression

When nonepithelial cell types expressing the delta F508-cystic fibrosis transmembrane conductance regulator (CFTR) mutation are grown at reduced temperatures, the mutant protein can be properly processed. The effect of low temperatures on Cl- channel activity in airway epithelial cells that endogenously express the delta F508-CFTR mutation has not been investigated. Therefore, we examined the effect of incubation temperature on both CFTR and outwardly rectifying Cl- channel (ORCC) activity in normal, in cystic fibrosis (CF)-affected, and in wild-type CFTR-complemented CF airway epithelia with use of a combination of inside-out and whole cell patch-clamp recording, 36Cl- efflux assays, and immunocytochemistry. We report that incubation of CF-affected airway epithelial cells at 25-27 degrees C is associated with the appearance of a protein kinase A-stimulated CFTR-like Cl- conductance. In addition to the appearance of CFTR Cl- channel activity, there is, however, a decrease in the number of active ORCC when cells are grown at 25-27 degrees C, suggesting that the decrease in incubation temperature may be associated with multiple alterations in ion channel expression and/or regulation in airway epithelial cells.

Basal chloride currents in murine airway epithelial cells: modulation by CFTR

1998 ◽  
Vol 274 (4) ◽  
pp. C904-C913 ◽  
Author(s):  
R. Tarran ◽  
M. A. Gray ◽  
M. J. Evans ◽  
W. H. Colledge ◽  
R. Ratcliff ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Airway Epithelial Cells ◽  
Transmembrane Conductance Regulator ◽  
Airway Epithelial ◽  
Wild Type ◽  
Patch Clamp Technique ◽  
Chloride Currents ◽  
Cation Permeability ◽  
Current Voltage ◽  
Respiratory Cells

We have isolated ciliated respiratory cells from the nasal epithelium of wild-type and cystic fibrosis (CF) null mice and used the patch-clamp technique to investigate their basal conductances. Current-clamp experiments on unstimulated cells indicated the presence of K+ and Cl− conductances and, under certain conditions, a small Na+conductance. Voltage-clamp experiments revealed three distinct Cl− conductances. I tv-indep was time and voltage independent with a linear current-voltage ( I- V) plot; I v-actexhibited activation at potentials greater than ±50 mV, giving an S-shaped I- Vplot; and I hyp-act was activated by hyperpolarizing potentials and had an inwardly rectified I- Vplot. The current density sequence was I hyp-act = I v-act ≫ I tv-indep. These conductances had Cl−-to- N-methyl-d-glucamine cation permeability ratios of between 2.8 and 10.3 and were unaffected by tamoxifen, flufenamate, glibenclamide, DIDS, and 5-nitro-2-(3-phenylpropylamino) benzoic acid but were inhibited by Zn2+ and Gd3+. I tv-indep and I v-act were present in wild-type and CF cells at equal density and frequency. However, I hyp-actwas detected in only 3% of CF cells compared with 26% of wild-type cells, suggesting that this conductance may be modulated by cystic fibrosis transmembrane conductance regulator (CFTR).

Ethical dilemma: ELX/TEZ/IVA or Lung Transplantation in Cystic Fibrosis and End Stage Lung Disease?

CHEST Journal ◽  
2021 ◽  
Author(s):  
Oded Breuer ◽  
David Shoseyov ◽  
Shifra Koretz ◽  
Nadia Alyan ◽  
Joel Reiter ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Transplantation ◽  
Lung Disease ◽  
Ethical Dilemma ◽  
End Stage

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.

Sign in / Sign up

Export Citation Format

Share Document