Sa1092 APICAL BK CHANNELS IN INTESTINAL EPITHELIA OF CYSTIC FIBROSIS (CF) PATIENTS: A POTENTIAL TARGET FOR STIMULATING POTASSIUMDRIVEN WATER SECRETION.

2020 ◽  
Vol 158 (6) ◽  
pp. S-272-S-273
Author(s):  
Michael Shires ◽  
Kate Marks ◽  
Daniel Peckham ◽  
Geoffrey I. Sandle
Keyword(s):  
Cystic Fibrosis ◽  
Bk Channels ◽  
Intestinal Epithelia ◽  
Potential Target ◽  
Water Secretion

scholarly journals Pathological mucus and impaired mucus clearance in cystic fibrosis patients result from increased concentration, not altered pH

2018 ◽  
Vol 52 (6) ◽  
pp. 1801297 ◽  
Author(s):  
David B. Hill ◽  
Robert F. Long ◽  
William J. Kissner ◽  
Eyad Atieh ◽  
Ian C. Garbarine ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disulfide Bonds ◽  
Chemical Reduction ◽  
Length Scales ◽  
Mucus Clearance ◽  
Alternative Hypotheses ◽  
Series Of Experiments ◽  
Airway Mucus ◽  
Water Secretion ◽  
Airway Acidification

Cystic fibrosis (CF) is a recessive genetic disease that is characterised by airway mucus plugging and reduced mucus clearance. There are currently alternative hypotheses that attempt to describe the abnormally viscous and elastic mucus that is a hallmark of CF airways disease, including: 1) loss of CF transmembrane regulator (CFTR)-dependent airway surface volume (water) secretion, producing mucus hyperconcentration-dependent increased viscosity, and 2) impaired bicarbonate secretion by CFTR, producing acidification of airway surfaces and increased mucus viscosity.A series of experiments was conducted to determine the contributions of mucus concentration versus pH to the rheological properties of airway mucus across length scales from the nanoscopic to macroscopic.For length scales greater than the nanoscopic, i.e. those relevant to mucociliary clearance, the effect of mucus concentration dominated over the effect of airway acidification.Mucus hydration and chemical reduction of disulfide bonds that connect mucin monomers are more promising therapeutic approaches than alkalisation.

scholarly journals In Vivo Measurement of Chloride and Water Secretion in the Jejunum of Cystic Fibrosis Patients

1996 ◽  
Vol 40 (4) ◽  
pp. 522-527 ◽  
Author(s):  
T M Teune ◽  
A J M Timmers-Reker ◽  
J Bouquet ◽  
J Bijman ◽  
H R De Jonge ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
In Vivo Measurement ◽  
Water Secretion

scholarly journals Consistent Assignment of Risk and Benign Allele at rs2303153 in the CF Modifier Gene SCNN1B in Three Independent F508del-CFTR Homozygous Patient Populations

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1554
Author(s):  
Frauke Stanke ◽  
Tim Becker ◽  
Haide Susanne Ismer ◽  
Inga Dunsche ◽  
Silke Hedtfeld ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Risk Allele ◽  
Association Studies ◽  
Regulatory Element ◽  
Genetic Modifier ◽  
Modifier Gene ◽  
Intestinal Epithelia ◽  
Transepithelial Sodium Transport ◽  
Homozygous Patient

CFTR encodes for a chloride and bicarbonate channel expressed at the apical membrane of polarized epithelial cells. Transepithelial sodium transport mediated by the amiloride-sensitive sodium channel ENaC is thought to contribute to the manifestation of CF disease. Thus, ENaC is a therapeutic target in CF and a valid cystic fibrosis modifier gene. We have characterized SCNN1B as a genetic modifier in the three independent patient cohorts of F508del-CFTR homozygotes. We could identify a regulatory element at SCNN1B to the genomic segment rs168748-rs2303153-rs4968000 by fine-mapping (Pbest = 0.0177), consistently observing the risk allele rs2303153-C and the contrasting benign allele rs2303153-G in all three patient cohorts. Furthermore, our results show that expression levels of SCNN1B are associated with rs2303153 genotype in intestinal epithelia (P = 0.003). Our data confirm that the well-established biological role of SCNN1B can be recognized by an association study on informative endophenotypes in the rare disease cystic fibrosis and calls attention to reproducible results in association studies obtained from small, albeit carefully characterized patient populations.

scholarly journals Potential of Intestinal Current Measurement for Personalized Treatment of Patients with Cystic Fibrosis

2021 ◽  
Vol 11 (5) ◽  
pp. 384
Author(s):  
Simon Y. Graeber ◽  
Constanze Vitzthum ◽  
Marcus A. Mall
Keyword(s):  
Cystic Fibrosis ◽  
Diagnostic Testing ◽  
Current Measurement ◽  
Personalized Treatment ◽  
Transmembrane Conductance Regulator ◽  
New Era ◽  
Intestinal Epithelia ◽  
Transport Defect ◽  
Culture Models ◽  
Cftr Mutations

Refinement of personalized treatment of cystic fibrosis (CF) with emerging medicines targeting the CF basic defect will likely benefit from biomarkers sensitive to detect improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function in individual patients. Intestinal current measurement (ICM) is a technique that enables quantitative assessment of CFTR chloride channel function in rectal tissues or other intestinal epithelia. ICM was originally developed to study the CF ion transport defect in the intestine and has been established as a sensitive biomarker of CFTR function and diagnostic test for CF. With the emergence of CFTR-directed therapeutics, ICM has become an important tool to estimate the level of rescue of CFTR function achieved by approved CFTR modulators, both at the level of CFTR genotype groups, as well as individual patients with CF. In combination with preclinical patient-derived cell culture models, ICM may aid the development of targeted therapies for patients with rare CFTR mutations. Here, we review the principles of ICM and examine how this CFTR biomarker may be used to support diagnostic testing and enhance personalized medicine for individual patients with common as well as rare CFTR mutations in the new era of medicines targeting the underlying cause of CF.

scholarly journals MDCK cells are capable of water secretion and reabsorption in response to changes in the ionic environment

2017 ◽  
Vol 95 (1) ◽  
pp. 72-83 ◽  
Author(s):  
Janne P. Capra ◽  
Sinikka M. Eskelinen
Keyword(s):  
Water Flow ◽  
Chloride Channels ◽  
Mdck Cells ◽  
Extracellular Fluid ◽  
Chloride Ion ◽  
Chloride Secretion ◽  
Chloride Ions ◽  
Intestinal Epithelia ◽  
Fluorescent Markers ◽  
Water Secretion

A prerequisite for tissue electrolyte homeostasis is highly regulated ion and water transport through kidney or intestinal epithelia. In the present work, we monitored changes in the cell and luminal volumes of type II Madin-Darby canine kidney (MDCK) cells grown in a 3D environment in response to drugs, or to changes in the composition of the basal extracellular fluid. Using fluorescent markers and high-resolution spinning disc confocal microscopy, we could show that lack of sodium and potassium ions in the basal fluid (tetramethylammonium chloride (TMACl) buffer) induces a rapid increase in the cell and luminal volumes. This transepithelial water flow could be regulated by inhibitors and agonists of chloride channels. Hence, the driving force for the transepithelial water flow is chloride secretion, stimulated by hyperpolarization. Chloride ion depletion of the basal fluid (using sodium gluconate buffer) induces a strong reduction in the lumen size, indicating reabsorption of water from the lumen to the basal side. Lumen size also decreased following depolarization of the cell interior by rendering the membrane permeable to potassium. Hence, MDCK cells are capable of both absorption and secretion of chloride ions and water; negative potential within the lumen supports secretion, while depolarizing conditions promote reabsorption.

Cystic Fibrosis Diagnosis in Newborns, Children, and Adults

2019 ◽  
Vol 40 (06) ◽  
pp. 701-714 ◽  
Author(s):  
Carlo Castellani ◽  
Barry Linnane ◽  
Iwona Pranke ◽  
Federico Cresta ◽  
Isabelle Sermet-Gaudelus ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Presentation ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Sweat Test ◽  
Intestinal Epithelia ◽  
Sweat Testing ◽  
Cftr Protein ◽  
Cf Transmembrane Conductance Regulator

AbstractThe diagnosis of cystic fibrosis (CF) has traditionally relied on the presence of clinical features of the disease. Today, diagnosis through newborn screening (NBS) is becoming the standard of modern CF care. CF NBS programs can identify CF prior to clinical presentation, but for the advantages of an early diagnosis to accrue a scrupulous system must be in place to ensure all steps in the program are performing. As we move rapidly into the era of CF transmembrane conductance regulator (CFTR) protein modulators, the opportunity to start a presymptomatic infant, identified through CF NBS, on these agents offers the prospect of true disease-modifying interventions which could result in a paradigm shift in CF care.Conversely, the introduction of NBS has resulted in many children being asymptomatic at the time of diagnosis. Some screened newborns are classified as “CF Screening Positive, Inconclusive Diagnosis”, or “CFTR-related metabolic syndrome” when the diagnosis can neither be confirmed nor excluded. Appropriate assessment and follow-up should be arranged at specialist centers as a proportion of these infants and adults will eventually be diagnosed with CF.Symptoms and signs are particularly pertinent when considering a diagnosis of CF outside the context of NBS. In older patients with a late diagnosis, the spectrum of clinical presentation can be very variable with vigilant clinicians from multiple specialties suspecting the diagnosis in conditions such as recurrent pulmonary infections, male infertility, pancreatitis, nasal polyposis, and malabsorption.In addition to clinical symptoms or positive NBS results, sweat test and genetic analysis are cornerstones in the diagnosis of CF, but in some cases the diagnosis cannot be confirmed on genetic or sweat testing. Difficult diagnosis may be supported by in vivo or ex vivo electrophysiology measurements on respiratory or intestinal epithelia. This can be done by either measuring transepithelial nasal potential difference or intestinal current measurements.

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